Neurologische Klinik und Poliklinik
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Sonstige beteiligte Institutionen
- Datenintegrationszentrum Würzburg (DIZ) (1)
- Institut für Musikphysiologie und Musiker-Medizin der Hochschule für Musik, Theater und Medien, Hannover (1)
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- Sahin Lab, F.M. Kirby Neurobiology Center Boston Children’s Hospital, Department of Neurology, Harvard Medical School (1)
- Wurzburg Fabry Center for Interdisciplinary Therapy (FAZIT), Wurzburg, Germany (1)
- Würzburg Fabry Center for Interdisciplinary Therapy (FAZIT), University of Würzburg, Würzburg, Germany (1)
Multiple sclerosis (MS) is a prevalent neurological disease of complex etiology. Here, we describe the characterization of a multi-incident MS family that nominated a rare missense variant (p.G420D) in plasminogen (PLG) as a putative genetic risk factor for MS. Genotyping of PLG p.G420D (rs139071351) in 2160 MS patients, and 886 controls from Canada, identified 10 additional probands, two sporadic patients and one control with the variant. Segregation in families harboring the rs139071351 variant, identified p.G420D in 26 out of 30 family members diagnosed with MS, 14 unaffected parents, and 12 out of 30 family members not diagnosed with disease. Despite considerably reduced penetrance, linkage analysis supports cosegregation of PLG p.G420D and disease. Genotyping of PLG p.G420D in 14446 patients, and 8797 controls from Canada, France, Spain, Germany, Belgium, and Austria failed to identify significant association with disease (P = 0.117), despite an overall higher prevalence in patients (OR = 1.32; 95% CI = 0.93–1.87). To assess whether additional rare variants have an effect on MS risk, we sequenced PLG in 293 probands, and genotyped all rare variants in cases and controls. This analysis identified nine rare missense variants, and although three of them were exclusively observed in MS patients, segregation does not support pathogenicity. PLG is a plausible biological candidate for MS owing to its involvement in immune system response, blood-brain barrier permeability, and myelin degradation. Moreover, components of its activation cascade have been shown to present increased activity or expression in MS patients compared to controls; further studies are needed to clarify whether PLG is involved in MS susceptibility.
Background
Chronic neuropathic pain is often associated with anxiety, depressive symptoms, and cognitive impairment with relevant impact on patients` health related quality of life. To investigate the influence of a pro-inflammatory phenotype on affective and cognitive behavior under neuropathic pain conditions, we assessed mice deficient of the B7 homolog 1 (B7-H1), a major inhibitor of inflammatory response.
Results
Adult B7-H1 ko mice and wildtype littermates (WT) received a chronic constriction injury (CCI) of the sciatic nerve, and we assessed mechanical and thermal sensitivity at selected time points. Both genotypes developed mechanical (p < 0.001) and heat hypersensitivity (p < 0.01) 7, 14, and 20 days after surgery. We performed three tests for anxiety-like behavior: the light–dark box, the elevated plus maze, and the open field. As supported by the results of these tests for anxiety-like behavior, no relevant differences were found between genotypes after CCI. Depression-like behavior was assessed using the forced swim test. Also, CCI had no effect on depression like behavior. For cognitive behavior, we applied the Morris water maze for spatial learning and memory and the novel object recognition test for object recognition, long-, and short-term memory. Learning and memory did not differ in B7-H1 ko and WT mice after CCI.
Conclusions
Our study reveals that the impact of B7-H1 on affective-, depression-like- and learning-behavior, and memory performance might play a subordinate role in mice after nerve lesion.
Die Small Fiber Neuropathie (SFN) bildet eine Untergruppe der sensiblen Neuropathien, bei der die Aδ- und C-Fasern betroffen sind. Die Patienten berichten v.a. von brennenden Schmerzen und Dysästhesien, seltener auch von autonomen Funktionsstörungen. Bei fehlendem Goldstandard und normalen Nervenleitungsstudien ist die Diagnostik erschwert, da selbst nach Spezialuntersuchungen wie Hautstanzbiopsie und quantitativer sensorischer Testung (QST) viele Patienten trotz typischer Anamnese der Diagnosestellung entgehen. Wir rekrutierten 55 Patienten und 31 gesunde Kontrollen. Nach neurologischer Untersuchung und Ausschluss einer Polyneuropathie mittels Elektroneurographie wurden bei allen Studienteilnehmern Hautstanzbiopsien am Ober- und Unterschenkel zur Ermittlung der intraepidermalen Nervenfaserdichte (IENFD) entnommen sowie eine QST zur Funktionsprüfung der kleinen Nervenfasern durchgeführt. Die Studienteilnehmer wurden zudem mit cornealer confocaler Mikroskopie (CCM) und der Ableitung Schmerz-assoziierter evozierter Potentiale (PREP) untersucht. Zur autonomen Testung erfolgte die Messung der Schweißproduktion mittels quantitativem sudomotorischem Axonreflextest (QSART). Die neurologische Untersuchung zeigte in 55% der Patienten Hinweise auf eine Kleinfaserpathologie. Die distale IENFD war bei 62% der Patienten reduziert, die QST bei 22% der Patienten auffällig. Die PREP Latenzen waren in der Patientengruppe länger als bei den Kontrollen, die Amplituden niedriger. Bei der cornealen Innervation zeigte sich eine Reduktion der Nervenfaserdichte, Nervenfaserlänge und Nervenastdichte. Die in QSART gemessenen Parameter zeigten sich zu 86% unauffällig. Während nach klinischer Untersuchung, Hautbiopsie und QST in 53% der Fälle in 2 von 3 Untersuchungen eine Pathologie der kleinen Fasern festgestellt werden konnte, stieg die Rate bei zusätzlicher Anwendung von PREP und CCM auf 80% (ohne Berücksichtigung von QST). Zusammenfassend sollten die klinische Untersuchung und die Hautstanzbiopsie bei allen Patienten mit Verdacht auf SFN erfolgen. PREP und CCM sind unter den verfügbaren zusätzlichen Untersuchungen diagnostisch am wertvollsten. Wichtig ist allerdings, dass bei fehlendem Goldstandard eine SFN auch bei unauffälligen Tests nicht ausgeschlossen werden kann. Zusätzlich können die Mikroneurographie und die genetische Analyse wertvolle Hinweise auf eine Kleinfaserfunktionsstörung und deren Pathophysiologie geben.
Cervical dystonia (CD) is a movement disorder which affects daily living of many patients. In clinical practice, several unmet treatment needs remain open. This article focuses on the four main aspects of treatment. We describe existing and emerging treatment approaches for CD, including botulinum toxin injections, surgical therapy, management of non-motor symptoms, and rehabilitation strategies. The unsolved issues regarding each of these treatments are identified and discussed, and possible future approaches and research lines are proposed.
Anti-CNTN1 IgG3 induces acute conduction block and motor deficits in a passive transfer rat model
(2019)
Background:
Autoantibodies against the paranodal protein contactin-1 have recently been described in patients with severe acute-onset autoimmune neuropathies and mainly belong to the IgG4 subclass that does not activate complement. IgG3 anti-contactin-1 autoantibodies are rare, but have been detected during the acute onset of disease in some cases. There is evidence that anti-contactin-1 prevents adhesive interaction, and chronic exposure to anti-contactin-1 IgG4 leads to structural changes at the nodes accompanied by neuropathic symptoms. However, the pathomechanism of acute onset of disease and the pathogenic role of IgG3 anti-contactin-1 is largely unknown.
Methods:
In the present study, we aimed to model acute autoantibody exposure by intraneural injection of IgG of patients with anti-contacin-1 autoantibodies to Lewis rats. Patient IgG obtained during acute onset of disease (IgG3 predominant) and IgG from the chronic phase of disease (IgG4 predominant) were studied in comparison.
Results:
Conduction blocks were measured in rats injected with the “acute” IgG more often than after injection of “chronic” IgG (83.3% versus 35%) and proved to be reversible within a week after injection. Impaired nerve conduction was accompanied by motor deficits in rats after injection of the “acute” IgG but only minor structural changes of the nodes. Paranodal complement deposition was detected after injection of the “acute IgG”. We did not detect any inflammatory infiltrates, arguing against an inflammatory cascade as cause of damage to the nerve. We also did not observe dispersion of paranodal proteins or sodium channels to the juxtaparanodes as seen in patients after chronic exposure to anti-contactin-1.
Conclusions:
Our data suggest that anti-contactin-1 IgG3 induces an acute conduction block that is most probably mediated by autoantibody binding and subsequent complement deposition and may account for acute onset of disease in these patients. This supports the notion of anti-contactin-1-associated neuropathy as a paranodopathy with the nodes of Ranvier as the site of pathogenesis.
Ureaplasma species are common colonizers of the adult genitourinary tract and often considered as low-virulence commensals. Intraamniotic Ureaplasma infections, however, facilitate chorioamnionitis and preterm birth, and cases of Ureaplasma-induced neonatal sepsis, pneumonia, and meningitis raise a growing awareness of their clinical relevance. In vitro studies are scarce but demonstrate distinct Ureaplasma-driven impacts on immune mechanisms. The current study addressed cytokine and chemokine responses upon exposure of native or lipopolysaccharide (LPS) co-stimulated human brain microvascular endothelial cells (HBMEC) to Ureaplasma urealyticum or U. parvum, using qRT-PCR, RNA sequencing, multi-analyte immunoassay, and flow cytometry. Ureaplasma exposure in native HBMEC reduced monocyte chemoattractant protein (MCP)-3 mRNA expression (p < 0.01, vs. broth). In co-stimulated HBMEC, Ureaplasma spp. attenuated LPS-evoked mRNA responses for C-X-C chemokine ligand 5, MCP-1, and MCP-3 (p < 0.05, vs. LPS) and mitigated LPS-driven interleukin (IL)-1α protein secretion, as well as IL-8 mRNA and protein responses (p < 0.05). Furthermore, Ureaplasma isolates increased C-X-C chemokine receptor 4 mRNA levels in native and LPS co-stimulated HBMEC (p < 0.05). The presented results may imply immunomodulatory capacities of Ureaplasma spp. which may ultimately promote chronic colonization and long-term neuroinflammation.
Platelet collagen interactions at sites of vascular injuries predominantly involve glycoprotein VI (GPVI) and the integrin α2β1. Both proteins are primarily expressed on platelets and megakaryocytes whereas GPVI expression is also shown on endothelial and integrin α2β1 expression on epithelial cells. We recently showed that depletion of GPVI improves stroke outcome without increasing the risk of cerebral hemorrhage. Genetic variants associated with higher platelet surface integrin α2 (ITGA2) receptor levels have frequently been found to correlate with an increased risk of ischemic stroke in patients. However until now, no preclinical stroke study has addressed whether platelet integrin α2β1 contributes to the pathophysiology of ischemia/reperfusion (I/R) injury. Focal cerebral ischemia was induced in C57BL/6 and Itga2\(^{−/−}\) mice by a 60 min transient middle cerebral artery occlusion (tMCAO). Additionally, wild-type animals were pretreated with anti-GPVI antibody (JAQ1) or Fab fragments of a function blocking antibody against integrin α2β1 (LEN/B). In anti-GPVI treated animals, intravenous (IV) recombinant tissue plasminogen activator (rt-PA) treatment was applied immediately prior to reperfusion. Stroke outcome, including infarct size and neurological scoring was determined on day 1 after tMCAO. We demonstrate that targeting the integrin α2β1 (pharmacologic; genetic) did neither reduce stroke size nor improve functional outcome on day 1 after tMCAO. In contrast, depletion of platelet GPVI prior to stroke was safe and effective, even when combined with rt-PA treatment. Our results underscore that GPVI, but not ITGA2, is a promising and safe target in the setting of ischemic stroke.
Objective
To establish individually expandable primary fibroblast and keratinocyte cultures from 3‐mm skin punch biopsies for patient‐derived in vitro skin models to investigate of small fiber pathology.
Methods
We obtained 6‐mm skin punch biopsies from the calf of two patients with small fiber neuropathy (SFN) and two healthy controls. One half (3 mm) was used for diagnostic intraepidermal nerve fiber density (IENFD). From the second half, we isolated and cultured fibroblasts and keratinocytes. Cells were used to generate patient‐derived full‐thickness three‐dimensional (3D) skin models containing a dermal and epidermal component. Cells and skin models were characterized morphologically, immunocyto‐ and ‐histochemically (vimentin, cytokeratin (CK)‐10, CK 14, ki67, collagen1, and procollagen), and by electrical impedance.
Results
Distal IENFD was reduced in the SFN patients (2 fibers/mm each), while IENFD was normal in the controls (8 fibers/mm, 7 fibers/mm). Two‐dimensional (2D) cultured skin cells showed normal morphology, adequate viability, and proliferation, and expressed cell‐specific markers without relevant difference between SFN patient and healthy control. Using 2D cultured fibroblasts and keratinocytes, we obtained subject‐derived 3D skin models. Morphology of the 3D model was analogous to the respective skin biopsy specimens. Both, the dermal and the epidermal layer carried cell‐specific markers and showed a homogenous expression of extracellular matrix proteins.
Interpretation
Our protocol allows the generation of disease‐specific 2D and 3D skin models, which can be used to investigate the cross‐talk between skin cells and sensory neurons in small fiber pathology.
Introduction: Striatal dopamine depletion disrupts basal ganglia function and causes Parkinson’s disease (PD). The pathophysiology of the dopamine-dependent relationship between basal ganglia signaling and motor control, however, is not fully understood. We obtained simultaneous recordings of local field potentials (LFPs) from the subthalamic nucleus (STN) and electromyograms (EMGs) in patients with PD to investigate the impact of dopaminergic state and movement on long-range beta functional connectivity between basal ganglia and lower motor neurons.
Methods: Eight PD patients were investigated 3 months after implantation of a deep brain stimulation (DBS)-system capable of recording LFPs via chronically-implanted leads (Medtronic, ACTIVA PC+S®). We analyzed STN spectral power and its coherence with EMG in the context of two different movement paradigms (tonic wrist extension vs. alternating wrist extension and flexion) and the effect of levodopa (L-Dopa) intake using an unbiased data-driven approach to determine regions of interest (ROI).
Results: Two ROIs capturing prominent coherence within a grand average coherogram were identified. A trend of a dopamine effect was observed for the first ROI (50–150 ms after movement start) with higher STN-EMG coherence in medicated patients. Concerning the second ROI (300–500 ms after movement start), an interaction effect of L-Dopa medication and movement task was observed with higher coherence in the isometric contraction task compared to alternating movements in the medication ON state, a pattern which was reversed in L-Dopa OFF.
Discussion: L-Dopa medication may normalize functional connectivity between remote structures of the motor system with increased upper beta coherence reflecting a physiological restriction of the amount of information conveyed between remote structures. This may be necessary to maintain simple movements like isometric contraction. Our study adds dynamic properties to the complex interplay between STN spectral beta power and the nucleus’ functional connectivity to remote structures of the motor system as a function of movement and dopaminergic state. This may help to identify markers of neuronal activity relevant for more individualized programming of DBS therapy.
Deep brain stimulation of the mesencephalic locomotor region (MLR) improves the motor symptoms in Parkinson’s disease and experimental stroke by intervening in the motor cerebral network. Whether high-frequency stimulation (HFS) of the MLR is involved in non-motor processes, such as neuroprotection and inflammation in the area surrounding the photothrombotic lesion, has not been elucidated. This study evaluates whether MLR-HFS exerts an anti-apoptotic and anti-inflammatory effect on the border zone of cerebral photothrombotic stroke. Rats underwent photothrombotic stroke of the right sensorimotor cortex and the implantation of a microelectrode into the ipsilesional MLR. After intervention, either HFS or sham stimulation of the MLR was applied for 24 h. The infarct volumes were calculated from consecutive brain sections. Neuronal apoptosis was analyzed by TUNEL staining. Flow cytometry and immunohistochemistry determined the perilesional inflammatory response. Neuronal apoptosis was significantly reduced in the ischemic penumbra after MLR-HFS, whereas the infarct volumes did not differ between the groups. MLR-HFS significantly reduced the release of cytokines and chemokines within the ischemic penumbra. MLR-HFS is neuroprotective and it reduces pro-inflammatory mediators in the area that surrounds the photothrombotic stroke without changing the number of immune cells, which indicates that MLR-HFS enables the function of inflammatory cells to be altered on a molecular level.
Comprehensive investigation in motor neuron disease is vital not to miss a treatable differential diagnosis. Neuroborreliosis should be considered during an ALS work‐up. However, false‐positive CSF results do occur, and thus, results should be interpreted carefully in context of all clinical test results.
Chemokines (C-X-C) motif ligand (CXCL) 5 and 8 are overexpressed in patients with multiple sclerosis, where CXCL5 serum levels were shown to correlate with blood–brain barrier dysfunction as evidenced by gadolinium-enhanced magnetic resonance imaging. Here, we studied the potential role of CXCL5/CXCL8 receptor 2 (CXCR2) as a regulator of paraendothelial brain barrier function, using the well-characterized human cerebral microvascular endothelial cell line hCMEC/D3. Low basal CXCR2 mRNA and protein expression levels in hCMEC/D3 were found to strongly increase under inflammatory conditions. Correspondingly, immunohistochemistry of brain biopsies from two patients with active multiple sclerosis revealed upregulation of endothelial CXCR2 compared to healthy control tissue. Recombinant CXCL5 or CXCL8 rapidly and transiently activated Akt/protein kinase B in hCMEC/D3. This was followed by a redistribution of tight junction-associated protein zonula occludens-1 (ZO-1) and by the formation of actin stress fibers. Functionally, these morphological changes corresponded to a decrease of paracellular barrier function, as measured by a real-time electrical impedance-sensing system. Importantly, preincubation with the selective CXCR2 antagonist SB332235 partially prevented chemokine-induced disturbance of both tight junction morphology and function. We conclude that human brain endothelial CXCR2 may contribute to blood–brain barrier disturbance under inflammatory conditions with increased CXCL5 and CXCL8 expression, where CXCR2 may also represent a novel pharmacological target for blood–brain barrier stabilization.
Blood–brain barrier (BBB) disruption is a critical event after ischemic stroke, which results in edema formation and hemorrhagic transformation of infarcted tissue. BBB dysfunction following stroke is partly mediated by proinflammatory agents. We recently have shown that high frequency stimulation of the mesencephalic locomotor region (MLR-HFS) exerts an antiapoptotic and anti-inflammatory effect in the border zone of cerebral photothrombotic stroke in rats. Whether MLR-HFS also has an impact on BBB dysfunction in the early stage of stroke is unknown. In this study, rats were subjected to photothrombotic stroke of the sensorimotor cortex and implantation of a stimulating microelectrode into the ipsilesional MLR. Thereafter, either HFS or sham stimulation of the MLR was applied for 24 h. After scarifying the rats, BBB disruption was assessed by determining albumin extravasation and tight junction integrity (claudin 3, claudin 5, and occludin) using Western blot analyses and immunohistochemistry. In addition, by applying zymography, expression of pro-metalloproteinase-9 (pro-MMP-9) was analyzed. No differences were found regarding infarct size and BBB dysfunction between stimulated and unstimulated animals 24 h after induction of stroke. Our results indicate that MLR-HFS neither improves nor worsens the damaged BBB after stroke. Attenuating cytokines/chemokines in the perilesional area, as mediated by MLR-HFS, tend to play a less significant role in preventing the BBB integrity.
Symptomatic vs. asymptomatic 20–40% internal carotid artery stenosis: Does the plaque size matter?
(2019)
Background: Around 9–15% of ischemic strokes are related to internal carotid artery (ICA)-stenosis ≥50%. However, the extent to which ICA-stenosis <50% causes ischemic cerebrovascular events is uncertain. We examined the relation between plaque cross-sectional area and length and the risk of ischemic stroke or TIA among patients with ICA-stenosis of 20–40%.
Methods: We retrospectively identified patients admitted to the Department of Neurology, University Hospital of Würzburg, from January 2011 until September 2016 with ischemic stroke or TIA and concomitant ICA-stenosis of 20–40%, either symptomatic or asymptomatic. Plaque length and cross-sectional area were assessed on ultrasound scans.
Results: We identified 41 patients with ischemic stroke or TIA and ICA-stenosis of 20–40%; 14 symptomatic and 27 asymptomatic. The plaque cross-sectional area was significantly larger among symptomatic than asymptomatic ICA-stenosis; median values (IQR) were 0.45 (0.21–0.69) cm2 and 0.27 (0.21–0.38) cm2, p = 0.03, respectively. A plaque cross-sectional area ≥0.36 cm2 had a sensitivity of 71% and a specificity of 76% for symptomatic compared with asymptomatic ICA-stenosis. In a sex-adjusted multivariate logistic regression, a plaque cross-sectional area ≥0.36 cm2 and a plaque length ≥1.65 cm were associated with an OR (95% CI) of 5.54 (1.2–25.6), p = 0.028 and 1.78 (0.36–8.73), p = 0.48, respectively, for symptomatic ICA-stenosis.
Conclusion: Large plaques might increase the risk of ischemic stroke or TIA among patients with low-grade ICA-stenosis of 20–40%. Sufficiently powered prospective longitudinal cohort studies are needed to definitively test the stroke risk stratification value of carotid plaque length and cross-sectional area in the setting of current optimal medical treatment.
Background and purpose: Previous studies delivered contradicting results regarding the relation between the presence of an internal carotid artery stenosis (ICAS) and the occurence of white matter lesions (WMLs). We hypothesize that special characteristics related to the ICAS might be related to the WMLs. We examined the relation between the presence of bilateral ICAS, the degree and length of stenosis and ipsi-, contralateral as well as mean white matter lesion load (MWMLL).
Methods: In a retrospective cohort, patients with ischemic stroke or transient ischemic attack (TIA) as well as ipsi- and/or contralateral ICAS were identified. The length and degree of ICAS, as well as plaque morphology (hypoechoic, mixed or echogenic), were assessed on ultrasound scans and, if available, the length was also measured on magnetic resonance angiography (MRA) scans, and/or digital subtraction angiography (DSA). The WMLs were assessed in 4 areas separately, (periventricular and deep WMLs on each hemispherer), using the Fazekas scale. The MWMLL was calculated as the mean of these four values.
Results: 136 patients with 177 ICAS were identified. A significant correlation between age and MWMLL was observed (Spearman correlation coefficient, ρ = 0.41, p < 0.001). Before adjusting for other risk factors, a significantly positive relation was found between the presence of bilateral ICAS and MWMLL (p = 0.039). The length but not the degree of ICAS showed a very slight trend toward association with ipsilateral WMLs and with MWMLL. In an age-adjusted multivariate logistic regression with MWMLL ≥2 as the outcome measure, atrial fibrillation (OR 3.54, 95% CI 1.12–11.18, p = 0.03), female sex (OR 3.11, 95% CI 1.19–8.11, p = 0.02) and diabetes mellitus (OR 2.76, 95% CI 1.16–6.53, p = 0.02) were significantly related to WMLs, whereas the presence of bilateral stenosis showed a trend toward significance (OR 2.25, 95% CI 0.93–5.45, p = 0.074). No relation was found between plaque morphology and MWMLL, periventricular, or deep WMLs.
Conclusion: We have shown a slight correlation between the length of stenosis and the presence of WMLs which might be due to microembolisation originating from the carotid plaque. However, the presence of bilateral ICAS seems also to be related to WMLs which may point to common underlying vascular risk factors contributing to the occurrence of WML.
Background
Increasing attention is payed to the contribution of somatosensory processing in motor control. In particular, temporal somatosensory discrimination has been found to be altered differentially in common movement disorders. To date, there have only been speculations as to how impaired temporal discrimination and clinical motor signs may relate to each other. Prior to disentangling this relationship, potential confounders of temporal discrimination, in particular age and peripheral nerve conduction, should be assessed, and a quantifiable measure of proprioceptive performance should be established.
ObjectiveTo assess the influence of age and polyneuropathy (PNP) on somatosensory temporal discrimination threshold (STDT), temporal discrimination movement threshold (TDMT), and behavioral measures of proprioception of upper and lower limbs.
Methods
STDT and TDMT were assessed in 79 subjects (54 healthy, 25 with PNP; age 30–79 years). STDT was tested with surface electrodes over the thenar or dorsal foot region. TDMT was probed with needle electrodes in flexor carpi radialis (FCR) and tibialis anterior (TA) muscle. Goniometer-based devices were used to assess limb proprioception during (i) active pointing to LED markers, (ii) active movements in response to variable visual cues, and (iii) estimation of limb position following passive movements. Pointing (or estimation) error was taken as a measure of proprioceptive performance.
Results
In healthy subjects, higher age was associated with higher STDT and TDMT at upper and lower extremities, while age did not correlate with proprioceptive performance. Patients with PNP showed higher STDT and TDMT values and decreased proprioceptive performance in active pointing tasks compared to matched healthy subjects. As an additional finding, there was a significant correlation between performance in active pointing tasks and temporal discrimination thresholds.
Conclusion
Given their notable impact on measures of temporal discrimination, age and peripheral nerve conduction need to be accounted for if STDT and TDMT are applied in patients with movement disorders. As a side observation, the correlation between measures of proprioception and temporal discrimination may prompt further studies on the presumptive link between these two domains.
Background and Purpose: Internal carotid artery stenosis (ICAS)≥70% is a leading cause of ischemic cerebrovascular events (ICVEs). However, a considerable percentage of stroke survivors with symptomatic ICAS (sICAS) have <70% stenosis with a vulnerable plaque. Whether the length of ICAS is associated with high risk of ICVEs is poorly investigated. Our main aim was to investigate the relation between the length of ICAS and the development of ICVEs.
Methods: In a retrospective cross-sectional study, we identified 95 arteries with sICAS and another 64 with asymptomatic internal carotid artery stenosis (aICAS) among 121 patients with ICVEs. The degree and length of ICAS as well as plaque echolucency were assessed on ultrasound scans.
Results: A statistically significant inverse correlation between the ultrasound-measured length and degree of ICAS was detected for sICAS≥70% (Spearman correlation coefficient ρ = –0.57, p < 0.001, n = 51) but neither for sICAS<70% (ρ = 0.15, p = 0.45, n = 27) nor for aICAS (ρ = 0.07, p = 0.64, n = 54). The median (IQR) length for sICAS<70% and ≥70% was 17 (15–20) and 15 (12–19) mm (p = 0.06), respectively, while that for sICAS<90% and sICAS 90% was 18 (15–21) and 13 (10–16) mm, respectively (p < 0.001). Among patients with ICAS <70%, a cut-off length of ≥16 mm was found for sICAS rather than aICAS with a sensitivity and specificity of 74.1% and 51.1%, respectively. Irrespective of the stenotic degree, plaques of the sICAS compared to aICAS were significantly more often echolucent (43.2 vs. 24.6%, p = 0.02).
Conclusion: We found a statistically insignificant tendency for the ultrasound-measured length of sICAS<70% to be longer than that of sICAS≥70%. Moreover, the ultrasound-measured length of sICAS<90% was significantly longer than that of sICAS 90%. Among patients with sICAS≥70%, the degree and length of stenosis were inversely correlated. Larger studies are needed before a clinical implication can be drawn from these results.
Background: Cervical dystonia is a movement disorder causing abnormal postures and movements of the head. While the exact pathophysiology of cervical dystonia has not yet been fully elucidated, a growing body of evidence points to the cerebellum as an important node.
Methods: Here, we examined the impact of cerebellar interference by transcranial magnetic stimulation on finger-tapping related brain activation and neurophysiological measures of cortical excitability and inhibition in cervical dystonia and controls. Bilateral continuous theta-burst stimulation was used to modulate cerebellar cortical excitability in 16 patients and matched healthy controls. In a functional magnetic resonance imaging arm, data were acquired during simple finger tapping before and after cerebellar stimulation. In a neurophysiological arm, assessment comprised motor-evoked potentials amplitude and cortical silent period duration. Theta-burst stimulation over the dorsal premotor cortex and sham stimulation (neurophysiological arm only) served as control conditions.
Results: At baseline, finger tapping was associated with increased activation in the ipsilateral cerebellum in patients compared to controls. Following cerebellar theta-burst stimulation, this pattern was even more pronounced, along with an additional movement-related activation in the contralateral somatosensory region and angular gyrus. Baseline motor-evoked potential amplitudes were higher and cortical silent period duration shorter in patients compared to controls. After cerebellar theta-burst stimulation, cortical silent period duration increased significantly in dystonia patients.
Conclusion: We conclude that in cervical dystonia, finger movements—though clinically non-dystonic—are associated with increased activation of the lateral cerebellum, possibly pointing to general motor disorganization, which remains subclinical in most body regions. Enhancement of this activation together with an increase of silent period duration by cerebellar continuous theta-burst stimulation may indicate predominant disinhibitory effects on Purkinje cells, eventually resulting in an inhibition of cerebello-thalamocortical circuits.
Parkinson Patienten sind im Gegensatz zu gesunden Probanden in der kognitiven Verarbeitung zeitlicher Parameter, im Sinne einer Diskriminierungsfähigkeit für zeitliche Fehler innerhalb der Musikwahrnehmung beeinträchtigt. Dies betrifft lediglich die Zeiterkennung in höheren Intervallbereichen (> 600ms) und ist am ehesten durch Fluktuationen der Aufmerksamkeit, des Gedächtnisses, aber auch im Vergleich zu anderen Studien durch methodische Ansätze zu erklären. Durch die Koppelung des Audiostimulus an klare Rhythmusstrukturen weist diese Studie jedoch darauf hin, dass Überschneidungen zu anderen neuronalen Netzwerken existieren, die zur Kompensationsstrategie rekrutiert und nutzbar gemacht werden können. Dazu gehören etwa die Verarbeitung zeitlicher (Cerebellum) und musikperzeptiver Leistungen, wie etwa die Verarbeitung musikalischer Syntax (BA 6, 22, 44). Etwaige Wahrnehmungsdefizite können durch Mechanismen musiksyntaktischer Verarbeitung kompensiert werden, da zeitliche und syntaktische Strukturen in der Musik auf ihre Kongruenz hin abgeglichen und somit multineuronal mediiert werden (Paradigma der Zeit-Syntax-Kongruenz in der Musikwahrnehmung). Weiterhin sind vermutlich top-down-bottom-up-Prozesse als multimodale Interaktionen an diesem Kompensationsmechanismus beteiligt. Außerdem ist festzuhalten, dass das Krankheitsstadium nicht zwangsläufig mit einem stärkeren Wahrnehmungsdefizit für zeitliche Strukturen einhergehen muss, obwohl – wenn auch noch tolerabel – mit Progression der Erkrankung dieses Kompensationsmodell über Prinzipien der Gestaltwahrnehmung zusammenbricht und es hier zu schlechteren perzeptiven Leistungen kommen kann.
Die Ergebnisse der OFF-Testungen und jener unter DBS-Therapie lassen weiterhin aufgrund der kleinen Stichprobe keine klare Aussage zu und machen weitere Untersuchungen notwendig. Das physiologische Alter korreliert außerdem mit der sensorischen Leistung, die allerdings starken, individuellen Unterschieden ausgesetzt ist und von multifaktoriellen Voraussetzungen abhängt. Auch zeigt die Studie, dass Menschen mit einem hohen Musikverständnis und einer musikalischen Ausbildung ein feineres Diskriminierungsvermögen in der zeitlichen Verarbeitung besitzen, welches v.a. im zeitlich niedrigen Intervallbereich (< 500ms) evident wird.
Der essentielle Tremor (ET) ist eine der häufigsten Bewegungsstörungen, welcher lange Zeit als rein motorische Störung angesehen wurde. Aufgrund zunehmender Belege über nicht-motorisch Begleitsymptome wandelte sich dieses Bild jedoch in den letzten Jahren zunehmend. In der vorliegenden Arbeit untersuchten wir 113 Probanden aus der Allgemeinbevölkerung mit klinisch definitiven oder wahrscheinlichen ET anhand einer breiten Batterie neuro-psychologischer Testverfahren. Es gelang hierbei signifikante Unterschiede im Vergleich zu gesunden Eichstichproben im Hinblick auf neuro-psychologische Charakteristika, wie Apathie, Ängstlichkeit und exekutive Dysfunktion, sowie deren negativen Einfluss auf die Lebensqualität der Probanden darzustellen. Bisher werden im klinischen Alltag nicht-motorische Begleitphänomene beim ET nicht regelhaft erfasst; aufgrund unserer Ergebnisse und der Relevanz vor allem im Hinblick auf die Lebensqualität des Einzelnen halten wir jedoch die Erfassung und gegebenenfalls Behandlung dieser Symptome für ebenso relevant.
Die Studienergebnisse stützen das Konzept, dass das periphere Nervensystem zu Schmerzen beim Fibromyalgie-Syndrom (FMS) beiträgt. An der Neurologischen Universitätsklinik Würzburg wurden 53 FMS Patientinnen und 35 gesunde Kontrollen rekrutiert, ausführlich anamnestiziert inklusive spezieller Schmerzfragebögen, neurologisch und mittels spezieller Tests auf eine Störung der kleinkalibrigen A-delta- und C-Nervenfasern untersucht. Hierzu gehörte eine quantitative sensorische Testung mit Pleasant touch Untersuchung und die schmerz-assoziierten elektrisch-evoziierten Potentiale für die Kleinfaserfunktion und die corneale confocale Mikroskopie, sowie die Analyse von Hautstanbiopsien für die Kleinfasermorphologie.
Im Unterschied zu gesunden Kontrollen wiesen die FMS Patientinnen eine Reduktion, als auch eine Funktionsänderung der kleinkalibrigen Nervenfasern auf. Des Weiteren konnten wir aus der heterogenen Patientenpopulation anhand von unterschiedlichen Nervenfaserdichten der Haut eine Subgruppe mit generalisierter Reduktion der Hautinnervation identifizieren, die besonders schwer betroffen ist.
Diese Subgruppenanalysen können künftig von großer Bedeutung für die
Therapiewahl sein.
Background and Purpose: Internal carotid artery stenosis ≥70% is a leading cause of ischemic cerebrovascular events. However, a considerable percentage of stroke survivors with symptomatic internal carotid artery stenosis have <70% stenosis with a vulnerable plaque. Whether the length of internal carotid artery stenosis is associated with high risk of ischemic cerebrovascular events or with white matter lesions is poorly investigated. Our main aim was to investigate the relation between the length of internal carotid artery stenosis and the development of ischemic cerebrovascular events as well as ipsi-, contralateral as well as mean white matter lesion load.
Methods: In a retrospective cross-sectional study, 168 patients with 208 internal carotid artery stenosis were identified. The degree and length of internal carotid artery stenosis as well as plaque morphology (hypoechoic, mixed or echogenic) were assessed on ultrasound scans. The white matter lesions were assessed in 4 areas separately, (periventricular and deep white matter lesions on each hemisphere), using the Fazekas scale. The mean white matter lesions load was calculated as the mean of these four values.
Results: A statistically significant inverse correlation between the ultrasound-measured length and degree of internal carotid artery stenosis was detected for symptomatic internal carotid artery stenosis ≥70% (Spearman correlation coefficient ρ = –0.57, p < 0.001, n = 51) but neither for symptomatic internal carotid artery stenosis <70% (ρ = 0.15, p = 0.45, n = 27) nor for asymptomatic internal carotid artery stenosis (ρ = 0.07, p = 0.64, n = 54). The median (IQR) length for symptomatic internal carotid artery stenosis <70% and ≥70% was 17 (15–20) and 15 (12–19) mm (p = 0.06), respectively, while that for symptomatic internal carotid artery stenosis <90% and symptomatic internal carotid artery stenosis 90% was 18 (15–21) and 13 (10–16) mm, respectively (p < 0.001). Among patients with internal carotid artery stenosis <70%, a cut-off length of ≥16 mm was found for symptomatic internal carotid artery stenosis rather than asymptomatic internal carotid artery stenosis with a sensitivity and specificity of 74.1% and 51.1%, respectively. Irrespective of the stenotic degree, plaques of the symptomatic internal carotid artery stenosis compared to asymptomatic internal carotid artery stenosis were significantly more often echolucent (43.2 vs. 24.6%, p = 0.02). The length but not the degree of internal carotid artery stenosis showed a very slight trend toward association with ipsilateral white matter lesions and with mean white matter lesions load.
Conclusion: We found a statistically insignificant tendency for the ultrasound-measured length of symptomatic internal carotid artery stenosis <70% to be longer than that of symptomatic internal carotid artery stenosis ≥70%. Moreover, the ultrasound-measured length of symptomatic internal carotid artery stenosis <90% was significantly longer than that of symptomatic internal carotid artery stenosis 90%. Among patients with symptomatic internal carotid artery stenosis ≥70%, the degree and length of stenosis were inversely correlated. Furthermore, we have shown that a slight correlation exists between the length of stenosis and the presence of ipsilateral white matter lesions which might be due to microembolisation originating from the carotid plaque. Larger studies are needed before a clinical implication can be drawn from these results.
In addition to bradykinesia and tremor, patients with Parkinson’s disease (PD) are known to exhibit non-motor symptoms such as apathy and hypomimia but also impulsivity in response to dopaminergic replacement therapy. Moreover, a plethora of studies observe differences in electrocortical and autonomic responses to both visual and acoustic affective stimuli in PD subjects compared to healthy controls. This suggests that the basal ganglia (BG), as well as the hyperdirect pathway and BG thalamocortical circuits, are involved in affective processing. Recent studies have shown valence and dopamine-dependent changes in synchronization in the subthalamic nucleus (STN) in PD patients during affective tasks. This thesis investigates the role of dopamine, valence, and laterality in STN electrophysiology by analyzing event-related potentials (ERP), synchronization, and inter-hemispheric STN connectivity. STN recordings were obtained from PD patients with chronically implanted electrodes for deep brain stimulation during a passive affective picture presentation task. The STN exhibited valence-dependent ERP latencies and lateralized ‘high beta’ (28–40 Hz) event-related desynchronization. This thesis also examines the role of dopamine, valence, and laterality on STN functional connectivity with the anterior cingulate cortex (ACC) and the amygdala. The activity of these limbic structures was reconstructed using simultaneously recorded electroencephalographic signals. While the STN was found to establish early coupling with both structures, STN-ACC coupling in the ‘alpha’ range (7–11 Hz) and uncoupling in the ‘low beta’ range (14–21 Hz) were lateralized. Lateralization was also observed at the level of synchrony in both reconstructed sources and for ACC ERP amplitude, whereas dopamine modulated ERP latency in the amygdala. These results may deepen our current understanding of the STN as a limbic node within larger emotional-motor networks in the brain.
Niemann–Pick type C disease (NP-C) presents with heterogeneous neurological and psychiatric symptoms. Adult onset is rare and possibly underdiagnosed due to frequent lack of specific and obvious key symptoms. For both early and adolescent/adult onset, the available data from studies and case reports describe a positive effect of Miglustat (symptom relief or stabilization). However, due to the low frequency of NP-C, experience with this therapy is still limited. We describe two adult-onset cases of NP-C. In both cases, vertical supranuclear gaze palsy was not recognized at symptom onset. Correct diagnosis was delayed from onset of symptoms by more than 10 years. The video demonstrates the broad spectrum of symptoms in later stages of the disease. Compared with published data, the treatment outcome observed in our cases after delayed initiation of Miglustat therapy was disappointing, with continuing disease progression in both cases. Thus, early treatment initiation could be necessary to achieve a good symptomatic effect. Hence, early biochemical testing for NP-C should be considered in patients suffering from atypical neurological/neuropsychological and psychiatric symptoms, even in cases of uncertainty.
Affective and cognitive behavior in the alpha-galactosidase A deficient mouse model of Fabry disease
(2017)
Fabry disease is an X-linked inherited lysosomal storage disorder with intracellular accumulation of globotriaosylceramide (Gb3) due to α-galactosidase A (α-Gal A) deficiency. Fabry patients frequently report of anxiety, depression, and impaired cognitive function. We characterized affective and cognitive phenotype of male mice with α-Gal A deficiency (Fabry KO) and compared results with those of age-matched male wildtype (WT) littermates. Young (3 months) and old (≥ 18 months) mice were tested in the naïve state and after i.pl. injection of complete Freund`s adjuvant (CFA) as an inflammatory pain model. We used the elevated plus maze (EPM), the light-dark box (LDB) and the open field test (OF) to investigate anxiety-like behavior. The forced swim test (FST) and Morris water maze (MWM) were applied to assess depressive-like and learning behavior. The EPM test revealed no intergroup difference for anxiety-like behavior in naïve young and old Fabry KO mice compared to WT littermates, except for longer time spent in open arms of the EPM for young WT mice compared to young Fabry KO mice (p<0.05). After CFA injection, young Fabry KO mice showed increased anxiety-like behavior compared to young WT littermates (p<0.05) and naïve young Fabry KO mice (p<0.05) in the EPM as reflected by shorter time spent in EPM open arms. There were no relevant differences in the LDB and the OF test, except for longer time spent in the center zone of the OF by young WT mice compared to young Fabry KO mice (p<0.05). Complementary to this, depression-like and learning behavior were not different between genotypes and age-groups, except for the expectedly lower memory performance in older age-groups compared to young mice. Our results indicate that genetic influences on affective and cognitive symptoms in FD may be of subordinate relevance, drawing attention to potential influences of environmental and epigenetic factors.
MicroRNAs (miRNAs) are increasingly recognized as regulators of immune and neuronal gene expression and are potential master switches in neuropathic pain pathophysiology. miR-21 is a promising candidate that may link the immune and the pain system. To investigate the pathophysiological role of miR-21 in neuropathic pain, we assessed mice deficient of B7 homolog 1 (B7-H1), a major inhibitor of inflammatory responses. In previous studies, an upregulation of miR-21 had been shown in mouse lymphocytes. Young (8 weeks), middle-aged (6 months), and old (12 months) B7-H1 ko mice and wildtype littermates (WT) received a spared nerve injury (SNI). We assessed thermal withdrawal latencies and mechanical withdrawal thresholds. Further, we performed tests for anxiety-like and cognitive behavior. Quantitative real time PCR was used to determine miR-21 relative expression in peripheral nerves, and dorsal root ganglia (DRG) at distinct time points after SNI. We found mechanical hyposensitivity with increasing age of naïve B7-H1 ko mice. Young and middle-aged B7-H1 ko mice were more sensitive to mechanical stimuli compared to WT mice (young: p < 0.01, middle-aged: p < 0.05). Both genotypes developed mechanical and heat hypersensitivity (p < 0.05) after SNI, without intergroup differences. No relevant differences were found after SNI in three tests for anxiety like behavior in B7-H1 ko and WT mice. Also, SNI had no effect on cognition. B7-H1 ko and WT mice showed a higher miR-21 expression (p < 0.05) and invasion of macrophages and T cells in the injured nerve 7 days after SNI without intergroup differences. Our study reveals that increased miR-21 expression in peripheral nerves after SNI is associated with reduced mechanical and heat withdrawal thresholds. These results point to a role of miR-21 in the pathophysiology of neuropathic pain, while affective behavior and cognition seem to be spared. Contrary to expectations, B7-H1 ko mice did not show higher miR-21 expression than WT mice, thus, a B7-H1 knockout may be of limited relevance for the study of miR-21 related pain.
Background
While hypercholesterolemia plays a causative role for the development of ischemic stroke in large vessels, its significance for cerebral small vessel disease (CSVD) remains unclear. We thus aimed to understand the detailed relationship between hypercholesterolemia and CSVD using the well described Ldlr\(^{−/-}\) mouse model.
Methods
We used Ldlr\(^{−/-}\) mice (n = 16) and wild-type (WT) mice (n = 15) at the age of 6 and 12 months. Ldlr\(^{−/-}\) mice develop high plasma cholesterol levels following a high fat diet. We analyzed cerebral capillaries and arterioles for intravascular erythrocyte accumulations, thrombotic vessel occlusions, blood-brain barrier (BBB) dysfunction and microbleeds.
Results
We found a significant increase in the number of erythrocyte stases in 6 months old Ldlr\(^{−/-}\) mice compared to all other groups (P < 0.05). Ldlr\(^{−/-}\) animals aged 12 months showed the highest number of thrombotic occlusions while in WT animals hardly any occlusions could be observed (P < 0.001). Compared to WT mice, Ldlr\(^{−/-}\) mice did not display significant gray matter BBB breakdown. Microhemorrhages were observed in one Ldlr\(^{−/-}\) mouse that was 6 months old. Results did not differ when considering subcortical and cortical regions.
Conclusions
In Ldlr\(^{−/-}\) mice, hypercholesterolemia is related to a thrombotic CSVD phenotype, which is different from hypertension-related CSVD that associates with a hemorrhagic CSVD phenotype. Our data demonstrate a relationship between hypercholesterolemia and the development of CSVD. Ldlr\(^{−/-}\) mice appear to be an adequate animal model for research into CSVD.
Objective: To investigate the association between levodopa‐induced dyskinesias and striatal cholinergic activity in patients with Parkinson's disease.
Methods: This study included 13 Parkinson's disease patients with peak‐of‐dose levodopa‐induced dyskinesias, 12 nondyskinetic patients, and 12 healthy controls. Participants underwent 5‐[\(^{123}\)I]iodo‐3‐[2(S)‐2‐azetidinylmethoxy]pyridine single‐photon emission computed tomography, a marker of nicotinic acetylcholine receptors, [\(^{123}\)I]N‐ω‐fluoropropyl‐2β‐carbomethoxy‐3β‐(4‐iodophenyl)nortropane single‐photon emission computed tomography, to measure dopamine reuptake transporter density and 2‐[\(^{18}\)F]fluoro‐2‐deoxyglucose positron emission tomography to assess regional cerebral metabolic activity. Striatal binding potentials, uptake values at basal ganglia structures, and correlations with clinical variables were analyzed.
Results: Density of nicotinic acetylcholine receptors in the caudate nucleus of dyskinetic subjects was similar to that of healthy controls and significantly higher to that of nondyskinetic patients, in particular, contralaterally to the clinically most affected side.
Interpretation: Our findings support the hypothesis that the expression of dyskinesia may be related to cholinergic neuronal excitability in a dopaminergic‐depleted striatum. Cholinergic signaling would play a role in maintaining striatal dopaminergic responsiveness, possibly defining disease phenotype and progression.
The aim of the study was to record movement-related single unit activity (SUA) in the human subthalamic nucleus (STN) during a standardized motor task of the upper limb. We performed microrecordings from the motor region of the human STN and registered kinematic data in 12 patients with Parkinson’s disease (PD) undergoing deep brain stimulation surgery (seven women, mean age 62.0 ± 4.7 years) while they intraoperatively performed visually cued reach-to-grasp movements using a grip device. SUA was analyzed offline in relation to different aspects of the movement (attention, start of the movement, movement velocity, button press) in terms of firing frequency, firing pattern, and oscillation. During the reach-to-grasp movement, 75/114 isolated subthalamic neurons exhibited movement-related activity changes. The largest proportion of single units showed modulation of firing frequency during several phases of the reach and grasp (polymodal neurons, 45/114), particularly an increase of firing rate during the reaching phase of the movement, which often correlated with movement velocity. The firing pattern (bursting, irregular, or tonic) remained unchanged during movement compared to rest. Oscillatory single unit firing activity (predominantly in the theta and beta frequency) decreased with movement onset, irrespective of oscillation frequency. This study shows for the first time specific, task-related, SUA changes during the reach-to-grasp movement in humans.
Autophagy-mediated degradation of synaptic components maintains synaptic homeostasis but also constitutes a mechanism of neurodegeneration. It is unclear how autophagy of synaptic vesicles and components of presynaptic active zones is regulated. Here, we show that Pleckstrin homology containing family member 5 (Plekhg5) modulates autophagy of synaptic vesicles in axon terminals of motoneurons via its function as a guanine exchange factor for Rab26, a small GTPase that specifically directs synaptic vesicles to preautophagosomal structures. Plekhg5 gene inactivation in mice results in a late-onset motoneuron disease, characterized by degeneration of axon terminals. Plekhg5-depleted cultured motoneurons show defective axon growth and impaired autophagy of synaptic vesicles, which can be rescued by constitutively active Rab26. These findings define a mechanism for regulating autophagy in neurons that specifically targets synaptic vesicles. Disruption of this mechanism may contribute to the pathophysiology of several forms of motoneuron disease.
Juvenile neuronal ceroid lipofuscinosis (JNCL or Batten disease) caused by mutations in the CLN3 gene is the most prevalent inherited neurodegenerative disease in childhood resulting in widespread central nervous system dysfunction and premature death. The consequences of CLN3 mutation on the progression of the disease, on neuronal transmission, and on central nervous network dysfunction are poorly understood. We used Cln3 knockout (Cln3\(^{Δex1-6}\)) mice and found increased anxiety-related behavior and impaired aversive learning as well as markedly affected motor function including disordered coordination. Patch-clamp and loose-patch recordings revealed severely affected inhibitory and excitatory synaptic transmission in the amygdala, hippocampus, and cerebellar networks. Changes in presynaptic release properties may result from dysfunction of CLN3 protein. Furthermore, loss of calbindin, neuropeptide Y, parvalbumin, and GAD65-positive interneurons in central networks collectively support the hypothesis that degeneration of GABAergic interneurons may be the cause of supraspinal GABAergic disinhibition.
This paper provides an overview of current progress in the technological advances and the use of deep brain stimulation (DBS) to treat neurological and neuropsychiatric disorders, as presented by participants of the Fourth Annual DBS Think Tank, which was convened in March 2016 in conjunction with the Center for Movement Disorders and Neurorestoration at the University of Florida, Gainesveille FL, USA. The Think Tank discussions first focused on policy and advocacy in DBS research and clinical practice, formation of registries, and issues involving the use of DBS in the treatment of Tourette Syndrome. Next, advances in the use of neuroimaging and electrochemical markers to enhance DBS specificity were addressed. Updates on ongoing use and developments of DBS for the treatment of Parkinson's disease, essential tremor, Alzheimer's disease, depression, post-traumatic stress disorder, obesity, addiction were presented, and progress toward innovation(s) in closed-loop applications were discussed. Each section of these proceedings provides updates and highlights of new information as presented at this year's international Think Tank, with a view toward current and near future advancement of the field.
Background and Purpose
Ischemic stroke provokes severe brain damage and remains a predominant disease in industrialized countries. The coagulation factor XII (FXII)-driven contact activation system plays a central, but not yet fully defined pathogenic role in stroke development. Here, we investigated the efficacy of the FXIIa inhibitor rHA-Infestin-4 in a rat model of ischemic stroke using both a prophylactic and a therapeutic approach.
Methods
For prophylactic treatment, animals were treated intravenously with 100 mg/kg rHA-Infestin-4 or an equal volume of saline 15 min prior to transient middle cerebral artery occlusion (tMCAO) of 90 min. For therapeutic treatment, 100 mg/kg rHA-Infestin-4, or an equal volume of saline, was administered directly after the start of reperfusion. At 24 h after tMCAO, rats were tested for neurological deficits and blood was drawn for coagulation assays. Finally, brains were removed and analyzed for infarct area and edema formation.
Results
Within prophylactic rHA-Infestin-4 treatment, infarct areas and brain edema formation were reduced accompanied by better neurological scores and survival compared to controls. Following therapeutic treatment, neurological outcome and survival were still improved although overall effects were less pronounced compared to prophylaxis.
Conclusions
With regard to the central role of the FXII-driven contact activation system in ischemic stroke, inhibition of FXIIa may represent a new and promising treatment approach to prevent cerebral ischemia/reperfusion injury.
Background
The aim of the present study was to assess manifestations of and applied treatment concepts for females with Fabry disease (FD) according to the current European Fabry Guidelines.
Methods
Between 10/2008 and 12/2014, data from the most recent visit of 261 adult female FD patients from six German Fabry centers were retrospectively analyzed. Clinical presentation and laboratory data, including plasma lyso-Gb3 levels were assessed.
Results
Fifty-five percent of females were on enzyme replacement therapy (ERT), according to recent European FD guidelines. Thirty-three percent of females were untreated although criteria for ERT initiation were fulfilled. In general, the presence of left ventricular hypertrophy (LVH) seemed to impact more on ERT initiation than impaired renal function. In ERT-naïve females RAAS blockers were more often prescribed if LVH was present rather than albuminuria. Affected females with missense mutations showed a similar disease burden compared to females with nonsense mutations. Elevated plasma lyso-Gb3 levels in ERT-naïve females seem to be a marker of disease burden, since patients showed comparable incidences of organ manifestations even if they were ~8 years younger than females with normal lyso-Gb3 levels.
Conclusion
The treatment of the majority of females with FD in Germany is in line with the current European FD guidelines. However, a relevant number of females remain untreated despite organ involvement, necessitating a careful reevaluation of these females.
Aberrant immune responses represent the underlying cause of central nervous system (CNS) autoimmunity, including multiple sclerosis (MS). Recent evidence implicated the crosstalk between coagulation and immunity in CNS autoimmunity. Here we identify coagulation factor XII (FXII), the initiator of the intrinsic coagulation cascade and the kallikrein–kinin system, as a specific immune cell modulator. High levels of FXII activity are present in the plasma of MS patients during relapse. Deficiency or pharmacologic blockade of FXII renders mice less susceptible to experimental autoimmune encephalomyelitis (a model of MS) and is accompanied by reduced numbers of interleukin-17A-producing T cells. Immune activation by FXII is mediated by dendritic cells in a CD87-dependent manner and involves alterations in intracellular cyclic AMP formation. Our study demonstrates that a member of the plasmatic coagulation cascade is a key mediator of autoimmunity. FXII inhibition may provide a strategy to combat MS and other immune-related disorders.
LTD-artige zentralmotorische Plastizität im Schubereignis bei Patienten mit Multipler Sklerose
(2019)
Die Multiple Sklerose ist eine chronisch entzündliche Erkrankung des zentralen Nervensystems. Durch ein komplexes Zusammenspiel von Genetik, Autoimmunvorgängen und proinflammatorischen Prozessen kommt es zur Demyelinisierung sowie zu axonalen Schäden und kortikalen Läsionen (Calabrese et al., 2010; Ciccarelli et al., 2014; International Multiple Sclerosis Genetics et al., 2011; Leray et al., 2015). In den Industrieländern ist diese Erkrankung eine der häufigsten Ursachen für langfristige Behinderung bereits im frühen Lebensalter (Flores-Alvarado, Gabriel-
46 Ortiz, Pacheco-Mois, & Bitzer-Quintero, 2015). Die Diskrepanz allerdings zwischen klinischer Symptomatik und den Befunden der Bildgebung (Barkhof, 2002) gibt Anlass dafür, Adaptionsmöglichkeiten detailliert zu erforschen. Vorgänge der Neuroplastizität mit LTP und LTD als Basismechanismen erscheinen dabei zunehmend Beachtung zu finden (Dayan & Cohen, 2011; Zeller et al., 2011). Welche Rolle diese Prozesse allerdings im akuten Schub, während der häufig stark ausgeprägten Symptomatik, insbesondere aber auch während ihrer Rückbildung spielen, bleibt bisher weitgehend ungeklärt. Eine Untersuchung zu stimulationsinduzierter LTP-artiger Plastizität im Schub deutete auf einen möglichen Zusammenhang zwischen Ausmaß der Symptomrückbildung und PAS25-induziertem LTP-Effekt hin (Mori et al., 2014).
In der vorliegenden Arbeit wurde komplementär hierzu die stimulationsinduzierte LTD-artige Plastizität bei 19 MS- bzw. CIS-Patienten während des steroidbehandelten akuten Schubes untersucht. Als Kontrollgruppe wurden alters- und geschlechtsgematchte gesunde Probanden untersucht. Die Messungen wurden mithilfe eines Protokolls der assoziativen Paarstimulation durchgeführt. Paarstimulation wird die Kombination aus der peripher elektrischen und transkraniell magnetischen Stimulation genannt. Das in unserer Studie verwendete Protokoll sieht ein Interstimulusintervall von 10ms vor (PAS10). Der Effekt der Paarstimulation wird durch Messungen der Exzitabilität des motorischen Kortex mittels motorisch evozierter Potenziale (MEP) jeweils vor und nach der Intervention gemessen. Bei den MS-Patienten wurden diese Daten zum Zeitpunkt des Schubes (t1) und 12 Wochen danach (t2) erhoben; die gesunden Kontrollen wurden nur einmal gemessen. Daneben wurde bei den Schubpatienten zur Quantifizierung der klinischen Symptomatik jeweils zum ersten und zum zweiten Zeitpunkt der MSFC erhoben.
Die MS-Patienten zeigten im akuten MS-Schub im Gegensatz zu der Kontrollgruppe aus Gesunden keinen LTD-artigen, sondern einen inversen, sprich einen signifikant LTP-artigen Effekt; dieser war zum Zeitpunkt t2 nicht mehr zu erkennen. Der Unterschied zwischen den PAS10-Effekten der MS- und der Kontrollgruppe war ebenfalls signifikant. Der Vergleich der MSFC-Werte der MS-Gruppe zwischen t1 und t2 erbrachte eine signifikante klinische Besserung. Eine signifikante Korrelation zwischen
47
den neurophysiologischen und klinischen Daten bzw. ihren Veränderungen zwischen t1 und t2 zeigte sich nicht.
Diese Ergebnisse untermauern und erweitern bereits bestehende Hinweise, dass während der akuten Inflammationsprozesse des MS-Schubes veränderte Voraussetzungen für die Induzierbarkeit von Plastizität gegeben sind. Nicht nur, wie bereits gezeigt, die LTP-artige, sondern offenbar auch die LTD-artige assoziative Plastizität zeigt sich stark von den humoralen Veränderungen im steroidbehandelten Schub beeinflusst. Weitere Studien in stärker vorselektierten Patientengruppen sollten der Frage nachgehen, inwieweit LTD-artige Plastizität sich in verschiedenen Subgruppen mit unterschiedlichen Schubsymptomen unterscheidet. Des Weiteren ist der Frage weiter nachzugehen, ob LTD-artige Plastizität funktional zur Adaption im Rahmen des Schubereignisses notwendig ist und inwieweit deren Unterdrückung bzw. Ersatz durch Langzeitpotenzierung potenziell einer Adaption im Wege steht. Sollten potenzielle Folgestudien bestätigen, dass LTD- und LTP-artige Plastizität im Schub möglicherweise häufig dysfunktional ausgeprägt ist und einer optimalen Regeneration entgegensteht, wären daraus praktische Implikationen zu ziehen. Die Entwicklung neuer Trainingsprogramme oder elektrophysiologischer Konzepte könnte ein nächstes Ziel dieses Forschungszweiges sein, um potenziell dysfunktionale Plastizität zu vermeiden und physiologische Prozesse bereits im Schub zu fördern.
Background:
Cerebellar liponeurocytoma is an extremely rare tumour entity of the central nervous system. It is histologically characterised by prominent neuronal/neurocytic differentiation with focal lipidisation and corresponding histologically to WHO grade II. It typically develops in adults, and usually shows a low proliferative potential. Recurrences have been reported in almost 50% of cases, and in some cases the recurrent tumour may display increased mitotic activity and proliferation index, vascular proliferations and necrosis. Thus pathological diagnosis of liponeurocytoma is challenging. This case presentation highlights the main clinical, radiographic and pathological features of a cerebellar liponeurocytoma.
Case presentation:
A 59-year-old, right-handed woman presented at our department with a short history of persistent headache, vertigo and gait disturbances. Examination at presentation revealed that the patient was awake, alert and fully oriented. The cranial nerve status was normal. Uncertainties were noted in the bilateral finger-to-nose testing with bradydiadochokinesis on both sides. Strength was full and no pronator drift was observed. Sensation was intact. No signs of pyramidal tract dysfunction were detected. Her gait appeared insecure. The patient underwent surgical resection. Afterward no further disturbances could be detected.
Conclusions:
To date >40 cases of liponeurocytoma have been reported, including cases with supratentorial location. A review of the 5 published cases of recurrent cerebellar. Liponeurocytoma revealed that the median interval between the first and second relapse was rather short, indicating uncertain malignant potential. The most recent WHO classification of brain tumours (2016) classifies the cerebellar liponeurocytoma as a separate entity and assigns the tumour to WHO grade II. Medulloblastoma is the most important differential diagnosis commonly seen in children and young adults. In contrast, cerebellar liponeurocytoma is typically diagnosed in adults. The importance of accurate diagnosis should not be underestimated especially in the view of possible further therapeutic interventions and for the determination of the patient's prognosis.
Ziel der Studie war ein Zusammenhang zwischen cholinerger Innervation in den Basalganglien mit Levodopa-induzierter Dyskinesie darzustellen.
26 Patienten mit idiopatischem Parkinson-Syndrom ohne Demenz und Depression wurden in zwei Gruppen mit und ohne Dyskinesie eingeteilt. Es wurde nach klinischer Untersuchung eine SPECT-Bildgebung mit 5-[123I]iodo-3-[2(S)-2-azetidinylmethoxy]pyridine (5IA) durchgeführt und anschließend die Ergebnisse in Zusammenschau mit den klinischen Daten und mit den Ergebnissen der SPECT mit [123I]N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane (FP-CIT) bewertet.
Dyskinetische Patienten hatten eine höhere Dichte an nikotinergen Acetylcholinrezeptoren im Nucleus caudatus, hauptsächlich der Halbseite mit stärkerer dopaminerger Degeneration.
Dies stützt die Hypothese, dass sich die Dyskinesie nach Levodopa-Therapie aufgrund einer verstärkten cholinergen Modulation im stärker degenerierten Striatum entwickelt.
Background:
ATF5 suppresses differentiation of neuroprogenitor cells and is overexpressed in glioblastoma (GBM). A reduction of its expression leads to apoptotic GBM cell death. Data on ATF5 expression in astrocytoma WHO grade II (low-grade astrocytoma [LGA]) are scarce and lacking on recurrent GBM.
Patients and methods:
ATF5 mRNA was extracted from frozen samples of patients’ GBM (n=79), LGA (n=40), and normal brain (NB, n=10), quantified by duplex qPCR and correlated with retrospectively collected clinical data. ATF5 protein expression was evaluated by measuring staining intensity on immunohistochemistry.
Results:
ATF5 mRNA was overexpressed in LGA (sevenfold, P<0.001) and GBM (tenfold, P<0.001) compared to NB, which was confirmed on protein level. Although ATF5 mRNA expression in GBM showed a considerable fluctuation range, groups of varying biological behavior, that is, local/multifocal growth or primary tumor/relapse and the tumor localization at diagnosis, were not significantly different. ATF5 mRNA correlated with the patients’ age (r=0.339, P=0.028) and inversely with Ki67-staining (r=-0.421, P=0.007). GBM patients were allocated to a low and a high ATF5 expression group by the median ATF5 overexpression compared to NB. Kaplan–Meier analysis and Cox regression indicated that ATF5 mRNA expression significantly correlated with short-term survival (t<12 months, median survival 18 vs 13 months, P=0.022, HR 2.827) and progression-free survival (PFS) (12 vs 6 months, P=0.024). This advantage vanished after 24 months (P=0.084).
Conclusion:
ATF5 mRNA expression could be identified as an additional, though not independent factor correlating with overall survival and PFS. Since its inhibition might lead to the selective death of glioma cells, it might serve as a potential ubiquitous therapeutic target in astrocytic tumors.
Background:
Fabry disease is an inherited metabolic disorder characterized by progressive lysosomal accumulation of lipids in a variety of cell types, including neural cells. Small, unmyelinated nerve fibers are particularly affected and small fiber peripheral neuropathy often clinically manifests at young age. Peripheral pain can be chronic and/or occur as provoked attacks of excruciating pain. Manifestations of dysfunction of small autonomic fibers may include, among others, impaired sweating, gastrointestinal dysmotility, and abnormal pain perception. Patients with Fabry disease often remain undiagnosed until severe complications involving the kidney, heart, peripheral nerves and/or brain have arisen.
Methods:
An international expert panel convened with the goal to provide guidance to clinicians who may encounter unrecognized patients with Fabry disease on how to diagnose these patients early using simple diagnostic tests. A further aim was to offer recommendations to control neuropathic pain.
Results:
We describe the neuropathy in Fabry disease, focusing on peripheral small fiber dysfunction - the hallmark of early neurologic involvement in this disorder. The clinical course of peripheral pain is summarized, and the importance of medical history-taking, including family history, is highlighted. A thorough physical examination (e. g., angiokeratoma, corneal opacities) and simple non-invasive sensory perception tests could provide clues to the diagnosis of Fabry disease. Reported early clinical benefits of enzyme replacement therapy include reduction of neuropathic pain, and adequate management of residual pain to a tolerable and functional level can substantially improve the quality of life for patients.
Conclusions:
Our recommendations can assist in diagnosing Fabry small fiber neuropathy early, and offer clinicians guidance in controlling peripheral pain. This is particularly important since management of pain in young patients with Fabry disease appears to be inadequate.
Background:
To analyze whether magnesium has a neuroprotective effect during episodes that indicate a critical brain perfusion after aneurysmal subarachnoid hemorrhage (SAH).
Methods:
107 patients with aSAH were randomized to continuously receive intravenous magnesium sulfate with target serum levels of 2.0 – 2.5 mmol/l (n = 54) or isotonic saline (n = 53). Neurological examination and transcranial Doppler sonography (TCD) were performed daily, Perfusion-CT (PCT) was acquired in 3-day intervals, angiography in case of suspected vasospasm. The primary endpoint was the development of secondary infarction following episodes of delayed ischemic neurological deficit (DIND), elevated mean flow velocity (MFV) in TCD or pathological findings in PCT.
Results:
In the magnesium group, 9 episodes of DIND were registered, none was followed by secondary infarction. In the control group, 23 episodes of DIND were registered, 9 were followed by secondary infarction (p < 0.05). In the magnesium group, 114 TCD-measurements showed an elevated MFV(> 140 cm/s). 7 were followed by new infarction. In control patients, 135 measurements showed elevated MFV, 32 were followed by new infarction (p < 0.05). 10 of 117 abnormal PCT-findings were followed by new infarction, compared to 30 of 122 in the control-group (p < 0.05).
Conclusion:
DIND, elevated MFV in TCD and abnormal PCT are findings which are associated with an increased risk to develop delayed secondary infarction. The results of this analysis suggest that magnesium-treatment may reduce the risk to develop infarction in a state of critical brain perfusion.
Background:
Genetically caused neurological disorders of the central nervous system (CNS) are mostly characterized by poor or even fatal clinical outcome and few or no causative treatments are available. Often, these disorders are associated with low-grade, disease-promoting inflammation, another feature shared by progressive forms of multiple sclerosis (PMS). We previously generated two mouse lines carrying distinct mutations in the oligodendrocytic PLP1 gene that have initially been identified in patients diagnosed with MS. These mutations cause a loss of PLP function leading to a histopathological and clinical phenotype common to both PMS and genetic CNS disorders, like hereditary spastic paraplegias. Importantly, neuroinflammation promotes disease progression in these models, suggesting that pharmacological modulation of inflammation might ameliorate disease outcome.
Methods:
We applied teriflunomide, an approved medication for relapsing-remitting MS targeting activated T-lymphocytes, in the drinking water (10 mg/kg body weight/day). Experimental long-term treatment of PLP mutant mice was non-invasively monitored by longitudinal optical coherence tomography and by rotarod analysis. Immunomodulatory effects were subsequently analyzed by flow cytometry and immunohistochemistry and treatment effects regarding neural damage, and neurodegeneration were assessed by histology and immunohistochemistry.
Results:
Preventive treatment with teriflunomide attenuated the increase in number of CD8+ cytotoxic effector T cells and fostered the proliferation of CD8+ CD122+ PD-1+ regulatory T cells in the CNS. This led to an amelioration of axonopathic features and neuron loss in the retinotectal system, also reflected by reduced thinning of the innermost retinal composite layer in longitudinal studies and ameliorated clinical outcome upon preventive long-term treatment. Treatment of immune-incompetent PLP mutants did not provide evidence for a direct, neuroprotective effect of the medication. When treatment was terminated, no rebound of neuroinflammation occurred and histopathological improvement was preserved for at least 75 days without treatment. After disease onset, teriflunomide halted ongoing axonal perturbation and enabled a recovery of dendritic arborization by surviving ganglion cells. However, neither neuron loss nor clinical features were ameliorated, likely due to already advanced neurodegeneration before treatment onset.
Conclusions:
We identify teriflunomide as a possible medication not only for PMS but also for inflammation-related genetic diseases of the nervous system for which causal treatment options are presently lacking.
Background:
Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) for which several new treatment options were recently introduced. Among them is the monoclonal anti-CD52 antibody alemtuzumab that depletes mainly B cells and T cells in the immune periphery. Considering the ongoing controversy about the involvement of B cells and in particular the formation of B cell aggregates in the brains of progressive MS patients, an in-depth understanding of the effects of anti-CD52 antibody treatment on the B cell compartment in the CNS itself is desirable.
Methods:
We used myelin basic protein (MBP)-proteolipid protein (PLP)-induced experimental autoimmune encephalomyelitis (EAE) in C57BL/6 (B6) mice as B cell-dependent model of MS. Mice were treated intraperitoneally either at the peak of EAE or at 60 days after onset with 200 μg murine anti-CD52 vs. IgG2a isotype control antibody for five consecutive days. Disease was subsequently monitored for 10 days. The antigen-specific B cell/antibody response was measured by ELISPOT and ELISA. Effects on CNS infiltration and B cell aggregation were determined by immunohistochemistry. Neurodegeneration was evaluated by Luxol Fast Blue, SMI-32, and Olig2/APC staining as well as by electron microscopy and phosphorylated heavy neurofilament serum ELISA.
Results:
Treatment with anti-CD52 antibody attenuated EAE only when administered at the peak of disease. While there was no effect on the production of MP4-specific IgG, the treatment almost completely depleted CNS infiltrates and B cell aggregates even when given as late as 60 days after onset. On the ultrastructural level, we observed significantly less axonal damage in the spinal cord and cerebellum in chronic EAE after anti-CD52 treatment.
Conclusion:
Anti-CD52 treatment abrogated B cell infiltration and disrupted existing B cell aggregates in the CNS.
Polyneuropathien (PNP) können zu einer Reorganisation der nodalen und paranodalen Membranproteine mit in der Folge fehlerhafter Axon-Schwann-Zell-Interaktionen führen. Im Rahmen der Basisdiagnostik einer Polyneuropathie haben sich Hautbiopsien als weniger invasive Ergänzung zur Suralisbiopsie mit einem geringen Nebenwirkungsrisiko entwickelt. Die Morphologie dermaler Nervenfasern lässt sich mittels Immunohistochemie in der Haut gezielt untersuchen. In der vorliegenden Studie wurde die Hypothese überprüft, ob pathologisch auffällige Ranvier-Schnürringe Hinweise auf Unterschiede bei PNP-Subgruppen und Schädigungsmuster liefern. Daneben wurden die Hypothesen überprüft, ob Entzündungszellen an myelinisierten Nervenfasern kolokalisiert nachweisbar sind und ob Hautbiopsien einen zusätzlichen Nutzen zur PNP-Basisdiagnostik liefern. Von 92 Patienten wurden Hautbiopsien von Finger, Ober-und Unterschenkel wurden entnommen, daraus gewonnene myelinisierte Nervenfasern der Haut wurden mittels immunohistochemischer Antikörper-Doppelfärbungen analysiert. Neuropathische Schädigungsformen vom axonalen und demyelinisierenden Typ zeigten keine signifikante Korrelation mit dem Auftreten von verlängerten Ranvier-Schnürringen und der Dispersion charakteristischer paranodaler und nodaler Membranproteine (Neurofascin, Caspr, Pan-Natrium-Kanäle). Kolokalisierte Entzündungszellen an myelinisierten Nervenfasern bei entzündlichen PNP ließen sich nicht nachweisen. PNP-Subgruppen zeigten keine signifikanten Unterschiede in Hinblick auf eine pathologische nodale oder paranodale Organisation. Der Zusatznutzen von Hautbiopsien in der PNP-Basisdiagnostik kann in Bezug auf die vorliegende Arbeit nur eingeschränkt bestätigt werden. Da Fingerbiopsien im Vergleich zu Proben aus Ober- und Unterschenkel eine signifikant höhere Dichte myelinisierter Nervenbündel pro Fläche Dermis aufweisen, wäre es durchaus denkbar, zukünftig primär Fingerbiopsien zu entnehmen um diese auf etwaige pathologische Veränderungen infolge neuropathischer Erkrankungen zu untersuchen. Anamnese, Basisdiagnostik und klinischer Befund erbringen nach wie vor den wichtigsten Beitrag zur PNP-Diagnostik.
Background:
Atypical chemokine receptor 3 (ACKR3, synonym CXCR7) is increasingly considered relevant in neuroinflammatory conditions, in which its upregulation contributes to compromised endothelial barrier function and may ultimately allow inflammatory brain injury. While an impact of ACKR3 has been recognized in several neurological autoimmune diseases, neuroinflammation may also result from infectious agents, including Ureaplasma species (spp.). Although commonly regarded as commensals of the adult urogenital tract, Ureaplasma spp. may cause invasive infections in immunocompromised adults as well as in neonates and appear to be relevant pathogens in neonatal meningitis. Nonetheless, clinical and in vitro data on Ureaplasma-induced inflammation are scarce.
Methods:
We established a cell culture model of Ureaplasma meningitis, aiming to analyze ACKR3 variances as a possible pathomechanism in Ureaplasma-associated neuroinflammation. Non-immortalized human brain microvascular endothelial cells (HBMEC) were exposed to bacterial lipopolysaccharide (LPS) or tumor necrosis factor-α (TNF-α), and native as well as LPS-primed HBMEC were cultured with Ureaplasma urealyticum serovar 8 (Uu8) and U. parvum serovar 3 (Up3). ACKR3 responses were assessed via qRT-PCR, RNA sequencing, flow cytometry, and immunocytochemistry.
Results:
LPS, TNF-α, and Ureaplasma spp. influenced ACKR3 expression in HBMEC. LPS and TNF-α significantly induced ACKR3 mRNA expression (p < 0.001, vs. control), whereas Ureaplasma spp. enhanced ACKR3 protein expression in HBMEC (p < 0.01, vs. broth control). Co-stimulation with LPS and either Ureaplasma isolate intensified ACKR3 responses (p < 0.05, vs. LPS). Furthermore, stimulation wielded a differential influence on the receptor’s ligands.
Conclusions:
We introduce an in vitro model of Ureaplasma meningitis. We are able to demonstrate a pro-inflammatory capacity of Ureaplasma spp. in native and, even more so, in LPS-primed HBMEC, underlining their clinical relevance particularly in a setting of co-infection. Furthermore, our data may indicate a novel role for ACKR3, with an impact not limited to auto-inflammatory diseases, but extending to infection-related neuroinflammation as well. AKCR3-induced blood-brain barrier breakdown might constitute a potential common pathomechanism.
Introduction:
Evidence from a number of open-label, uncontrolled studies has suggested that rituximab may benefit patients with autoimmune diseases who are refractory to standard-of-care. The objective of this study was to evaluate the safety and clinical outcomes of rituximab in several standard-of-care-refractory autoimmune diseases (within rheumatology, nephrology, dermatology and neurology) other than rheumatoid arthritis or non-Hodgkin’s lymphoma in a real-life clinical setting.
Methods:
Patients who received rituximab having shown an inadequate response to standard-of-care had their safety and clinical outcomes data retrospectively analysed as part of the German Registry of Autoimmune Diseases. The main outcome measures were safety and clinical response, as judged at the discretion of the investigators.
Results:
A total of 370 patients (299 patient-years) with various autoimmune diseases (23.0% with systemic lupus erythematosus, 15.7% antineutrophil cytoplasmic antibody-associated granulomatous vasculitides, 15.1% multiple sclerosis and 10.0% pemphigus) from 42 centres received a mean dose of 2,440 mg of rituximab over a median (range) of 194 (180 to 1,407) days. The overall rate of serious infections was 5.3 per 100 patient-years during rituximab therapy. Opportunistic infections were infrequent across the whole study population, and mostly occurred in patients with systemic lupus erythematosus. There were 11 deaths (3.0% of patients) after rituximab treatment (mean 11.6 months after first infusion, range 0.8 to 31.3 months), with most of the deaths caused by infections. Overall (n = 293), 13.3% of patients showed no response, 45.1% showed a partial response and 41.6% showed a complete response. Responses were also reflected by reduced use of glucocorticoids and various immunosuppressives during rituximab therapy and follow-up compared with before rituximab. Rituximab generally had a positive effect on patient well-being (physician’s visual analogue scale; mean improvement from baseline of 12.1 mm)
Transient receptor potential channels are important mediators of thermal and mechanical stimuli and play an important role in neuropathic pain. The contribution of hereditary variants in the genes of transient receptor potential channels to neuropathic pain is unknown. We investigated the frequency of transient receptor potential ankyrin 1, transient receptor potential melastin 8 and transient receptor potential vanilloid 1 single nucleotide polymorphisms and their impact on somatosensory abnormalities in neuropathic pain patients. Within the German Research Network on Neuropathic Pain (Deutscher Forscbungsverbund Neuropathischer Schmerz) 371 neuropathic pain patients were phenotypically characterized using standardized quantitative sensory testing. Pyrosequencing was employed to determine a total of eleven single nucleotide polymorphisms in transient receptor potential channel genes of the neuropathic pain patients and a cohort of 253 German healthy volunteers. Associations of quantitative sensory testing parameters and single nucleotide polymorphisms between and within groups and subgroups, based on sensory phenotypes, were analyzed. Single nucleotide polymorphisms frequencies did not differ between both the cohorts. However, in neuropathic pain patients transient receptor potential ankyrin 1 710G>A (rs920829, E179K) was associated with the presence of paradoxical heat sensation (p=0.03), and transient receptor potential vanilloid 1 1911A>G (rs8065080, I585V) with cold hypoalgesia (p=0.0035). Two main subgroups characterized by preserved (1) and impaired (2) sensory function were identified. In subgroup 1 transient receptor potential vanilloid 1 1911A>G led to significantly less heat hyperalgesia, pinprick hyperalgesia and mechanical hypaesthesia (p=0.006, p=0.005 and p<0.001) and transient receptor potential vanilloid 1 1103C>G (rs222747, M315I) to cold hypaesthesia (p=0.002), but there was absence of associations in subgroup 2. In this study we found no evidence that genetic variants of transient receptor potential channels are involved in the expression of neuropathic pain, but transient receptor potential channel polymorphisms contributed significantly to the somatosensory abnormalities of neuropathic pain patients.
Charcot-Marie-Tooth Neuropathien sind die häufigsten hereditären Erkrankungen des peripheren Nervensystems und dennoch bis heute nicht therapierbar. Die Lebensqualität der Patienten ist durch motorische und sensorische Defizite der Extremitäten häufig stark eingeschränkt. Ursache können unter anderem Mutationen in Schwann-Zellen sein, die zu dem typischen Bild von Demyelinisierung und axonalem Schaden führen. In den letzten Jahren konnte in Mausmodellen das Immunsystem als wichtiger Mediator in der Pathogenese der CMT 1 Subtypen A, B und X identifiziert werden. Insbesondere Makrophagen spielen eine tragende Rolle bei dem Verlust der axonalen Integrität, bei der Schädigung der Myelinscheiden, sowie bei der Dedifferenzierung von Schwann-Zellen. Entscheidender Faktor für Proliferation und Aktivierung der Makrophagen ist hierbei das Zytokin CSF-1, dessen korrespondierender Rezeptor auf Makrophagen exprimiert wird. Der CSF-1/CSF1R Signalweg bietet somit einen vielversprechenden Angriffspunkt.
In der vorliegenden Arbeit wurden Mausmodelle der CMT 1 Subtypen A, B und X mit einem niedermolekularen CSF-1-Rezeptor Inhibitor behandelt. Anschließend erfolgte eine funktionelle und strukturelle Auswertung der peripheren Nerven.
Das beste Ansprechen auf die Therapie zeigten Cx32def Mutanten. Strukturell fielen ein verringerter axonaler Schaden und eine verbesserte axonale Regenerationsfähigkeit sowie erhaltene neuromuskuläre Synapsen auf. Funktionell äußerte sich dies in verbesserten elektrophysiologischen Parametern und einem Krafterhalt, welcher als klinischer Parameter die größte Relevanz für betroffene Patienten hat und somit besonders hervorzuheben ist.
Auch P0het Mutanten zeigten Verbesserungen nach der CSF1RI Behandlung. Anders als bei Cx32def Tieren zeigte sich hier jedoch vor allem ein Erhalt der Myelinintegrität. Weiterhin wirkte sich die Therapie positiv auf elektrophysiologische Parameter und Krafttests aus. Vor allem besonders stark betroffene Individuen schienen hierbei von der CSF1RI Behandlung zu profitieren.
Bei PMP22tg Mutanten hingegen konnten keine positiven Effekte der CSF1RI Behandlung nachgewiesen werden. Strukturelle und funktionelle Parameter behandelter Tiere unterschieden sich nicht von unbehandelten.
Diese Ergebnisse unterstreichen die Relevanz der sekundären Entzündungsreaktion in CMT 1 Neuropathien als wichtigen Mediator in der Pathogenese. Weiterhin konnte gezeigt werden, dass eine Intervention im CSF-1/CSF1R Signalweg einen vielversprechenden möglichen Ansatz für die Therapie der bisher nicht behandelbaren CMT 1 Subypen X und B darstellt. Unausweichlich ist hierbei ein möglichst früher Therapiestart vor Ausprägung der ersten molekularen und histologischen Veränderungen. Im Hinblick auf die nicht die Lebenserwartung reduzierende Erkrankung muss ferner eine Minimierung der Nebenwirkungen der Therapie gewährleistet sein. Besonders hervorzuheben ist hier die Verwendung eines Inhibitors, welcher nicht in das zentrale Nervensystem vordringen kann und somit die Funktion der Mikroglia nicht beeinträchtigt.
Background:
Inhibition of early platelet adhesion by blockade of glycoprotein-IB (GPIb) protects mice from ischemic stroke. To elucidate underlying mechanisms in-vivo, infarct development was followed by ultra-high field MRI at 17.6 Tesla.
Methods:
Cerebral infarction was induced by transient-middle-cerebral-artery-occlusion (tMCAO) for 1 hour in C57/BL6 control mice (N = 10) and mice treated with 100 mg Fab-fragments of the GPIb blocking antibody p0p/B 1 h after tMCAO (N = 10). To control for the effect of reperfusion, additional mice underwent permanent occlusion and received anti-GPIb treatment (N = 6; pMCAO) or remained without treatment (N = 3; pMCAO). MRI 2 h and 24 h after MCAO measured cerebral-blood-flow (CBF) by continuous arterial-spin labelling, the apparent-diffusion-coefficient (ADC), quantitative-T2 and T2-weighted imaging. All images were registered to a standard mouse brain MRI atlas and statistically analysed voxel-wise, and by cortico-subcortical ROI analysis.
Results:
Anti-GPIb treatment led to a relative increase of postischemic CBF vs. controls in the cortical territory of the MCA (2 h: 44.2 +/- 6.9 ml/100g/min versus 24 h: 60.5 +/- 8.4; p = 0.0012, F((1,18)) = 14.63) after tMCAO. Subcortical CBF 2 h after tMCAO was higher in anti-GPIb treated animals (45.3 +/- 5.9 vs. controls: 33.6 +/- 4.3; p = 0.04). In both regions, CBF findings were clearly related to a lower probability of infarction (Cortex/Subcortex of treated group: 35%/65% vs. controls: 95%/100%) and improved quantitative-T2 and ADC. After pMCAO, anti-GPIb treated mice developed similar infarcts preceded by severe irreversible hypoperfusion as controls after tMCAO indicating dependency of stroke protection on reperfusion.
Conclusion:
Blockade of platelet adhesion by anti-GPIb-Fab-fragments results in substantially improved CBF early during reperfusion. This finding was in exact spatial correspondence with the prevention of cerebral infarction and indicates in-vivo an increased patency of the microcirculation. Thus, progression of infarction during early ischemia and reperfusion can be mitigated by anti-platelet treatment.