[Show abstract][Hide abstract] ABSTRACT: The enteric nervous system (ENS) has to respond to continuously changing microenvironmental challenges within the gut and is therefore dependent on a neural stem cell niche to keep the ENS functional throughout life. In this study, we hypothesize that this stem cell niche is also affected during inflammation and therefore investigated lipopolysaccharides (LPS) effects on enteric neural stem/progenitor cells (NSPCs). NSPCs were derived from the ENS and cultured under the influence of different LPS concentrations. LPS effects upon proliferation and differentiation of enteric NSPC cultures were assessed using immunochemistry, flow cytometry, western blot, Multiplex ELISA and real-time PCR. LPS enhances the proliferation of enteric NSPCs in a dose-dependent manner. It delays and modifies the differentiation of these cells. The expression of the LPS receptor toll-like receptor 4 on NSPCs could be demonstrated. Moreover, LPS induces the secretion of several cytokines. Flow cytometry data gives evidence for individual subgroups within the NSPC population. ENS-derived NSPCs respond to LPS in maintaining at least partially their stem cell character. In the case of inflammatory disease or trauma where the liberation and exposure to LPS will be increased, the expansion of NSPCs could be a first step towards regeneration of the ENS. The reduced and altered differentiation, as well as the induction of cytokine signalling, demonstrates that the stem cell niche may take part in the LPS-transmitted inflammatory processes in a direct and defined way.
Journal of Cellular and Molecular Medicine 04/2014; · 4.75 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Acute stroke is one of the main causes of death and chronic disability. Thrombolysis with recombinant tissue plasminogen activator within the first hours after onset of symptoms is an effective therapeutic option for ischemic stroke. However, fewer than 2% to 7% of patients receive this treatment, primarily because most patients reach the hospital too late for the initiation of successful therapy. Several measures can reduce detrimental delay until treatment. It is of importance to use continual public awareness campaigns to reduce delays in patients' alarm of emergency medical services. Further relevant measures are repetitive education of emergency medical services teams to ensure the systematic use of scales designed for recognition of stroke symptoms and the proper triage of patients to stroke centers. A most important time-saving measure is prenotification of the receiving hospital by the emergency medical services team. In the future, treatment already at the emergency site may allow more than a small minority of patients to benefit from available treatment.
International Journal of Stroke 04/2014; · 2.75 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Idiopathic Parkinson's disease (IPD) is characterized by the clinical motor symptoms of hypokinesia, rigidity, and tremor. Apart from these motor symptoms, cognitive deficits often occur in IPD. The positive effect of cholinesterase inhibitors on cognitive deficits in IPD and findings of earlier molecular imaging studies suggest that the cholinergic system plays an important role in the origin of cognitive decline in IPD.Methods
Twenty-five non-demented patients with IPD underwent a 5-[123I]iodo-3-[2(S)-2-azetidinylmethoxy]pyridine (5-I-A-85380) SPECT to visualize α4β2 nicotinic acetylcholine receptors (nAchR) and cognitive testing with the CERAD (Consortium to Establish a Registry for Alzheimer's Disease) battery to identify domains of cognitive dysfunction.ResultsIn the CERAD, the IPD patients exhibited deficits in non-verbal memory, attention, psychomotor velocity, visuoconstructive ability, and executive functions. After Bonferroni correction for multiple comparisons, we found significant correlations between performance of the CERAD subtests Boston Naming Test (a specific test for visual perception and for detection of word-finding difficulties) and Word List Intrusions (a specific test for learning capacity and memory for language information) vs binding of α4β2 nAchR in cortical (the right superior parietal lobule) and subcortical areas (the left thalamus, the left posterior subcortical region, and the right posterior subcortical region).Conclusions
These significant correlations between the results of the CERAD subtests and the cerebral α4β2 nAchR density, as assessed by 5-I-A-85380 SPECT, indicate that cerebral cholinergic pathways are relevant to cognitive processing in IPD.
[Show abstract][Hide abstract] ABSTRACT: Aims: The aim was to determine the incidence of new ischaemic lesions on diffusion-weighted MR imaging (DWI) in a non-randomised cohort of patients after protected and unprotected carotid artery stent placement using the Parodi Anti-Emboli System (PAES). Methods and results: A retrospective review was conducted on 269 patients who received DWI prior to, and 24-72 hours after, stent placement. All patients were enrolled in one centre. Forty patients stented with the PAES device were matched with 229 patients stented without protection (control group). New diffusion restriction on DWI was detected in 25.8% (PAES) versus 32.3% (control group); p=0.64. On average there were 0.7 lesions (PAES) versus 0.8 lesions (control group) per patient. The area of lesions was 1.7 (PAES) versus 5.6 mm2. In a subanalysis of patients (32 PAES, 148 non-protected) with >80% stenosis, the area of restricted diffusion was less when proximal protection was used (p<0.05). The number and area of DWI lesions did not differ on the contralateral, non-stented side. When the PAES system was used, patients were more likely not to have any lesion at all (p=0.028). Conclusions: In high-grade stenosis, the use of the Gore PAES device significantly reduced the area of new DWI lesions and patients were more likely not to have any new DWI lesion at all.
EuroIntervention: journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology 02/2014; · 3.17 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Mechanical thrombectomy with stent retrievers in acute stroke has emerged as a promising new technique with the highest recanalization rate of the therapeutic procedures available so far. However, endovascular treatment is also associated with the risk of specific complications. One of those is the occurrence of peri-interventional subarachnoid hemorrhage (SAH), which has been reported in 5-16 % of the cases. Interestingly, this rate is higher than that of angiographically detectable perforations (0-3 %), leaving the majority of peri-interventional SAH to be due to angiographically occult perforations. Little is known about the influence of this finding on clinical outcome. The purpose of this study was to investigate the clinical relevance of SAH due to occult perforations during thrombectomy with stent retrievers.
Postinterventional computed tomography (CT) scans of 217 consecutive patients with acute occlusions of intracerebral arteries who were treated with stent retrievers in our department between October 2009 and October 2012 were retrospectively analyzed.
SAH was found on postinterventional CT scans in 5.5 % of the cases. Seven cases were included for further analysis and matched to controls by the following characteristics: (1) site of occlusion, (2) result of the recanalization procedure according to the modified thrombolysis in cerebral infarction score, (3) administration of intravenous recombinant tissue plasminogen activator, (4) presence of proximal extracranial occlusion, (5) age, and (6) sex. Comparison of the angiographic data of the two cohorts showed no significant difference in the length of the procedures or the number of maneuvers needed for recanalization, nor were there significant differences in clinical outcomes as measured by NIHSS and mRS scores. Secondary symptomatic ICH occurred in one case in either cohort and led to death in both cases. The rate of asymptomatic ICH within the first 24 h after recanalization was significantly higher in the group with peri-interventional SAH (57 vs. 0 %, P = 0.018).
This small retrospective case-control study did not reveal a significant influence of peri-interventional SAH due to angiographically occult perforations on neurologic outcome of patients treated with stent retrievers.
[Show abstract][Hide abstract] ABSTRACT: Introduction
Capecitabine, a 5-fluorouracil (5FU) pro-drug, is increasingly used in breast and gastrointestinal cancers due to its more convenient oral route of administration when compared to 5FU. Despite its widespread use, there are only a few reports on capecitabine CNS toxicity, while the pathogenic basis of such toxicity remains unclear.
A 69-year-old male presented with recurrent generalized seizures 2.5 months after preoperative chemoradiotherapy with capecitabine in locally advanced rectal cancer. Brain MRI revealed a diffuse, subcortical white matter alteration suggestive of vasogenic edema. The diagnosis of toxic encephalopathy was supported after elimination of alternative causes of the neurological dysfunction and complete resolution of clinical and imaging findings after 3 months of no further chemotherapy.
Given the expanding use of capecitabine, physicians should be aware of this potential complication when a neurological worsening occurs during or after treatment with this chemotherapeutic agent. In our case, as in previously described cases encephalopathy was characterized by a favorable course after cessation of the drug. Vasogenic edema rather than cytotoxic edema may play a pivotal pathogenetic role in this form of encephalopathy.
[Show abstract][Hide abstract] ABSTRACT: We investigated in vivo brain nicotinic acetylcholine receptor (nAChR) distribution in cognitively intact subjects with Parkinson's disease (PD) at an early stage of the disease. Fourteen patients and 13 healthy subjects were imaged with single photon emission computed tomography and the radiotracer 5-[(123)I]iodo-3-[2(S)-2-azetidinylmethoxy]pyridine ([(123)I]5IA). Patients were selected according to several criteria, including short duration of motor signs (<7 years) and normal scores at an extensive neuropsychological evaluation. In PD patients, nAChR density was significantly higher in the putamen, the insular cortex and the supplementary motor area and lower in the caudate nucleus, the orbitofrontal cortex, and the middle temporal gyrus. Disease duration positively correlated with nAChR density in the putamen ipsilateral (ρ = 0.56, p < 0.05) but not contralateral (ρ = 0.49, p = 0.07) to the clinically most affected hemibody. We observed, for the first time in vivo, higher nAChR density in brain regions of the motor and limbic basal ganglia circuits of subjects with PD. Our findings support the notion of an up-regulated cholinergic activity at the striatal and possibly cortical level in cognitively intact PD patients at an early stage of disease.
Frontiers in Aging Neuroscience 01/2014; 6:213. · 5.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Acute stroke is one of the main causes of death and chronic disability. Thrombolysis, achieved by administering recombinant tissue plasminogen activator within 4.5 h, is an effective therapeutic option for ischemic stroke. However, less than 2-12 % of patients receive this treatment and a major reason is that most patients reach the hospital too late. Several time-saving measures should be implemented. Firstly, optimized and continual public awareness campaigns for patients should be initiated to reduce delays in notifying the emergency medical service. Secondly, emergency medical service personnel should develop protocols for prenotification of the receiving hospital. Other suggested measures involve educating emergency medical service personnel to systematically use scales for recognizing the symptoms of stroke and to triage patients to experienced stroke centers. In the future, administering treatment at the emergency site (mobile stroke unit concept) may allow more than a small minority of patients to benefit from available recanalization treatment options.
[Show abstract][Hide abstract] ABSTRACT: Alzheimer's disease (AD) is characterized by a progressive decline of cognitive functions and represents the most common form of dementia and a major cause of morbidity and mortality in the modern, Westernized societies. There is accumulating evidence to support the hypothesis that a primary Cerebral vascular dysfunction initiates a cascade of events that lead to neuronal injury in Alzheimer's dementia. The endothelium, in specific, constitutes a part of the blood brain barrier, the dysfunction of which is thought to play an important role to disturbed amyloid-β homeostasis and infiltration of the brain parenchyma with circulating toxic molecules in the disease. Furthermore, the endothelium itself is under certain conditions capable of producing neurotoxic and inflammatory factors, whereas common growth factors regulate the development and maintenance of both neurons and blood vessels. Reliance of both endothelial and neuronal cells on mitochondrial integrity and common molecular pathways for apoptosis also imply that there is a link between vascular pathology and neurodegeneration. The present article intends to review available evidence on molecular players implicated in the above mechanisms with the potential to develop biomarkers or novel therapeutic targets.
Current Alzheimer research 11/2013; · 4.97 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Identification of risk factors and prodromal markers for Parkinson's disease (PD) and the understanding of the point in time of first occurrence is essential for the early detection of incident PD. In this three-center longitudinal, observational study, we evaluated the specific risk for PD associated with single or combinations of risk factors and prodromal markers. In addition, we evaluated which risk factors and prodromal markers emerge at which time before the diagnosis of PD. Of the 1,847 at-baseline PD-free individuals ≥50 years, 1,260 underwent the 5-year follow-up assessment. There were 21 cases of incident PD during the study period. Enlarged hyperechogenic substantia nigra was the most frequent baseline sign in individuals developing PD after 3 years (80.0 %) and 5 years (85.7 %) compared to healthy controls (17.5 %) followed by the occurrence of mild parkinsonian signs and hyposmia. Evaluation of the signs at the first follow-up assessment showed that individuals developing PD after two additional years showed the same pattern of signs as individuals who developed PD 3 years after baseline assessment.
Journal of Neurology 11/2013; · 3.58 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Patients with idiopathic Parkinson's disease (IPD) have a reduced myocardial MIBG uptake in MIBG scintigraphy, indicating myocardial sympathetic denervation. We were interested whether this myocardial sympathetic denervation coincides with clinical symptoms of autonomic impairment in IPD patients. We performed MIBG scintigraphy, the SCOPA-AUT scale, a standardized medical history (developed in our clinic) and autonomic nervous system testing in 47 IPD patients (21 female, 26 male patients). We correlated myocardial MIBG uptake with the results of the SCOPA-AUT scale, the standardized medical history and the autonomic nervous system testing through the use of Spearman's correlation. Myocardial MIBG uptake correlated significantly (p < 0.05) with several items of the SCOPA-AUT scale (in female patients: perspiration during the night, in male patients: sum score, saliva dribbling of the mouth, difficulty swallowing, fainting, constipation), of the standardized medical history (in male patients: swollen ankles) and of the autonomic nervous system testing (all patients: sum score, Ewing orthostasis test). Remarkably, we found more significant correlations in male than in female patients. Reduced myocardial sympathetic innervation-as revealed by MIBG scintigraphy-is associated with clinical symptoms of autonomic impairment. This association is more pronounced in male than in female patients. The cause for this gender-specific phenomenon is unclear.
Journal of Neurology 10/2013; · 3.58 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The diagnosis of idiopathic Parkinson's disease (IPD) is based on clinical criteria. In the last two decades several neuroimaging methods using transcranial sonography (TCS) or radiolabelled tracers such as the myocardial MIBG scintigraphy were applied to support diagnosis of IPD. They have been used independently of each other and their interrelation is not yet clear. In the present study we analyzed the relation between findings of TCS, MIBG scintigraphy, and clinical presentation in 42 patients with IPD who were clinically diagnosed and underwent clinical follow-up over ≥3 years in order to confirm IPD diagnosis throughout the clinical course. The extent of substantia nigra hyperechogenicity (SN+) contralateral to the clinically more affected body side (SNcontra) was compared to myocardial (123)I-MIBG uptake. SNcontra did not correlate with the myocardial MIBG uptake (r = -0.10; p = 0.52). Both myocardial MIBG uptake and TCS did not correlate significantly with Hoehn and Yahr stage (r = -0.03; p = 0.87 and r = -0.10; p = 0.54, respectively). Sensitivity of TCS in the diagnosis of IPD was 79%, of MIBG scintigraphy 81%. The combination of both measurements reached a sensitivity of 95%. TCS and MIBG scintigraphy may disclose complementary aspects of IPD. The combined use of both neuroimaging methods might improve the diagnostic sensitivity regarding IPD.
Parkinsonism & Related Disorders 07/2013; · 3.27 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Thrombolysis with alteplase administered within a narrow therapeutic window provides an effective therapy for acute ischaemic stroke. However, mainly because of prehospital delay, patients often arrive too late for treatment, and no more than 1-8% of patients with stroke obtain this treatment. We recommend that all links in the prehospital stroke rescue chain must be optimised so that in the future more than a small minority of patients can profit from time-sensitive acute stroke therapy. Measures for improvement include continuous public awareness campaigns, education of emergency medical service personnel, the use of standardised, validated scales for recognition of stroke symptoms and for triaging to the appropriate institution, and advance notification to the receiving hospital. In the future, use of telemedicine technologies for interaction between the emergency site and hospital, and the strategy of treatment directly at the emergency site (mobile stroke unit concept), could contribute to more efficient use of resources and reduce the time taken to instigate treatment to within 60 min-the golden hour-of the onset of the symptoms of stroke.
The Lancet Neurology 06/2013; 12(6):585-596. · 23.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Alzheimer's disease (AD) is a neurodegenerative disease characterized by deposits of amyloid β peptide (Aβ) and microglia-driven inflammatory activation. Tenascin-C (tnc) is an extracellular matrix protein that is upregulated in inflammation and induces further inflammatory responses. We hypothesized that tnc contributes to the inflammatory pathology in AD. Using real-time polymerase chain reaction, we observed that tnc gene transcription was upregulated in cultured microglia after Aβ challenge and in the brain of an AD mouse model that overexpresses mutated amyloid precursor protein (APP) in neural cells. By cross-breeding APP-transgenic mice and tenascin-C-deficient mice, we demonstrated using real-time polymerase chain reaction, Western blot analysis, enzyme-linked immunosorbent assay, and immunohistochemistry that tnc deficiency reduces pro- but enhances anti-inflammatory activation in the mutated APP-transgenic mouse brain, associated with a reduced cerebral Aβ load and higher levels of the postsynaptic density protein 95. Thus, our study indicates that functional inhibition of tnc exerts beneficial effects on AD pathogenesis, suggesting a potential for tnc as a new therapeutic target in AD.
Neurobiology of aging 05/2013; · 5.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In order to assess nigrostriatal function over time in healthy subjects with substantia nigra hyperechogenicity (SN+) believed to be at higher risk for Parkinson's disease (PD), ten healthy SN+ subjects underwent [(18)Fluoro] Dopa positron emission tomography (PET) twice-at baseline and after a mean of 7.3 years. Neurological examination took place at study inclusion followed by a structured telephone interview focusing on early Parkinsonian symptoms at the time point of second PET study and 3.5 years later. The [(18)Fluoro] Dopa uptake remained unchanged in eight of ten participants. In the other two subjects marked unilateral reduction of putaminal [(18)Fluoro] Dopa uptake ratios appeared over the time, followed by complaints of a clinically manifest PD in one. We suggest that the progressive pathological PET findings in 20 % and PD conversion in 10 % of our cohort may be in accordance with the presumed proportion of SN+ individuals eventually developing PD based on SN+ prevalence of 10 % within the healthy population, being ten times higher than PD prevalence in the age of over 60 years. Our findings hint towards a significance of SN+ indicating a high risk for PD in some extrapyramidally healthy SN+ individuals.
Journal of Neurology 04/2013; · 3.58 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In Alzheimer's disease (AD), fatal neuronal cell loss occurs long before relevant evidence can lead to a reliable diagnosis. If characteristic pathological alterations take place in the enteric nervous system (ENS), it could be one of the most promising targets for an early diagnosis, using submucosal biopsies from the gut. We therefore investigated time- and spatial-dependent changes in an amyloid-β protein precursor (AβPP) overexpressing transgenic mouse model to examine early changes within the ENS. Wholemount preparations and paraffin sections were analyzed for the expression of neuronal, glial, and innate immunity markers. Isolated myenteric networks were screened for differences in overall protein expression, and a motility analysis delivered functional data. The level of AβPP in the gut was significantly higher in the AD mouse model than in wild-type mice and also higher in the gut than in the brain at all ages investigated. The transcriptional level of Nestin, GFAP, and TLR4 increased with age with a peak at 3 months. At the protein level, human amyloid-β was located in myenteric neurons. Myenteric networks showed a reduction of the neuronal density in AβPP compared to wild-type mice, which was functionally relevant as revealed by motility analysis. The ENS undergoes significant changes during the early onset of AβPP expression in AD mouse models that appear before those seen in the brain as demonstrated in this study. Thus, there is a chance of determining similar alterations in the human gut of AD patients, which could be used to develop early diagnostic approaches.
Journal of Alzheimer's disease: JAD 03/2013; · 4.17 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We report on a 39-year-old female patient who developed catatonia after there had been schizomanic symptoms in the six months before. At admission the patient exhibited catatonia, a tetraspastic syndrome and focal epileptic seizures. The cranial MRI revealed bilateral subcortical hyperintense lesions which took up contrast agent. Examination of the cerebrospinal fluid disclosed a lymphocytic pleocytosis and autochthone oligoclonal bands. In the serum autoantibodies against the NMDA-NR-1 receptor were reproducibly detected. A detailed search for a tumour was negative. In detail, we could exclude a neoplasm of the ovaries which is often present in the paraneoplastic type of anti-NMDA-receptor encephalitis. Therefore we assume an autoimmune, not paraneoplastic, encephalitis in our patient. The symptoms improved significantly after an immunosuppressive therapy - initially with glucocorticoids followed by rituximab - had been initiated. This case illustrates that an autoimmune encephalitis should be looked for when first psychotic symptoms occur.
Fortschritte der Neurologie · Psychiatrie 03/2013; · 0.85 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVES: This study sought to assess the feasibility and safety of a recently described technique of mechanical recanalization with the help of a stent-like device. BACKGROUND: In the special group of acute stroke patients with an intracranial large vessel occlusion, intravenous tissue-type plasminogen activator on its own leads to a good clinical outcome (mRS ≤2) in only 15% to 25% of cases. The aforementioned technique of mechanical recanalization showed very promising clinical results. METHODS: Forty patients presenting within 6 h from stroke symptom onset were enrolled. Mechanical recanalization was performed using a Solitaire FR revascularization device. The primary endpoint of the study was the clinical outcome rated with the help of the modified Rankin Scale (mRS) after 90 days. RESULTS: Twenty-four patients (60%) showed a good clinical outcome (mRS ≤2) at 90 days. One symptomatic hemorrhage was detected on follow-up computed tomography. The death rate was 12.5% (5 patients). Successful recanalization (Thrombolysis In Cerebral Infarction score ≥2b) of the target vessel was achieved in 95% of the patients with a mean of 1.8 runs with the device. CONCLUSIONS: The ReFlow (Mechanical Recanalization With Flow Restoration in Acute Ischemic Stroke) study shows that mechanical recanalization with flow restoration is highly effective in stroke patients with a large intracranial vessel occlusion presenting within 4.5 h after symptom onset. (Mechanical Recanalization With Flow Restoration in Acute Ischemic Stroke [ReFlow]; NCT01210729).