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1.
Brain Pathol ; : e13280, 2024 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-38946137

RESUMO

Demyelination of corticospinal tract neurons contributes to long-term disability after cortical stroke. Nonetheless, poststroke myelin loss has not been addressed as a therapeutic target, so far. We hypothesized that an antibody-mediated inhibition of the Nogo receptor-interacting protein (LINGO-1, leucine-rich repeat and immunoglobulin domain-containing Nogo receptor-interacting protein) may counteract myelin loss, enhance remyelination and axonal growth, and thus promote functional recovery following stroke. To verify this hypothesis, mice were subjected to photothrombotic stroke and received either an antibody against LINGO-1 (n = 19) or a control treatment (n = 18). Behavioral tests were performed to assess the effects of anti-LINGO-1 treatment on the functional recovery. Seven weeks after stroke, immunohistochemical analyses were performed to analyze the effect of anti-LINGO-1 treatment on myelination and axonal loss of corticospinal tract neurons, proliferation of oligodendrocytes and neurogenesis. Anti-LINGO-1 treatment resulted in significantly improved functional recovery (p < 0.0001, repeated measures analysis of variance), and increased neurogenesis in the hippocampus and subventricular zone of the ipsilateral hemisphere (p = 0.0094 and p = 0.032, t-test). Notably, we observed a significant increase in myelin (p = 0.0295, t-test), platelet-derived growth factor receptor α-positive oligodendrocyte precursor cells (p = 0.0356, t-test) and myelinating adenomatous polyposis coli-positive cells within the ipsilateral internal capsule of anti-LINGO-1-treated mice (p = 0.0021, t-test). In conclusion, we identified anti-LINGO-1 as the first neuroregenerative treatment that counteracts poststroke demyelination of corticospinal tract neurons, presumably by increased proliferation of myelin precursor cells, and thereby improves functional recovery. Most importantly, our study presents myelin loss as a novel therapeutic target following stroke.

2.
Immunol Rev ; 314(1): 357-375, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36315403

RESUMO

Over the past millennia, life expectancy has drastically increased. While a mere 25 years during Bronze and Iron ages, life expectancy in many European countries and in Japan is currently above 80 years. Such an increase in life expectancy is a result of improved diet, life style, and medical care. Yet, increased life span and aging also represent the most important non-modifiable risk factors for several pathologies including cardiovascular disease, neurodegenerative diseases, and cancer. In recent years, neutrophils have been implicated in all of these pathologies. Hence, this review provides an overview of how aging impacts neutrophil production and function and conversely how neutrophils drive aging-associated pathologies. Finally, we provide a perspective on how processes of neutrophil-driven pathologies in the context of aging can be targeted therapeutically.


Assuntos
Envelhecimento , Neutrófilos , Humanos , Longevidade , Expectativa de Vida , Fatores de Risco
3.
Artigo em Inglês | MEDLINE | ID: mdl-34663675

RESUMO

BACKGROUND AND OBJECTIVES: To facilitate and improve the diagnostic and therapeutic process by systematically reviewing studies on patients with primary angiitis of the CNS (PACNS). METHODS: We searched PubMed, looking at the period between 1988 and February 2020. Studies with adult patients with PACNS were included. We extracted and pooled proportions using fixed-effects models. Main outcomes were proportions of patients with certain clinical, imaging, and laboratory characteristics and neurologic outcomes. RESULTS: We identified 46 cohort studies including a total of 911 patients (41% biopsy confirmed, 43% angiogram confirmed, and 16% without clear assignment to the diagnostic procedure). The most frequent onset symptoms were focal neurologic signs (63%), headache (51%), and cognitive impairment (41%). Biopsy- compared with angiogram-confirmed cases had higher occurrences of cognitive impairment (55% vs 39%) and seizures (36% vs 16%), whereas focal neurologic signs occurred less often (56% vs 95%). CSF abnormalities were present in 75% vs 65% and MRI abnormalities in 97% vs 98% of patients. Digital subtraction angiography was positive in 33% of biopsy confirmed, and biopsy was positive in 8% of angiogram-confirmed cases. In 2 large cohorts, mortality was 23% and 8%, and the relapse rate was 30% and 34%, during a median follow-up of 19 and 57 months, respectively. There are no randomized trials on the treatment of PACNS. The initial treatment usually includes glucocorticoids and cyclophosphamide. DISCUSSION: PACNS is associated with disabling symptoms, frequent relapses, and significant mortality. Differences in symptoms and neuroimaging results and low overlap between biopsy and angiogram suggest that biopsy- and angiogram-confirmed cases represent different histopathologic types of PACNS. The optimal treatment is unknown.


Assuntos
Vasculite do Sistema Nervoso Central/diagnóstico , Humanos , Vasculite do Sistema Nervoso Central/líquido cefalorraquidiano , Vasculite do Sistema Nervoso Central/patologia , Vasculite do Sistema Nervoso Central/fisiopatologia
4.
J Clin Immunol ; 41(6): 1229-1240, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33844127

RESUMO

While posterior reversible encephalopathy syndrome (PRES) is often characterized by an inflammatory cerebrospinal-fluid (CSF) profile, knowledge of immune cell patterns in PRES is lacking. Thus, we retrospectively characterized CSF and peripheral blood (PB) from 15 PRES patients, which we analyzed by multidimensional flow cytometry (FC). Results were compared to 72 controls, as well as to 9 patients with progressive multifocal leukoencephalopathy (PML, as a relevant differential diagnosis) and 15 multiple sclerosis patients (MS, as a classical neuroinflammatory disorder), respectively. Total protein level in CSF from PRES patients was elevated compared to that in controls, but not to MS and PML. In-depth FC analysis revealed no differences for adaptive immune cells (B cells, plasma cells, CD4+, and CD8+ T cells) in PB or CSF of PRES compared to controls. In contrast, we observed alterations of the adaptive immune response in CSF of PML and MS compared to PRES, indicating that the adaptive immune response is not a driver of disease in PRES. Indeed, PRES was characterized by an innate immune response with CD14++/CD16+ (intermediate) monocytes elevated in PB and CSF, while CD14++/CD16- (classical) monocytes were decreased in PB from PRES patients as compared to controls. Levels of CD14++/CD16+ monocytes correlated with the duration of hospital stay as a surrogate marker for disease severity in PRES patients. Our findings argue for a role of innate rather than adaptive immunity in the pathophysiology of PRES. The observed shift in monocyte subsets might provide valuable diagnostic clues for the clinical management of these patients.


Assuntos
Imunidade Inata/imunologia , Síndrome da Leucoencefalopatia Posterior/diagnóstico , Síndrome da Leucoencefalopatia Posterior/imunologia , Imunidade Adaptativa/imunologia , Adulto , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Feminino , Humanos , Leucoencefalopatia Multifocal Progressiva/diagnóstico , Leucoencefalopatia Multifocal Progressiva/imunologia , Receptores de Lipopolissacarídeos/imunologia , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Receptores de IgG/imunologia , Estudos Retrospectivos
5.
J Neurointerv Surg ; 13(11): 1053-1057, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33483457

RESUMO

BACKGROUND: Thrombus composition has been shown to be a major determinant of recanalization success and occurrence of complications in mechanical thrombectomy. The most important parameters of thrombus behavior during interventional procedures are relative fractions of fibrin and red blood cells (RBCs). We hypothesized that quantitative information from admission non-contrast CT (NCCT) and CT angiography (CTA) can be used for machine learning based prediction of thrombus composition. METHODS: The analysis included 112 patients with occlusion of the carotid-T or middle cerebral artery who underwent thrombectomy. Thrombi samples were histologically analyzed and fractions of fibrin and RBCs were determined. Thrombi were semi-automatically delineated in CTA scans and NCCT scans were registered to the same space. Two regions of interest (ROIs) were defined for each thrombus: small-diameter ROIs capture vessel walls and thrombi, large-diameter ROIs reflect peri-vascular tissue responses. 4844 quantitative image markers were extracted and evaluated for their ability to predict thrombus composition using random forest algorithms in a nested fivefold cross validation. RESULTS: Test set receiver operating characteristic area under the curve was 0.83 (95% CI 0.80 to 0.87) for differentiating RBC-rich thrombi and 0.84 (95% CI 0.80 to 0.87) for differentiating fibrin-rich thrombi. At maximum Youden-Index, RBC-rich thrombi were identified at 77% sensitivity and 74% specificity; for fibrin-rich thrombi the classifier reached 81% sensitivity at 73% specificity. CONCLUSIONS: Machine learning based analysis of admission imaging allows for prediction of clot composition. Perspectively, such an approach could allow selection of clot-specific devices and retrieval procedures for personalized thrombectomy strategies.


Assuntos
Trombose Intracraniana , Acidente Vascular Cerebral , Trombose , Angiografia por Tomografia Computadorizada , Humanos , Trombectomia , Trombose/diagnóstico por imagem , Tomografia Computadorizada por Raios X
6.
J Neurointerv Surg ; 13(5): 409-414, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-32690758

RESUMO

BACKGROUND: Different imaging characteristics such as clot burden score, collaterals, and pre-interventional thrombus migration are associated with functional outcome in patients with acute ischemic stroke. Moreover, histological thrombus composition is associated with pre-interventional thrombus migration. We hypothesized that smaller clots may more likely migrate and that collateral status in ischemic stroke patients may mediate this tendency of the clot to migrate. METHODS: In this prospective cohort of consecutive ischemic stroke patients, clot burden scores and collateral scores were rated and the retrieved thrombi were histologically analyzed. We then investigated the relationship between clot burden score, probability for thrombus migration, and collateral scores using mediation analysis. RESULTS: 163 patients are included of which 36 (22.1%) had a clot migration. Probability of thrombus migration was significantly associated with lower collateral scores (P<0.01), higher clot burden scores (P<0.01), shorter thrombi (P<0.01), and higher RBC count (P<0.01). In the mediator pathway, higher collateral scores were significantly associated with higher clot burden scores (P<0.01) and younger age (P=0.029). The total effect of an increase in clot burden score by one grade on thrombus migration is composed of the direct effect (+18%, P<0.01) and the collateral score-mediated indirect effect (-5%, P<0.01). CONCLUSIONS: Smaller, erythrocyte-rich thrombi tend to migrate more often. Good collaterals seem to have a considerable effect on limiting migration. This supports the hypothesis that larger clots have stronger adherence with the vessel wall and that good collaterals increase the counter pressure distal of the clot.


Assuntos
Isquemia Encefálica/diagnóstico por imagem , Circulação Colateral/fisiologia , Trombose Intracraniana/diagnóstico por imagem , AVC Isquêmico/diagnóstico por imagem , Idoso , Idoso de 80 Anos ou mais , Isquemia Encefálica/fisiopatologia , Angiografia Cerebral/métodos , Estudos de Coortes , Feminino , Humanos , Trombose Intracraniana/fisiopatologia , AVC Isquêmico/fisiopatologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Estudos Retrospectivos , Trombose/diagnóstico por imagem , Trombose/fisiopatologia
7.
Eur J Nucl Med Mol Imaging ; 47(9): 2131-2141, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-31960097

RESUMO

PURPOSE: Primary angiitis of the central nervous system (PACNS) is a heterogeneous, rare, and poorly understood inflammatory disease. We aimed at non-invasive imaging of activated microglia/macrophages in patients with PACNS by PET-MRI targeting the translocator protein (TSPO) with [18F]DPA-714 to potentially assist differential diagnosis, therapy monitoring, and biopsy planning. METHODS: In total, nine patients with ischemic stroke and diagnosed or suspected PACNS underwent [18F]DPA-714-PET-MRI. Dynamic PET scanning was performed for 60 min after injection of 233 ± 19 MBq [18F]DPA-714, and MRI was simultaneously acquired. RESULTS: In two PACNS patients, [18F]DPA-714 uptake patterns exceeded MRI correlates of infarction, whereas uptake was confined to the infarct in four patients where initial suspicion of PACNS could not be confirmed. About three patients with PACNS or cerebral predominant lymphocytic vasculitis showed no or only faintly increased uptake. Short-term [18F]DPA-714-PET follow-up in a patient with PACNS showed reduced lesional [18F]DPA-714 uptake after anti-inflammatory treatment. Biopsy in the same patient pinpointed the source of tracer uptake to TSPO-expressing immune cells. CONCLUSIONS: [18F]DPA-714-PET imaging may facilitate the diagnosis and treatment monitoring of PACNS. Further studies are needed to fully understand the potential of TSPO-PET in deciphering the heterogeneity of the disease.


Assuntos
Radioisótopos de Flúor , Tomografia por Emissão de Pósitrons , Humanos , Inflamação/diagnóstico por imagem , Pirazóis , Pirimidinas , Receptores de GABA , Vasculite do Sistema Nervoso Central
8.
Nervenarzt ; 90(10): 1013-1020, 2019 Oct.
Artigo em Alemão | MEDLINE | ID: mdl-31471619

RESUMO

As a whole, rare stroke causes represent a frequent stroke etiology. Since rare stroke causes affect primarily young patients, early diagnosis and treatment are of high socioeconomic relevance. In our everyday clinical practice, cervical artery dissection, which is the most common stroke etiology among patients < 45 years, and vasculitis are particularly important. In the case of vasculitis, devastating disease courses and potentially harmful treatment options complicate clinical decision-making. Non-vasculitic vasculopathies, infections, hematological disorders, coagulation disorders, metabolic disorders and malignancies are further rare causes of stroke with variable clinical manifestations, thus impeding an early diagnosis. If eligible, patients with rare stroke causes should be considered for thrombectomy. Except for infective endocarditis, most rare stroke causes are not per se a contraindication to thrombolysis, so that eligible patients should also be considered for thrombolysis. Evidence based recommendations for the secondary prevention of most rare stroke causes are still missing. In many cases, treatment regimens are adapted to the patients' individual risk of stroke recurrence and bleeding complications.


Assuntos
Acidente Vascular Cerebral , Fatores Etários , Contraindicações , Humanos , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/terapia , Trombectomia
9.
Front Neurol ; 10: 591, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31244756

RESUMO

Besides being affected by the rare and severe primary angiitis of the central nervous system (PACNS) the nervous system is also affected by primary systemic vasculitides (PSV). In contrast to PACNS, PSV affect not only the central but also the peripheral nervous system, resulting in a large array of potential symptoms. Given the high burden of disease, difficulties in distinguishing between differential diagnoses, and incomplete pathophysiological insights, there is an urgent need for additional precise diagnostic tools to enable an earlier diagnosis and initiation of effective treatments. Methods available to date, such as inflammatory markers, antibodies, cerebrospinal fluid (CSF) analysis, imaging, and biopsy, turn out to be insufficient to meet all current challenges. We highlight the use of biomarkers as an approach to extend current knowledge and, ultimately, improve patient management. Biomarkers are considered to be useful for disease diagnosis and monitoring, for predicting response to treatment, and for prognosis in clinical practice, as well as for establishing outcome parameters in clinical trials. In this article, we review the recent literature on biomarkers which have been applied in the context of different types of nervous system vasculitides including PACNS, giant-cell arteritis, Takayasu's arteritis, polyarteritis nodosa, ANCA (anti-neutrophil cytoplasm antibody)-associated vasculitides, cryoglobulinemic vasculitis, IgA vasculitis, and Behçet's disease. Overall, the majority of biomarkers is not specific for vasculitides of the nervous system.

10.
Ann Clin Transl Neurol ; 6(6): 1134-1137, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31211179

RESUMO

The rarity of primary angiitis of the central nervous system (PACNS) demands diagnostic and prognostic biomarkers. We retrospectively measured Neurofilament light chain (NFL) concentrations in cerebrospinal fluid in a severely relapsing PACNS patient at multiple time points during the course of the disease. A marked increase in NFL levels preceding the onset of neuro-axonal damage and arterial-vessel abnormalities was observed with magnetic resonance imaging as well as with MR- and conventional angiography. Thus, marked elevation of NFL in PACNS seems to occur ahead of definitive radiological abnormalities and might serve as a diagnostic biomarker.


Assuntos
Biomarcadores/líquido cefalorraquidiano , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Vasculite do Sistema Nervoso Central/diagnóstico , Vasculite do Sistema Nervoso Central/patologia , Adulto , Axônios , Encéfalo/diagnóstico por imagem , Angiografia Cerebral , Líquido Cefalorraquidiano/diagnóstico por imagem , Humanos , Masculino , Estudos Retrospectivos , Acidente Vascular Cerebral
11.
Brain ; 142(5): 1399-1407, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30859191

RESUMO

The impact of endovascular vessel recanalization on patients with a low initial Alberta Stroke Program Early Computer Tomography Score (ASPECTS) is still uncertain. We hypothesized that vessel recanalization leads to an improvement in mortality and degree of disability by reducing brain oedema and malignant mass effect. In this multicentre observational study, patients with acute ischaemic stroke due to large vessel occlusion in the anterior circulation and an ASPECTS of ≤ 5 were analysed. Patients were assembled into two groups: successful vessel recanalization (thrombolysis in cerebral infarctions, TICI scale 2b/3) or persistent vessel occlusion (no endovascular procedure or TICI scale 0-2a). Observers were blinded to clinical data. Net water uptake within brain infarct, a quantitative biomarker based on CT densitometry, was used to quantify oedema in admission and follow-up CT and Δ-water uptake was calculated as difference between water uptake at both time points. Occurrence of malignant infarctions and secondary parenchymal haemorrhage was documented. Furthermore, modified Rankin scale score at 90 days was used for functional outcome. We included 117 patients admitted between March 2015 and August 2017 in three German stroke centres: 71 with persistent vessel occlusion and 46 with successful recanalization. The mean water uptake in the admission imaging was not different between both groups: 10.0% (±4.8) in patients with persistent vessel occlusion and 9.0% (±4.8) in patients with vessel recanalization (P = 0.4). After follow-up CT, the mean Δ-water uptake was 16.0% (±7.5) in patients with persistent vessel occlusion and 8.0% (±5.7) in patients with vessel recanalization (P < 0.001). Successful reperfusion was independently associated with a lowered Δ-water uptake of 8.0% (95% confidence interval, CI: -10.5 to -5.3%; P < 0.001) and lowered modifed Rankin scale score after 90 days of 1.5 (95% CI: -2.2 to -0.8; P < 0.001). The prevalence of malignant infarctions was 44.3% in patients with persistent vessel occlusion and 26.1% in patients with vessel recanalization. There was no significant difference for secondary haemorrhage in both groups (P = 0.7). In conclusion, successful recanalization in patients with low initial ASPECTS resulted in a significant reduction of oedema formation and was associated with a decreased prevalence of malignant infarctions and an improvement of clinical outcome.


Assuntos
Edema Encefálico/cirurgia , Isquemia Encefálica/cirurgia , Acidente Vascular Cerebral/cirurgia , Trombectomia/métodos , Tomografia Computadorizada por Raios X/métodos , Idoso , Idoso de 80 Anos ou mais , Edema Encefálico/diagnóstico por imagem , Isquemia Encefálica/diagnóstico por imagem , Estudos de Coortes , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Estudos Retrospectivos , Método Simples-Cego , Acidente Vascular Cerebral/diagnóstico por imagem , Trombectomia/tendências , Tomografia Computadorizada por Raios X/tendências
12.
J Neurosurg ; 132(1): 1-9, 2019 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-30611135

RESUMO

OBJECTIVE: Decompressive craniectomies (DCs) are performed on patients suffering large cerebral infarctions. The efficacy of this procedure has been demonstrated in several trials. In some cases, however, this procedure alone is not sufficient and patients still suffer refractory elevations of intracranial pressure (ICP). The goal of this study was to determine whether resection of infarcted tissue, termed strokectomy, performed as a second-look procedure after DC, improves outcome in selected cases. METHODS: The authors retrospectively evaluated data of patients who underwent a DC due to a cerebral infarction at their institution from 2009 to 2016, including patients who underwent a strokectomy procedure after DC. Clinical records, imaging data, outcome scores, and neurological symptoms were analyzed, and clinical outcomes and mortality rates in the strokectomy group were compared to those for similar patients in recently published randomized controlled trials. RESULTS: Of 198 patients who underwent DC due to cerebral infarction, 12 patients underwent strokectomy as a second surgical procedure, with a median National Institutes of Health Stroke Scale (NIHSS) score of 19 for patients with versus 16 for those without secondary strokectomy (p = 0.029). Either refractory increases of ICP > 20 mm Hg or dilated pupils in addition to herniation visible on CT images were triggers for strokectomy surgery. Ten of 12 (83%) patients had infarctions in more than one territory (p < 0.001). After 12 months, 43% of patients had a good outcome according to the modified Rankin Scale (mRS) score (≤ 3). In the subgroup of patients suffering infarctions in more than one vascular territory, functional outcome after 12 months was better (mRS ≤ 3 in 40% of patients in comparison to 9%; p = 0.027). A 1:3 case-control analysis matched to age, side of infarction, sex, and vascular territory confirmed these results (mRS ≤ 3, 42% in comparison to 11%; p = 0.032). Age, NIHSS score on admission, and number of vascular territories involved were identified as risk factors in multivariate analysis (p < 0.05). Patients in the strokectomy group had more infections (p < 0.001). According to these results, the authors developed a scale (Münster Stroke Score, 0-6 points) to predict whether patients might benefit from additional strokectomy. Receiver-operating characteristic (ROC) curve analysis revealed an area under the curve (AUC) of 0.86 (p < 0.001). The authors recommend a Münster Stroke Score of ≥ 3 as a cutoff, with a sensitivity of 92% and specificity of 66%, for predicting benefit from strokectomy. CONCLUSIONS: In this study in comparison to former studies, mortality rates were lower and clinical outcome was comparable to that of previously published trials regarding large cerebral infarctions. Second surgery including strokectomy may help achieve better outcomes, especially in cases of infarction of more than one vascular territory.


Assuntos
Infarto Cerebral/cirurgia , Craniectomia Descompressiva/métodos , Encefalocele/etiologia , Hipertensão Intracraniana/etiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Infarto Cerebral/complicações , Encefalocele/mortalidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/cirurgia , Curva ROC , Estudos Retrospectivos , Cirurgia de Second-Look , Índice de Gravidade de Doença , Resultado do Tratamento
13.
Ther Adv Neurol Disord ; 11: 1756286418785071, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30034536

RESUMO

Primary angiitis of the central nervous system (PACNS) represents a rare inflammatory disease affecting the brain and spinal cord. Stroke, encephalopathy, headache and seizures are major clinical manifestations. The diagnosis of PACNS is based on the combination of clinical presentation, imaging findings (magnetic resonance imaging and angiography), brain biopsy, and laboratory and cerebral spinal fluid (CSF) values. PACNS can either be confirmed by magnetic resonance angiography (MRA)/conventional angiography or tissue biopsy showing the presence of typical histopathological patterns. Identification of PACNS mimics is often challenging in clinical practice, but crucial to avoid far-reaching treatment decisions. In view of the severity of the disease, with considerable morbidity and mortality, early recognition and treatment initiation is necessary. Due to the rareness and heterogeneity of the disease, there is a lack of randomized data on treatment strategies. Retrospective studies suggest the combined administration of cyclophosphamide and glucocorticoids as induction therapy. Immunosuppressants such as azathioprine, methotrexate or mycophenolate mofetil are often applied for maintenance therapy. In addition, the beneficial effects of two biological agents (anti-CD20 monoclonal antibody rituximab and tumour necrosis factor-α blocker) have been reported. Nevertheless, diagnosis and treatment is still a clinical challenge, and further insights into the immunopathogenesis of PACNS are required to improve the diagnosis and management of patients. The present review provides a comprehensive overview of diagnostics, differential diagnoses, and therapeutic approaches of adult PACNS.

14.
J Neuroimmunol ; 321: 109-116, 2018 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-29957380

RESUMO

Primary angiitis of the central nervous system (PACNS) is a rare and heterogeneous inflammatory disease of the CNS vasculature with poorly understood pathophysiology. Comprehensive immune-cell phenotyping revealed increased frequencies of leukocytes in the cerebrospinal fluid (CSF) of PACNS patients compared to patients with multiple sclerosis, ischemic stroke, and somatoform disorders (n = 18 per group). Changes in the intrathecal immune-cell profile were heterogeneous in PACNS. While proportions of T-cell subsets remained unaltered, some PACNS patients showed a shift toward NK- or B cells. Intrathecal immunoglobulin synthesis was observed in a subgroup of PACNS patients with an increased frequency of antibody producing plasma cells.


Assuntos
Linfócitos B/imunologia , Imunidade Celular/imunologia , Células Matadoras Naturais/imunologia , Linfócitos T/imunologia , Vasculite do Sistema Nervoso Central/sangue , Vasculite do Sistema Nervoso Central/imunologia , Adulto , Idoso , Linfócitos B/metabolismo , Biomarcadores/sangue , Biomarcadores/metabolismo , Feminino , Humanos , Células Matadoras Naturais/metabolismo , Masculino , Pessoa de Meia-Idade , Linfócitos T/metabolismo , Vasculite do Sistema Nervoso Central/diagnóstico
15.
Cerebrovasc Dis ; 44(5-6): 344-350, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29130956

RESUMO

BACKGROUND AND PURPOSE: The introduction of stent retrievers has made the complete extraction and histological analysis of human thrombi possible. A number of large randomized trials have proven the efficacy of thrombectomy for ischemic stroke; however, thrombus composition could have an impact on the efficacy and risk of the intervention. We therefore investigated the impact of histologic thrombus features on interventional outcome and procedure-related embolisms. For a pre-interventional estimation of histologic features and outcome parameters, we assessed the pre-interventional CT attenuation of the thrombi. METHODS: We prospectively included all consecutive patients with occlusion of the middle cerebral artery who underwent thrombectomy between December 2013 and February 2016 at our university medical center. Samples were histologically analyzed (H&E, Elastica van Gieson, Prussian blue); additionally, immunohistochemistry for CD3, CD20, and CD68/KiM1P was performed. Main thrombus components (fibrin, erythrocytes, and white blood cells) were determined and compared to intervention time, frequency of secondary embolisms, as well as additional clinical and interventional parameters. Additionally, we assessed the pre-interventional CT attenuation of the thrombi in relation to the unaffected side (rHU) and their association with histologic features. RESULTS: One hundred eighty patients were included; of these, in 168 patients (93.4%), complete recanalization was achieved and 27 patients (15%) showed secondary embolism in the control angiogram. We observed a significant association of high amounts of fibrin (p < 0.001), low percentage of red blood cells (p < 0.001), and lower rHU (p < 0.001) with secondary embolism. Higher rHU values were significantly associated with higher amounts of fibrin (p ≤ 0.001) and low percentage of red blood cells (p ≤ 0.001). Additionally, high amounts of fibrin were associated with longer intervention times (p ≤ 0.001), whereas thrombi with high amounts of erythrocytes correlated with shorter intervention times (p ≤ 0.001). ROC analysis revealed reliable prediction of secondary embolisms for low rHU (AUC = 0.746; p ≤ 0.0001), low amounts of RBC (AUC = 0.764; p ≤ 0.0001), and high amounts of fibrin (AUC = 0.773; p ≤ 0.0001). CONCLUSIONS: Fibrin-rich thrombi with low erythrocyte percentage are significantly associated with longer intervention times. Embolisms in the thrombectomy process occur more often in thrombi with a small fraction of red blood cells and a low CT-density, suggesting a higher fragility of these thrombi.


Assuntos
Angiografia Cerebral/métodos , Artérias Cerebrais/diagnóstico por imagem , Artérias Cerebrais/cirurgia , Angiografia por Tomografia Computadorizada/métodos , Procedimentos Endovasculares/efeitos adversos , Infarto da Artéria Cerebral Média/tratamento farmacológico , Embolia Intracraniana/etiologia , Trombose Intracraniana/diagnóstico por imagem , Trombectomia/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/análise , Biópsia , Artérias Cerebrais/química , Artérias Cerebrais/patologia , Procedimentos Endovasculares/métodos , Feminino , Alemanha , Humanos , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/patologia , Infarto da Artéria Cerebral Média/cirurgia , Embolia Intracraniana/diagnóstico por imagem , Trombose Intracraniana/metabolismo , Trombose Intracraniana/patologia , Trombose Intracraniana/cirurgia , Masculino , Pessoa de Meia-Idade , Duração da Cirurgia , Segurança do Paciente , Valor Preditivo dos Testes , Estudos Retrospectivos , Fatores de Risco , Trombectomia/métodos , Fatores de Tempo , Resultado do Tratamento
16.
Stroke ; 48(4): 1061-1069, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28292872

RESUMO

BACKGROUND AND PURPOSE: Peripheral immune cell infiltration contributes to neural injury after ischemic stroke. However, in contrast to lymphocytes and neutrophils, the role of different monocyte/macrophage subsets remains to be clarified. Therefore, we evaluated the effects of selective and unselective monocyte/macrophage depletion and proinflammatory (M1-) and anti-inflammatory (M2-) macrophage transfer on the outcome after experimental cerebral ischemia. METHODS: To assess short-term effects of monocytes/macrophages in acute ischemic stroke, mice underwent transient middle cerebral artery occlusion and received either clodronate liposomes for unselective macrophage depletion, MC-21-antibody for selective depletion of proinflammatory Ly-6Chigh monocytes, or proinflammatory (M1-) or anti-inflammatory (M2-) macrophage transfer. In addition, the impact of MC-21-antibody administration and M2-macrophage transfer on long-term neural recovery was investigated after photothrombotic stroke. Neurobehavioral tests were used to analyze functional outcomes, infarct volumes were determined, and immunohistochemical analyses were performed to characterize the postischemic inflammatory reaction. RESULTS: Selective and unselective monocyte/macrophage depletion and M1- and M2-macrophage transfer did not influence tissue damage and neurobehavioral outcomes in the acute phase after middle cerebral artery occlusion. Beyond, selective depletion of Ly-6Chigh monocytes and M2-macrophage transfer did not have an impact on neural recovery after photothrombotic stroke. CONCLUSIONS: Targeting different monocyte/macrophage subsets has no impact on outcome after ischemic stroke in mice. Altogether, our study could not identify monocytes/macrophages as relevant therapeutic targets in acute ischemic stroke.


Assuntos
Isquemia Encefálica/imunologia , Inflamação/imunologia , Macrófagos/imunologia , Monócitos/imunologia , Acidente Vascular Cerebral/imunologia , Animais , Isquemia Encefálica/etiologia , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média/complicações , Camundongos , Distribuição Aleatória , Acidente Vascular Cerebral/etiologia
17.
Neurochem Int ; 107: 117-126, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27884770

RESUMO

Neutrophil granulocytes (or polymorphonuclear cells, PMNs) have long been considered as crude killing machines, particularly trained to attack bacterial or fungal pathogens in wounds or infected tissues. That perspective has fundamentally changed over the last decades, as PMNs have been shown to exert a livery exchange between other cells of the innate and adaptive immune system. PMNs do provide major immunomodulatory contribution during acute inflammation and subsequent clearance. Following sterile inflammation like cerebral ischemia, PMNs are among the first hematogenous cells attracted to the ischemic tissue. As inflammation is a crucial component within stroke pathophysiology, several studies regarding the role of PMNs following cerebral ischemia have been carried out. And indeed, recent research suggests a direct connection between PMNs' influx and brain damage severity. This review highlights the latest research regarding the close interconnection between PMNs and co-working cells following cerebral ischemia. We describe how PMNs are attracted to the site of injury and their tasks within the inflamed brain tissue and the periphery. We further report of new findings regarding the interaction of PMNs with resident microglia, immigrating macrophages and T cells after stroke. Finally, we discuss recent research results from experimental studies in the context with current clinical trials and point out potential new therapeutic applications that could emerge from this new knowledge on the action and interaction of PMNs following cerebral ischemia.


Assuntos
Isquemia Encefálica/metabolismo , Granulócitos/metabolismo , Macrófagos/metabolismo , Microglia/metabolismo , Neutrófilos/metabolismo , Animais , Isquemia Encefálica/imunologia , Granulócitos/imunologia , Humanos , Macrófagos/imunologia , Microglia/imunologia , Neutrófilos/imunologia
18.
Stroke ; 47(3): 852-62, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26839353

RESUMO

BACKGROUND AND PURPOSE: Bone marrow cell (BMC)-based therapies, either the transplantation of exogenous cells or stimulation of endogenous cells by growth factors like the granulocyte colony-stimulating factor (G-CSF), are considered a promising means of treating stroke. In contrast to large preclinical evidence, however, a recent clinical stroke trial on G-CSF was neutral. We, therefore, aimed to investigate possible synergistic effects of co-administration of G-CSF and BMCs after experimental stroke in mice to enhance the efficacy compared with single treatments. METHODS: We used an animal model for experimental stroke as paradigm to study possible synergistic effects of co-administration of G-CSF and BMCs on the functional outcome and the pathophysiological mechanism. RESULTS: G-CSF treatment alone led to an improved functional outcome, a reduced infarct volume, increased blood vessel stabilization, and decreased overall inflammation. Surprisingly, the combination of G-CSF and BMCs abrogated G-CSFs' beneficial effects and resulted in increased hemorrhagic infarct transformation, altered blood-brain barrier, excessive astrogliosis, and altered immune cell polarization. These increased rates of infarct bleeding were mainly mediated by elevated matrix metalloproteinase-9-mediated blood-brain barrier breakdown in G-CSF- and BMCs-treated animals combined with an increased number of dilated and thus likely more fragile vessels in the subacute phase after cerebral ischemia. CONCLUSIONS: Our results provide new insights into both BMC-based therapies and immune cell biology and help to understand potential adverse and unexpected side effects.


Assuntos
Transplante de Medula Óssea/efeitos adversos , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Hemorragia/induzido quimicamente , Imunidade Celular/imunologia , Acidente Vascular Cerebral/terapia , Animais , Células da Medula Óssea/imunologia , Terapia Combinada/efeitos adversos , Terapia Combinada/métodos , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Hemorragia/imunologia , Imunidade Celular/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Acidente Vascular Cerebral/imunologia
19.
PLoS One ; 11(1): e0146679, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26752421

RESUMO

We have previously shown that granulocyte-colony stimulating factor (G-CSF) treatment alone, or in combination with constraint movement therapy (CIMT) either sequentially or concomitantly, results in significantly improved sensorimotor recovery after photothrombotic stroke in rats in comparison to untreated control animals. CIMT alone did not result in any significant differences compared to the control group (Diederich et al., Stroke, 2012;43:185-192). Using a subset of rat brains from this former experiment the present study was designed to evaluate whether dendritic plasticity would parallel improved functional outcomes. Five treatment groups were analyzed (n = 6 each) (i) ischemic control (saline); (ii) CIMT (CIMT between post-stroke days 2 and 11); (iii) G-CSF (10 µg/kg G-CSF daily between post-stroke days 2 and 11); (iv) combined concurrent group (CIMT plus G-CSF) and (v) combined sequential group (CIMT between post-stroke days 2 and 11; 10 µg/kg G-CSF daily between post-stroke days 12 and 21, respectively). After impregnation of rat brains with a modified Golgi-Cox protocol layer V pyramidal neurons in the peri-infarct cortex as well as the corresponding contralateral cortex were analyzed. Surprisingly, animals with a similar degree of behavioral recovery exhibited quite different patterns of dendritic plasticity in both peri-lesional and contralesional areas. The cause for these patterns is not easily to explain but puts the simple assumption that increased dendritic complexity after stroke necessarily results in increased functional outcome into perspective.


Assuntos
Dendritos/patologia , Luz , Plasticidade Neuronal , Modalidades de Fisioterapia , Recuperação de Função Fisiológica , Acidente Vascular Cerebral/fisiopatologia , Acidente Vascular Cerebral/terapia , Animais , Terapia Combinada , Dendritos/efeitos dos fármacos , Fator Estimulador de Colônias de Granulócitos/farmacologia , Masculino , Movimento , Plasticidade Neuronal/efeitos dos fármacos , Células Piramidais/efeitos dos fármacos , Células Piramidais/metabolismo , Células Piramidais/patologia , Ratos Wistar , Recuperação de Função Fisiológica/efeitos dos fármacos
20.
Expert Rev Neurother ; 16(2): 173-86, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26689223

RESUMO

Over recent decades, experimental and clinical stroke studies have identified a number of neurorestorative treatments that stimulate neural plasticity and promote functional recovery. In contrast to the acute stroke treatments thrombolysis and endovascular thrombectomy, neurorestorative treatments are still effective when initiated days after stroke onset, which makes them applicable to virtually all stroke patients. In this article, selected physical, pharmacological and cell-based neurorestorative therapies are discussed, with special emphasis on interventions that have already been transferred from the laboratory to the clinical setting. We explain molecular and structural processes that promote neural plasticity, discuss potential limitations of neurorestorative treatments, and offer a speculative viewpoint on how neurorestorative treatments will evolve.


Assuntos
Isquemia Encefálica/reabilitação , Reabilitação Neurológica/métodos , Plasticidade Neuronal , Nootrópicos/uso terapêutico , Regeneração , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Transplante de Células-Tronco/métodos , Reabilitação do Acidente Vascular Cerebral , Axônios , Encéfalo/fisiologia , Encéfalo/fisiopatologia , Isquemia Encefálica/complicações , Citidina Difosfato Colina/uso terapêutico , Eritropoetina/uso terapêutico , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Humanos , Proteínas da Mielina/antagonistas & inibidores , Neovascularização Fisiológica , Neurogênese , Proteínas Nogo , Inibidores da Fosfodiesterase 5/uso terapêutico , Recuperação de Função Fisiológica , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/fisiopatologia
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