Neurologische Klinik und Poliklinik
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Background
Patients with acute leukaemia have a high incidence of fungal infections. This has primarily been shown in acute myeloid leukaemia and is different for acute lymphoblastic leukaemia. Until now no benefit of mould active prophylaxis has been demonstrated in the latter population.
Methods
In this retrospective single‐centre study, we analysed the incidence, clinical relevance, and outcome of invasive fungal diseases (IFD) as well as the impact of antifungal prophylaxis for the first 100 days following the primary diagnosis of acute lymphoblastic leukaemia.
Results
In 58 patients a high rate of proven, probable, and possible fungal infections could be demonstrated with a 3.4%, 8.6%, and 17.2% likelihood, respectively. The incidence might be even higher, as nearly 40% of all patients had no prolonged neutropenia for more than 10 days, excluding those from the European Organization of Research and Treatment of cancer and the Mycoses Study Group criteria for probable invasive fungal disease. The diagnosed fungal diseases had an impact on the duration of hospitalisation, which was 13 days longer for patients with proven/probable IFD compared to patients with no signs of fungal infection. Use of antifungal prophylaxis did not significantly affect the risk of fungal infection.
Conclusion
Patients with acute lymphoblastic leukaemia are at high risk of acquiring an invasive fungal disease. Appropriate criteria to define fungal infections, especially in this population, and strategies to reduce the risk of infection, including antifungal prophylaxis, need to be further evaluated.
Background and Objective
This updated systematic review evaluated the efficacy, tolerability and safety of opioids compared to placebo in non‐malignant chronic low back pain.
Databases and Data Treatment
Clinicaltrials.gov, CENTRAL, MEDLINE and PsycINFO were searched from October 2013 to May 2019. Randomized controlled trials comparing opioids with placebo and at least 4 weeks of double‐blinded duration were analysed. Primary outcomes were pain relief of 50% or greater, disability, tolerability and safety. Effects were summarized by a random effects model using risk differences or standardized mean differences. We added nine new studies with 2,980 participants for a total of 21 studies with 7,650 participants. Study duration ranged between 4 and 15 weeks. Studies with a parallel and cross‐over design: Based on very low to low‐quality evidence, opioids provided no clinically relevant pain relief of 50% or greater, but a clinically relevant reduction of disability compared to placebo. Enriched enrolment randomized withdrawal (EERW) design: Based on very low to low‐quality evidence, opioids provided a clinically relevant pain relief of 50% or greater, but not a clinically relevant reduction of disability compared to placebo. There was no clinically relevant harm with regard to serious adverse events by opioids compared to placebo in studies with parallel/cross‐over and EERW design. There was a relevant harm with regard to drop out rates due to adverse events in studies with parallel/cross‐over, but not in studies with EERW design.
Conclusions
Opioids may provide a safe and clinically relevant pain relief for 4–15 weeks in highly selected patients.
Significance
Within the context of randomized controlled trials of 4–15 weeks, opioids provided a clinically relevant pain relief of 30% or greater and a clinically relevant reduction of disability compared to placebo in non‐malignant chronic low back pain. Number needed to treat for an additional drop out due to side effects was 11 (95% confidence interval: 6–33). Assessment of abuse and addiction was incomplete. The frequency of serious adverse events including deaths did not differ from placebo.
In our study, we aimed at investigating corneal langerhans cells (LC) in patients with fibromyalgia syndrome (FMS) and small fiber neuropathy (SFN) as potential contributors to corneal small fiber pathology. We enrolled women with FMS (n = 134) and SFN (n = 41) who underwent neurological examination, neurophysiology, prostaglandin analysis in tear fluid, and corneal confocal microscopy (CCM). Data were compared with those of 60 age‐matched female controls. After screening for dry eye disease, corneal LC were counted and sub‐classified as dendritic (dLC) and non‐dendritic (ndLC) cells with or without nerve fiber association. We further analyzed corneal nerve fiber density (CNFD), length (CNFL), and branch density (CNBD). Neurological examination indicated deficits of small fiber function in patients with SFN. Nerve conduction studies were normal in all participants. Dry eye disease was more prevalent in FMS (17%) and SFN (28%) patients than in controls (5%). Tear fluid prostaglandin levels did not differ between FMS patients and controls. While corneal LC density in FMS and SFN patients was not different from controls, there were fewer dLC in association with nerve fibers in FMS and SFN patients than in controls (P < .01 each). Compared to controls, CNFL was lower in FMS and SFN patients (P < .05 each), CNFD was lower only in FMS patients (P < .05), and CNBD was lower only in SFN patients (P < .001). There was no difference in any CCM parameter between patients with and without dry eyes. Our data indicate changes in corneal innervation and LC distribution in FMS and SFN, potentially based on altered LC signaling.
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.
Lewy bodies and Lewy neurites are neuropathological hallmarks of Parkinson’s disease (PD). These depositions in the brain mostly consist of aggregated α-synuclein (α-syn) phosphorylated at Ser129. A number of studies reported detection of phosphorylated α-syn (p-α-syn) in the dermal nerve fibers in Parkinson’s disease. The objective of this study was to investigate whether pathological α-syn accumulations detected in the skin represent aggregated protein. A number of methods aimed at detecting α-syn oligomers and aggregates were first tested and optimized on the brain samples in PD and normal control. These methods included proximity ligation assay (PLA), PET-blot, immunohistochemical (IHC) stains with α-syn aggregate (5G4) or oligomer specific (ASyO5) antibodies and a stain against native α-syn (syn211) after proteinase K (PK) digestion. Subsequently, the most specific methods (stains with 5G4, ASyO5 and syn211 after PK digestion) were studied in two separate patient and control cohorts. Anti-p-α-syn stain was performed in parallel.
Single sections from at least 2 biopsy sites from 44 patients and 22 controls (cohort 1) as well as serial sections of 4 biopsy sites from 27 patients and 5 controls (cohort 2) were systematically studied for presence of aggregated and oligomeric α-syn. In total, 5G4 positive deposits were found in 24% (cohort 1) and 37% (cohort 2), ASyO5 positive lesions in 17,7% (cohort 1) and 33% (cohort 2), syn211 positive lesions after PK digestion in 38,7% (cohort 1) and 48% (cohort 2) of cases. There was a major overlap among positivity for a particular staining on the patient level and in most cases, the same nerve fiber was found to be positive for all 4 markers in neighboring sections. Among the skin biopsies which contained p-α-syn accumulation, 59% were also PK resistant, 41% were 5G4 positive and 45% were ASyO5 positive. The samples belonging to normal controls did not show any positive signal in either of the newly established stainings or in the anti-p-α-syn staining.
Using 3 distinct IHC methods, α-syn oligomers and aggregates were detectable in the majority of p-α-syn positive skin biopsies. This finding supports the hypothesis that α-syn aggregation occurs in the peripheral (i.e. dermal) nerves and can be specifically detected using skin biopsy.
Die aneurysmatische SAB ist trotz etablierter Therapieverfahren (Coiling und Clipping) weiterhin ein Krankheitsbild mit hoher Mortalität. In unserer Arbeit haben wir retrospektiv die Patientenakten der Patienten, die mit der Diagnose aneurysmatische SAB am Universitätsklinikum Würzburg zwischen dem 01.01.1999 und dem 31.12.2009 aufgenommen wurden, ausgewertet. Es konnte dargestellt werden das als Hauptrisikofaktoren für ein schlechtes Therapieergebnis ein schlechter Aufnahmestatus des Patienten und das Auftreten von Komplikationen im Verlauf verantwortlich sind.
In den Jahren von 2006 bis 2016 sind am Universitätsklinikum Würzburg insgesamt 26 Patienten mit der Diagnose einer Autoimmunen Enzephalitis behandelt worden. Diese Arbeit zeigt ihre Krankheitsverläufe, Outcome, die gefundenen Antikörper und die Therapien der jeweiligen Patienten. Im zweiten Schritt wurden die Daten mit den in der Literatur bereits beschrieben Fällen verglichen, um Gemeinsamkeiten, aber auch Unterschiede aufzeigen zu können.
Objective
Bridging the gap between experimental stroke and patients by ischemic blood probing during the hyperacute stage of vascular occlusion is crucial to assess the role of inflammation in human stroke and for the development of adjunct treatments beyond recanalization.
Methods
We prospectively observed 151 consecutive ischemic stroke patients with embolic large vessel occlusion of the anterior circulation who underwent mechanical thrombectomy. In all these patients, we attempted microcatheter aspiration of 3 different arterial blood samples: (1) within the core of the occluded vascular compartment and controlled by (2) carotid and (3) femoral samples obtained under physiological flow conditions. Subsequent laboratory analyses comprised leukocyte counting and differentiation, platelet counting, and the quantification of 13 proinflammatory human chemokines/cytokines.
Results
Forty patients meeting all clinical, imaging, interventional, and laboratory inclusion criteria could be analyzed, showing that the total number of leukocytes significantly increased under the occlusion condition. This increase was predominantly driven by neutrophils. Significant increases were also apparent for lymphocytes and monocytes, accompanied by locally elevated plasma levels of the T‐cell chemoattractant CXCL‐11. Finally, we found evidence that short‐term clinical outcome (National Institute of Health Stroke Scale at 72 hours) was negatively associated with neutrophil accumulation.
Interpretation
We provide the first direct human evidence that neutrophils, lymphocytes, and monocytes, accompanied by specific chemokine upregulation, accumulate in the ischemic vasculature during hyperacute stroke and may affect outcome. These findings strongly support experimental evidence that immune cells contribute to acute ischemic brain damage and indicate that ischemic inflammation initiates already during vascular occlusion. Ann Neurol 2020;87:466–479
Fatigue als ein „überwältigendes Gefühl von Müdigkeit, Energielosigkeit und Erschöpfung” stellt bei Patienten mit MS ein häufig auftretendes und oft im Alltag beeinträchtigendes Symptom dar, das sowohl mit körperlichen als auch mit kognitiven Erschöpfungssymptomen einhergeht. Die objektive Erfassung des Schweregrades der Fatigue beim einzelnen Patienten stellt ein Problem dar, da bisher keine objektiven Messverfahren zur Erfassung der Fatigue existieren. Im klinischen Alltag kommen meist Fragebögen zum Einsatz, die das Ausmaß der subjektiven Beeinträchtigung durch Fatigue im Alltag quantifizieren sollen.
Ziel dieser Arbeit war es, zu untersuchen, inwieweit bestimmte im klinischen Alltag erhobene Parameter Rückschlüsse auf die subjektive Fatigue bei Patienten mit MS erlauben, auch im Hinblick darauf, ob sich einzelne Parameter besonders zur Einschätzung der körperlichen bzw. kognitiven Fatigue eignen. Zudem sollte untersucht werden, ob die untersuchten klinischen Parameter bei bestimmten Patientengruppen besser als bei anderen Rückschlüsse auf die subjektive Fatigue erlauben. Erfasst wurde die subjektive Fatigue durch das Würzburger Erschöpfungsinventar bei Multipler Sklerose (WEIMuS), einer Serie von Fragen, die zwischen körperlicher und kognitiver Fatigue unterscheiden.
Dazu wurden Korrelationsanalysen zwischen der WEIMuS-Gesamtskala bzw. deren Subskalen für körperliche und kognitive Fatigue und EDSS-Wert, MSFC Z-Score einschließlich dessen Subscores und der Zeit des 50-Meter-Gehversuchs durchgeführt. Bezüglich der körperlichen Fatigue ergaben sich zwischen der WEIMuS-Subskala für körperliche Fatigue und dem EDSS sowie der Zeit des 50-Meter-Gehversuchs im Vergleich die stärksten, absolut gesehen als mittelstark zu wertende, Korrelationen. Bezüglich der kognitiven Fatigue ergab sich die stärkste Korrelation zwischen der WEIMuS-Subskala für kognitive Fatigue und dem PASAT3, die allerdings trotzdem als gering zu werten ist. Mit EDSS und 50-Meter-Gehversuch scheinen also zwei objektive klinische Parameter zu existieren, die in einem gewissen Maß auf die subjektive Fatigue rückschließen lassen. Ziel weiterer Untersuchungen wird es sein müssen, einen geeigneten klinischen Parameter zu finden, der bessere Rückschlüsse auf die subjektive kognitive Fatigue erlaubt als der PASAT3.
Zwischen der WEIMuS-Gesamtskala bzw. deren Subskalen für körperliche und kognitive Fatigue und Alter, Geschlecht und Erkrankungsdauer fanden sich bestenfalls geringe Korrelationen, weshalb diese Parameter ungeeignet erscheinen, Aussagen über die subjektive Fatigue zu machen.
Durch die Einteilung der Patienten nach Alter und Geschlecht konnte untersucht werden, inwieweit diese Parameter Einfluss auf die untersuchten Zusammenhänge zwischen klinischen Parametern und subjektiver Fatigue haben. Die Korrelationen zwischen den WEIMuS-Subskalen für körperliche und kognitive Fatigue mit den untersuchten klinischen Parametern waren für junge Patienten überwiegend stärker als für ältere Patienten, insbesondere ältere Männer. Somit scheinen die untersuchten klinischen Parameter bei jüngeren Patienten besser geeignet, Aussagen über die subjektive Fatigue zu machen als bei älteren.
Insgesamt ist festzuhalten, dass EDSS und 50-Meter-Gehversuch insbesondere bei jungen Patienten zu einer besseren objektiven Beurteilbarkeit vor allem der körperlichen Fatigue im klinischen Alltag beitragen können.
Mesenchymal stem cell (MSC)-secreted factors have been shown to significantly promote oligodendrogenesis from cultured primary adult neural stem cells (aNSCs) and oligodendroglial precursor cells (OPCs). Revealing underlying mechanisms of how aNSCs can be fostered to differentiate into a specific cell lineage could provide important insights for the establishment of novel neuroregenerative treatment approaches aiming at myelin repair. However, the nature of MSC-derived differentiation and maturation factors acting on the oligodendroglial lineage has not been identified thus far. In addition to missing information on active ingredients, the degree to which MSC-dependent lineage instruction is functional in vivo also remains to be established. We here demonstrate that MSC-derived factors can indeed stimulate oligodendrogenesis and myelin sheath generation of aNSCs transplanted into different rodent central nervous system (CNS) regions, and furthermore, we provide insights into the underlying mechanism on the basis of a comparative mass spectrometry secretome analysis. We identified a number of secreted proteins known to act on oligodendroglia lineage differentiation. Among them, the tissue inhibitor of metalloproteinase type 1 (TIMP-1) was revealed to be an active component of the MSC-conditioned medium, thus validating our chosen secretome approach.
LSVT-BIG therapy in Parkinson's disease: physiological evidence for proprioceptive recalibration
(2020)
Background
There is growing evidence for proprioceptive dysfunction in patients with Parkinson's disease (PD). The Lee Silvermann Voice Treatment-BIG therapy (LSVT-BIG), a special training program aiming at an increase of movement amplitudes in persons with PD (PwPD), has shown to be effective on motor symptoms. LSVT-BIG is conceptionally based on improving bradykinesia, in particular the decrement of repetitive movements, by proprioceptive recalibration.
Objective
To assess proprioceptive impairment in PwPD as compared to matched controls and to probe potential recalibration effects of the LSVT-BIG therapy on proprioception.
Methods
Proprioceptive performance and fine motor skills were assessed in 30 PwPD and 15 matched controls. Measurements with significant impairment in PwPD were chosen as outcome parameters for a standardized 4 weeks amplitude-based training intervention (LSVT-BIG) in 11 PwPD. Proprioceptive performance served as primary outcome measure. Secondary outcome measures included the motor part of the MDS-UPDRS, the nine-hole-peg test, and a questionnaire on quality of life. Post-interventional assessments were conducted at weeks 4 and 8. Results Compared to the control group, PwPD showed significantly larger pointing errors. After 4 weeks of LSVT-BIG therapy and even more so after an additional 4 weeks of continued training, proprioceptive performance improved significantly. In addition, quality of life improved as indicated by a questionnaire.
Conclusion
LSVT-BIG training may achieve a recalibration of proprioceptive processing in PwPD. Our data indicates a probable physiological mechanism of a symptom-specific, amplitude-based behavioral intervention in PwPD.
Background and Objective
This updated systematic review evaluated the efficacy, tolerability and safety of opioids compared to placebo in chronic non‐cancer neuropathic pain.
Databases and Data Treatment
Clinicaltrials.gov, CENTRAL, PubMed and PsycINFO were searched from October 2013 to June 2019. Randomized controlled trials comparing opioids with placebo and at least 4 weeks double‐blinded duration were analysed. Primary outcomes were pain relief of 50% or greater, disability, tolerability and safety. Effects were summarized by a random effects model using risk differences (RD) or standardized mean differences (SMD). We added four new studies with 662 participants for a total of 16 included studies with 2,199 participants. Study duration ranged between 4 and 12 weeks. Studies with a parallel and cross‐over design: Based on low to moderate quality evidence, opioids (buprenorphine, hydromorphone, morphine, oxycodone, tramadol) provided a clinically relevant pain relief of 50% or greater and reduction of disability compared to placebo. There was no clinically relevant harm with regards to the drop out rate due to adverse and serious adverse events by opioids compared to placebo. Enriched enrolment randomized withdrawal design: Based on low to moderate quality evidence, tapentadol provided a clinically relevant pain relief of 50% or greater and reduction of disability compared to placebo in diabetic polyneuropathy. There was no clinically relevant harm with regards to the drop out rate due to adverse and serious adverse events by tapentadol compared to placebo.
Conclusions
Some opioids provided a short‐term substantial pain relief in highly selected patients in some neuropathic pain syndromes.
Significance
Some opioids (buprenorphine, morphine, oxycodone, tramadol, tapentadol) provide substantial pain relief compared to placebo in postherpetic neuralgia and peripheral neuropathies of different aetiologies for 4–12 weeks. There is insufficient evidence to support or refute the suggestion that these drugs are effective in other neuropathic pain conditions. The safety of opioids with regards to abuse and deaths in the studies analysed cannot be extrapolated to routine clinical care.
Prädiktion des Verschlusses großer intrakranieller Arterien anhand präklinischer Schlaganfallscores
(2021)
2015 konnte in mehreren Studien ESCAPE, EXTENDED IA, MR CLEAN, REVASCAT, SWIFT-PRIME eine signifikante Überlegenheit der mechanischen Thrombektomie verglichen mit der alleinigen i. v. Lysetherapie mit rtPA bezogen auf Revaskularisierung bei Patienten mit einer LVO (large vessel occlusion) nachgewiesen werden. Diese neue Therapiemöglichkeit erforderte eine Aufteilung der Patienten die von einer Thrombektomie profitieren (LVO) und der Patienten, die keiner Thrombektomie zugeführt werden können (nLVO). Die zentrale Fragestellung der Studie ist: Kann ein symptomorientierter Schlaganfallscore die Wahrscheinlichkeit eines großen intrakraniellen Gefäßverschlusses mit hinreichender Präzision vorhersagen und kann auf Basis dieser Vorhersage ein Patient direkt in ein übergeordnetes Schlagfanfallzentrum gebracht werden, obwohl sich dadurch eine Bridging Lysetherapie verzögern würde?
Um diesen Fragen auf den Grund zu gehen führten wir eine monozentrische Querschnittstudie durch, in deren Rahmen 215 Patienten rekrutiert wurden. Die Rekrutierung erfolgte mittels eines aus Subitems bereits etablierter Schlafanfallscores (FAST, CPSS, LAPSS, 3ISS, RACE), zusammengesetzten Fragebogens. Die ausgefüllten Fragebögen wurde in Excel digitalisiert und mittels SPSS, Signifikanz und Odds Ratio berechnet. Anschließend wurde aus den signifikanten Subitems mit der höchsten Odds Ratio ein neuer einfach anzuwendender Schlaganfallscore, bestehend aus den präklinisch erhobenen Daten gebildet (Würzburg Score of Large Vessel Occlusions, WOLVE- Score). Weiter wurden Signifikanz, Odds Ratio, Sensitivität und Spezifität des WOLVE-Score mit denen der oben genannten etablieren Scores verglichen.
Veränderung der Ranvier’schen Schnürringarchitektur bei Patienten mit diabetischer Neuropathie
(2021)
In der Krankheitsentstehung der diabetischen Neuropathie wird die paranodale Demyelinisierung als ein möglicher Pathomechanismus diskutiert, wobei Studien mit Gewebeproben von Patienten aufgrund der Invasivität limitiert sind. In der vorliegenden Studie wurden periphere Nervenfasern in Hautbiopsien von Patienten mit diabetischer Neuropathie und in Patienten mit Diabetes mellitus ohne Neuropathie untersucht. Ziel war es, nodale und paranodale Veränderungen, wie eine Dispersion der paranodalen Proteine Caspr und Neurofascin oder der nodalen Na-Kanäle, zu detektieren und die Proben auf verlängerte Ranvier`sche Schnürringe zu untersuchen.
Es wurde die Hypothese überprüft, dass paranodale Demyelinisierungen bei Patienten mit diabetischer Neuropathie in Hautbiopsien, als minimal-invasive Methode, nachweisbar sind. Hautproben von Patienten mit Diabetes mellitus ohne Neuropathie sollten zudem in einem frühen Krankheitsstadium untersucht werden.
Für die Untersuchung konnten 35 Patienten mit einer diabetischen Neuropathie, 17 Patienten mit Diabetes mellitus und 31 Kontrollen eingeschlossen werden. Immunfluoreszenzfärbungen mit Antikörpern gegen Caspr, Neurofascin und Natrium-Kanälen wurden zur Analyse der Ranvier`schen Schnürringarchitektur durchgeführt und ausgewertet.
Eine erhöhte Anzahl an verlängerten Schnürringen, als Zeichen einer segmentalen Demyelinisierung, konnte in den Patienten mit diabetischer Neuropathie aber auch in Patienten mit Diabetes mellitus nachgewiesen werden. Weiterhin waren vermehrt Veränderungen der paranodalen Proteine, wie eine Dispersion von Caspr und Neurofascin in den Proben des Fingers der Patienten mit diabetischer Neuropathie sowie eine Dispersion von Neurofascin im Unterschenkel in beiden Patientengruppen nachweisbar. Interessanterweise waren einzelne Veränderungen auch in den gesunden Kontrollen auffindbar.
Veränderungen der Schnürringarchitektur lassen sich mithilfe der Hautbiopsie nachweisen und quantifizieren. Nodale und paranodale Veränderungen weisen auf demyelinisierende Prozesse in Patienten mit diabetischer Neuropathie hin und finden sich auch bereits in einem frühen Krankheitsstadium.
Im Zeitraum von 2004 bis 2016 erhielten an der Neurologischen Universitätsklinik Würzburg Patienten mit einer chronisch progredienten Multiplen Sklerose insgesamt 595 Injektionen von intrathekalem Triamcinolonacetonid. Diese Arbeit befasst sich mit Sicherheit, Nebenwirkungen und Wirksamkeit der intrathekalen Therapieform.
Eine Prognoseeinschätzung bei Patienten mit hypoxischer Enzephalopathie (HIE) nach Reanimation wird frühestens 72 Stunden nach Reanimation empfohlen. Bis zu diesem Zeitpunkt besteht eine für Ärzte und Angehörige belastende prognostische Lücke. Und auch nach 72 Stunden bestehen nur ungenaue Angaben zum weiteren Vorgehen, sodass eine fundierte Prognoseeinschätzung aktuell eine deutliche Herausforderung im Alltag klinisch tätiger Ärzte darstellt.
Der Nervus opticus ist als Bestandteil des zentralen Nervensystems mit dem Liquorsystem verbunden. Intrazerebrale Druckerhöhungen wirken sich daher unmittelbar auf die ihn ummantelnde Nervenscheide und deren Durchmesser aus, sodass sich die Bestimmung des Optikusnervenscheidendurchmessers (ONSD) mittels transorbitaler Sonographie in der Diagnostik unterschiedlicher intrakranieller Erkrankungen bereits bewährt hat. Das Krankheitsbild der HIE wurde als weiteres mögliches Einsatzgebiet des ONSD jedoch bisher nicht untersucht.
Ziel dieser Dissertation war es daher, den ONSD grundsätzlich auf seine Verlässlichkeit als Prognoseparameter bei HIE nach Reanimation zu überprüfen. Besonderes Augenmerk lag hierbei auf der Ermöglichung einer frühzeitigen Prognoseeinschätzung innerhalb von 24 Stunden sowie auf der Definition eines prognostischen Cut-Off-Wertes als klare Entscheidungshilfe für weitere therapeutische Strategien.
24, 48 und 72 Stunden nach Reanimation werden signifikant unterschiedliche ONSD unter überlebenden und verstorbenen Patienten nachgewiesen. Letztere weisen dabei im Vergleich sowohl höhere als auch im zeitlichen Verlauf signifikant ansteigende ONSD-Werte auf. Als prognostischer Cut-Off-Wert konnte eine Grenze bei 5,75mm festgelegt werden.
Zusammenfassend stellt die sonographische Bestimmung des ONSD eine sinnvolle Zusatzdiagnostik in der Prognoseeinschätzung bei Patienten mit HIE nach Reanimation dar.
Die tiefe Hirnstimulation ist eine etablierte und hocheffiziente operative Behandlungsmethode für Patienten mit idiopathischem Parkinson- Syndrom (IPS). Als Zielgebiet dient in den meisten Fällen der Nucleus subthalamicus. Die Indikationen zur Implantation einer tiefen Hirnstimulation (THS) sind medikamentös nicht behandelbare motorische Fluktuationen und Dyskinesien oder ein medikamentös nicht kontrollierbarer Tremor.
Bislang erfolgt eine kontinuierliche Stimulation. Little et al. konnten jedoch bereits in ihrer 2013 veröffentlichen Studie zeigen, dass eine adaptive Stimulation, gemessen am UPDRS, um 27 % effektiver war und entsprechend die Stimulationszeit um 56 % gesenkt werden konnte.
Voraussetzung für die Anwendbarkeit einer adaptiven Stimulation im klinischen Alltag ist der Nachweis eines oder mehrerer Physiomarker, welche als Rückkopplungssignal für den Stimulationsbeginn dienen. Diese Marker müssen verlässlich mit dem Auftreten und der Ausprägung der Bewegungsstörungen korrelieren. Die Systeme müssen die Signale auslesen und entsprechend darauf reagieren können, damit ein sogenanntes Closed- loop- Verfahren entstehen kann. Bei diesen Markern handelt es sich um sogenannte lokale Feldpotenzialaktivitäten, das heißt niederfrequente Potentialänderungen von Zellen in subkortikalen Arealen des Gehirns, welche über Elektroden der THS abgeleitet werden können. Der Stimulator Activa PC+S (Medtronic) ermöglicht es erstmalig Aufzeichnungen von LFP- Daten, außerhalb eines experimentellen Laboraufbaus, mittels dauerhaft implantiertem Gerät vorzunehmen und damit auch Langzeitanalysen durchzuführen.
Erkenntnisse vergangener Studien ergaben, dass die synchronisierte, pathologisch gesteigerte oszillatorische Aktivität im Beta-Frequenzband (13- 35 Hz) eine bedeutende Rolle im Bezug auf die Pathophysiologie des IPS spielt und als krankheitsspezifische Aktivität gilt. Es konnte bereits belegt werden, dass die Verbesserung der motorischen Symptome (Bradykinese und Rigor) mit dem Ausmaß der Suppression der Betaband- Aktivität korreliert. Die Betabandaktivität als lokale Feldpotentialaktivität kann als Physiomarker einer adaptiven Stimulation dienen.
Unser Hauptaugenmerk galt daher der Analyse der Betabandaktivität oder anderer Frequenzbereiche während des Schlafes um hier die THS bedarfsgerecht einzusetzen. Hierfür wurden nächtliche subkortikale LFP- Aufzeichnungen parallel zur Schlaf- Polysomnographie durchgeführt. Zudem erfolgte in der vorliegenden Arbeit sowohl in unserem Vorversuch als auch in unserem Hauptversuch die Anwendung des UPDRS Teil III zur Erfassung der motorischen Symptome, sowie die Durchführung von Fragebögen zur Erfassung der nicht- motorischen Symptome, insbesondere des Schlafes vor und nach Implantation der tiefen Hirnstimulation.
Wir konnten belegen, dass es nach Implantation der THS zu einer Erhöhung der Schlafeffizienz und zu einer Erhöhung des Anteils der Schlafstadien II und III und damit einhergehend zu einer Steigerung der Schlafqualität kommt. Übereinstimmend mit anderen Studien konnten wir zeigen, dass sich die Motorik unter Stimulation deutlich verbessert. Im Vorversuch reduzierte sich der mittlere präoperative MDS- UPDRS III im MedsOFF verglichen mit dem mittleren postoperativ MDS- UPDRS III im MedsOFF/StimON um 37 %. In der PC+S- Studie imponierte eine Reduktion um 67%. Zudem zeigte sich eine Reduktion der nicht- motorischen Symptome durch die THS, insbesondere in der Kategorie Schlaf. Die Ergebnisse der vorliegenden Arbeit ergaben außerdem, dass die Betabandaktivität im Schlafstadium II und vor allem im Schlafstadium III am geringsten ist. Im Schlafstadium I und REM ist die Betabandaktivität höher als im Schlafstadium II und III. Hierbei war entscheidend, dass die Patienten eine klar abgrenzbare Betabandaktivität im Wachstadium aufwiesen und die Elektrodenkontakte im dorsolateralen Kerngebiet des STN lokalisiert waren.
Gegenläufig dazu verhält sich die Deltaaktivität. Sie ist im Schlafstadium II und besonders im Stadium III am höchsten. Stadium I ist mit durchschnittlich um 7,3 % niedriger als im Wachstadium. Am geringsten ist sie jedoch im REM-Schlafstadium.
Indem wir mit der Betabandaktivität und Deltaaktivität in den einzelnen Schlafstadien einen stabilen und reproduzierbaren Physiomarker finden konnten, sind wir unserem Ziel der adaptiven THS ein Stück näher gekommen.
Neuropathies are a group of potentially treatable diseases with an often disabling and restricting course. Amyotrophic lateral sclerosis (ALS) is a lethal disease without causal treatment possibilities. The objective of this study was to examine the diagnostic utility of HRUS for the differentiation of subtypes of axonal and demyelinating neuropathies and to investigate its utility for the sonological differentiation of ALS.
The hypothetical statement that neuropathy causes enlargement of peripheral nerves compared to healthy controls proved to be right, but the adjunctive assumption that ALS does not cause enlargement of peripheral nerves proved to be wrong – in patients with ALS slight enlargement of peripheral nerves was visible as well. The statement that nerve enlargement can be detected by measurement of the cross-sectional area (CSA) and the longitudinal diameter (LD) with comparable results proved to be right, but the enlargement was slightly less present by measurement of the LD. The statement that axonal and demyelinating neuropathies show distinct patterns of nerve enlargement must be answered differentiated: The comparison between axonal and demyelinating neuropathies showed a stronger nerve enlargement in patients with demyelinating neuropathies than in patients with axonal neuropathies at proximal nerve segments of upper extremities. In the comparison of diagnose-defined subgroups of inflammatory demyelinating neuropathies a respective specific pattern of nerve enlargement was visible. However, remarkable in this context was the strong nerve enlargement found in patients with NSVN, which is classified as an axonal neuropathy. Stratification for specific findings in nerve biopsy did not lead to constructive differences in comparison between the different groups.
To sum up, HRUS showed to provide a useful contribution in the diagnostic process of neuropathies and ALS but needs to be integrated in a multimodal diagnostic approach.
In der vorliegenden Studie wurde untersucht, ob zerebrale Mikroblutungen (CMB) bereits im frühen Verlauf nach ischämischem Schlaganfall (IS) oder Transitorisch-Ischämischer Attacke (TIA) mit kognitivem Abbau assoziiert sind und ob spezifische kognitive Domänen besonders betroffen sind. Der Vergleich zweier Probandengruppen mit IS/TIA und CMB bzw. IS/TIA ohne CMB hinsichtlich ihrer Ergebnisse in der neuropsychologischen Testbatterie CERAD ergab, dass CMB bereits sechs Monate nach dem zerebrovaskulären Ereignis mit einem kognitiven Abbau assoziiert sind. Multilokuläre CMB zeigen eine stärkere Auswirkung auf die Kognition als solche CMB, die in einer einzigen Hirnregion gefunden wurden. Zudem wurde eine signifikante Korrelation zwischen dem Grad der kognitiven Einschränkung und der Anzahl der CMB errechnet. Die separate Betrachtung derjenigen Testungen, welche das episodische Gedächtnis erfassen, zeigte eine Beeinträchtigung der Testpersonen beim Wiedererkennen von zuvor gelernten Wörtern. Bei der Untersuchung des semantischen Gedächtnisses der ProbandInnen fiel eine signifikant eingeschränkte phonematische Wortflüssigkeit auf, die semantische Flüssigkeit und das Benennen jedoch waren weniger betroffen. Die Domäne „Visuokonstruktive Fähigkeiten“ wurde ebenfalls in drei Untertests beurteilt. Hierbei zeigten sich keine Defizite der Testgruppe beim Abzeichnen der dargebotenen Figuren, die Reproduktion hingegen war signifikant gestört. Es zeigte sich keine CMB-bedingte Einschränkung der exekutiven Funktionen.
Auch wenn die Ätiopathogenese von Morbus Parkinson bis heute nicht vollständig geklärt ist, scheint α-Synuclein (α-Syn) eine zentrale Rolle zu spielen. Die Entdeckung als genetische Ursache der Erkrankung, als Hauptbestandteil der Lewy-Körper (LK) und seine Assoziation mit verschiedenen anderen potenziellen ätiologischen Faktoren verdeutlichen dies.
Bei Ratten und Affen führte eine AAV1/2-vermittelte Überexpression von A53T-α-Syn zu einer Degeneration dopaminerger Neurone in der Substantia nigra (SN), einem striatalen dopaminergen Defizit sowie Verhaltensauffälligkeiten. In Anbetracht bestimmter Vorteile der Mausspezies, war es das Ziel dieser Dissertation - die im Rahmen eines kollaborativen Projektes mit dem Toronto Western Research Institut in Ontario, Kanada entstanden ist - dieses auf AAV1/2-A53T-α-Syn basierende Parkinson-Modell auf Mäuse zu übertragen.
Dazu wurde AAV1/2-A53T-α-Syn oder leerer AAV1/2-Vektor in einer Dosis von 1,5 µl mit einer Konzentration von 5,16 x 10^12 gp/ml stereotaktisch einseitig in die rechte SN von C57BL/6-wt-Mäusen injiziert. Über einen Zeitraum von 11 Wochen wurden verschiedene Verhaltensexperimente durchgeführt und die beiden Versuchstiergruppen miteinander verglichen. Post-mortem erfolgten verschiedene immunhistochemische Untersuchungen.
Es konnte gezeigt werden, dass die einseitige Injektion von AAV1/2-A53T-α-Syn in die SN bei Mäusen eine weit verbreitete Überexpression von A53T-α-Syn in dopaminergen Neuronen der SN induzierte, die innerhalb von 10 Wochen zu signifikanten frühen und persistierenden motorischen Verhaltensauffälligkeiten, nigrostriataler Degeneration und Entwicklung einer Lewy-ähnlichen Pathologie führte.
Durch die Generierung und Charakterisierung dieses neuen Parkinson-Mausmodells, das klinische und histopathologische Merkmale der menschlichen Erkrankung widerspiegelt, besteht nun die Möglichkeit es weiterzuentwickeln und z.B. auf transgene Mäuse zu übertragen, um u.a. molekulare Mechanismen der Parkinson-Krankheit zu entschlüsseln und präklinische Tests von krankheitsmodifizierenden Therapien durchzuführen.
In der vorliegenden Studie untersuchten wir das Körperselbstgefühl von Patienten mit Morbus Parkinson und altersgematchten gesunden Teilnehmern mithilfe der Puppenhandillusion. Bei diesem Paradigma wird dadurch, dass die verdeckte Hand der Testperson zeitgleich mit einer sichtbaren Puppenhand bestrichen wird, das Gefühl hervorgerufen, die Kunsthand sei die eigene (gemessen mittels Fragebogen zur Illusion und propriozeptivem Drift). Eine zeitlich versetzte (asynchrone) Stimulation dient als Kontrollbedingung. Innerhalb der Parkinsonpatienten wurde darüber hinaus eine Untergruppe zusätzlich im medikamentösen OFF-Zustand untersucht.
Die Annahme, dass die Parkinsonerkrankung mit einer gestörten Körperselbstwahrnehmung einhergeht, spiegelt sich in den Ergebnissen wider: Bei den Patienten mit Parkinsonerkrankung trat unabhängig vom Stimulationsmodus ein höherer propriozeptiver Drift als bei den Gesunden ein. Wurden die Patienten anschließend nach dem Erleben der Illusion befragt, fielen die Antworten allerdings nur während der asynchronen Durchführung positiver als bei der Kontrollgruppe aus.
Die Untersuchungen des Drifts und Fragebogens im ON- gegenüber OFF-Zustand lieferten keinen Unterschied.
Die vorliegende Studie liefert Hinweise darauf, dass die gemessenen Unterschiede bei Parkinsonpatienten gegenüber Gesunden auf ein internes Rauschen eingehender sensorischer Signale beim Morbus Parkinson sowie auf die Beteiligung nicht-dopaminerger Systeme zurückzuführen sein könnten. Die zunehmende Aufmerksamkeit gegenüber einer veränderten Körperwahrnehmung bei Parkinsonpatienten und deren Grundlagen im Bereich der multisensorischen Integration könnte künftig neue Möglichkeiten in der ganzheitlichen Therapie liefern mit dem Ziel, die Lebensqualität der Patienten zu steigern.
Background and aims:
Small fiber neuropathy (SFN) is increasingly suspected in patients with pain of uncertain origin, and making the diagnosis remains a challenge lacking a diagnostic gold standard.
Methods:
In this case–control study, we prospectively recruited 86 patients with a medical history and clinical phenotype suggestive of SFN. Patients underwent neurological examination, quantitative sensory testing (QST), and distal and proximal skin punch biopsy, and were tested for pain-associated gene loci. Fifty-five of these patients additionally underwent pain-related evoked potentials (PREP), corneal confocal microscopy (CCM), and a quantitative sudomotor axon reflex test (QSART).
Results:
Abnormal distal intraepidermal nerve fiber density (IENFD) (60/86, 70%) and neurological examination (53/86, 62%) most frequently reflected small fiber disease. Adding CCM and/or PREP further increased the number of patients with small fiber impairment to 47/55 (85%). Genetic testing revealed potentially pathogenic gene variants in 14/86 (16%) index patients. QST, QSART, and proximal IENFD were of lower impact.
Conclusion:
We propose to diagnose SFN primarily based on the results of neurological examination and distal IENFD, with more detailed phenotyping in specialized centers.
In der Puppenhandillusion (PHI) wird durch die synchrone Berührung der nicht-sichtbaren Hand des Probanden und einer sichtbaren Puppenhand ein illusio-näres Körperzugehörigkeitsgefühl induziert. Dieses Paradigma erlaubt es zu untersuchen, wie das Gehirn widersprüchliche multisensorische Informationen während einer perzeptiven Inferenz auflöst.
Vorausgehende Studien weisen darauf hin, dass der Konflikt zwischen visueller und propriozeptiver Information vor der PHI durch eine Abschwächung des so-matosensiblen Inputs behoben wird. Um herauszufinden, ob eine Exzitabilitäts-Minderung des primären somatosensiblen Kortex die PHI verstärken kann, kam die kathodale transkranielle Gleichstromstimulation (c-tDCS) zum Einsatz.
An dreißig gesunden Probanden wurde die PHI ohne (=baseline) und während tDCS untersucht. Jeder Proband erhielt kathodale, anodale und sham-Stimulation an drei unterschiedlichen Tagen im Abstand von je einer Woche. Das PHI-Paradigma wurde in sechs Distanzen (von 17,5 bis 67,5 cm) zwischen der eigenen Hand und der Puppenhand durchgeführt. Das Auftreten der PHI wurde anhand eines Fragebogens (Illusionsscore, IS) und der Abweichung der gefühlten Handposition in Bezug zur realen Position (relativer Drift, RD) evalu-iert. Die kathodale Stimulation war mit einem signifikanten Anstieg des IS im Vergleich zur anodalen Stimulation assoziiert, wohingegen die RD-Werte über alle Stimulationsarten hinweg vergleichbar waren.
Die fehlende Signifikanz zwischen Verum und Sham-Stimulation wurde auf die geringe Effektstärke bei vergleichsweise kleinem Probandenkollektiv bezogen.
Die Ergebnisse dieser Studie zeigen jedoch eine verstärkte Wahrnehmung der PHI unabhängig von demographischen Faktoren, wenn kathodale tDCS über dem kontralateralen primären somatosensiblen Kortex appliziert wurde. Dies unterstützt unsere Hypothese, dass eine Abschwächung der somatosensiblen Präzision den Weg für eine erleichterte Integration eines fremden Körperteils in das eigene Körperschema ebnet.
The objective of this study was to examine the therapeutic potential of multiple sessions of training on a split-belt treadmill (SBT) combined with cerebellar anodal transcranial direct current stimulation (tDCS) on gait and balance in People with Multiple Sclerosis (PwMS). Twenty-two PwMS received six sessions of anodal (PwMS\(_{real}\), n = 12) or sham (PwMS\(_{sham}\), n = 10) tDCS to the cerebellum prior to performing the locomotor adaptation task on the SBT. To evaluate the effect of the intervention, functional gait assessment (FGA) scores and distance walked in 2 min (2MWT) were measured at the baseline (T0), day 6 (T5), and at the 4-week follow up (T6). Locomotor performance and changes of motor outcomes were similar in PwMS\(_{real}\) and PwMS\(_{sham}\) independently from tDCS mode applied to the cerebellum (anodal vs. sham, on FGA, p = 0.23; and 2MWT, p = 0.49). When the data were pooled across the groups to investigate the effects of multiple sessions of SBT training alone, significant improvement of gait and balance was found on T5 and T6, respectively, relative to baseline (FGA, p < 0.001 for both time points). The FGA change at T6 was significantly higher than at T5 (p = 0.01) underlining a long-lasting improvement. An improvement of the distance walked during the 2MWT was also observed on T5 and T6 relative to T0 (p = 0.002). Multiple sessions of SBT training resulted in a lasting improvement of gait stability and endurance, thus potentially reducing the risk of fall as measured by FGA and 2MWT. Application of cerebellar tDCS during SBT walking had no additional effect on locomotor outcomes.
We examined 143 patients suffering from FMS, a syndrome characterized by chronic widespread pain, sleep disturbances, and fatigue. Etiology and pathophysiology of FMS are scarcely understood. In recent years abnormalities of small Aδ- and C-nerve fibers have been found in subgroups of FMS patients. It is yet unclear how such SFP is caused in FMS patients and how it contributes to FMS symptoms.
We used CCM to analyze corneal small nerve fibers and associated LC, comparing FMS patients’ results to those from 65 healthy controls and 41 disease controls suffering from SFN. We, further, assessed expression levels of mRNA and miRNA in keratinocytes taken from skin punch biopsies of FMS patients and healthy controls kept as monocellular cell cultures. A screening was performed using NGS in a small cohort of 12 FMS patients and 5 healthy controls. Results were validated in larger cohorts by qRT-PCR.
As in previous studies IENFD and CNFD were reduced in a subgroup of FMS patients. We found identical LC densities in FMS patients, healthy controls, and SFN patients. The subpopulation of dLCfiber contact in FMS and SFN patients was lower than in healthy controls. Our RNA expression analysis revealed one mRNA that was expressed higher in FMS patients than in controls: PRSS21.
We conclude that reduced neurotrophic signaling of LC may contribute to SFP in the cornea. Epidermal PRSS21 expression and dLCfiber contact density are promising biomarker candidates for FMS diagnosis.
Beim idiopathischen Parkinson Syndrom (IPS) gewinnen nicht-motorische Symptome in Forschung und Klinik zunehmend an Bedeutung. So findet sich in der Literatur vermehrt Evidenz, dass die Propriozeption bei Patienten mit IPS (PmIPS) gestört ist. Verschiedene klinische und neuroanatomische Studien weisen darauf hin, dass es beim IPS zu einer fehlerhaften sensomotorischen Integration von propriozeptiven Informationen in den Basalganglien kommt. Zudem gibt es Hinweise, dass die passiv-sensible Wahrnehmung von Propriozeption pathologisch verändert ist. Außerdem wird vermutet, dass durch propriozeptives Training eine Verbesserung der Parkinsonsymptomatik erreicht werden kann. Ein spezielles Trainingsprogramm, die LSVT-BIG-Therapie, bei der gezielt trainiert wird, Bewegungen mit einer großen Amplitude durchzuführen, konnte motorische Symptome und Mobilität beim IPS effektiv verbessern.
In der vorliegenden Arbeit stellten wir folgende Hypothesen auf: Das IPS geht mit einer fehlerhaften sensomotorischen Integration von Propriozeption einher. Die afferente propriozeptive Wahrnehmung ist ebenfalls pathologisch verändert. Eine propriozeptive Rekalibrierung ist mithilfe der LSVT-BIG-Therapie möglich.
Für die Überprüfung dieser Hypothesen schlossen wir 30 PmIPS und 15 gesunde Probanden in unsere Fall-Kontroll-Studie ein und führten eine Eingangsuntersuchung durch. 11 PmIPS absolvierten anschließend eine vierwöchige LSVT-BIG-Therapie. Die Folgeuntersuchungen fanden 4 und 8 Wochen nach der Eingangsuntersuchung statt.
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Diese beinhalteten neuropsychologische Testungen, außerdem die Bestimmung der Lebensqualität, die Erhebung des motorischen Teils der Movement Disorder Society Unified Parkinson´s Disease Rating Scale (MDS-UPDRS III), Untersuchungen zur Feinmotorik, die Durchführung einer diagnostischen Transkraniellen Magnetstimulation (TMS) sowie Testverfahren zur Propriozeption, darunter sowohl Zeigeversuche, als auch die Bestimmung der Position einer Extremität, ohne visuelle Kontrolle.
Die Ergebnisse zeigten, dass die IPS-Gruppe gegenüber der gesunden Kontrollgruppe signifikant größere Zeigefehler machte, wohingegen die Bestimmung der Position einer Extremität in beiden Gruppen vergleichbar präzise möglich war. Zusätzlich zeigte eine von sieben Messungen der Feinmotorik einen signifikanten Unterschied zwischen PmIPS und Kontrollen. Die Messungen der TMS erbrachten hingegen keine signifikant messbaren Unterschiede zwischen den Gruppen.
In den Folgeuntersuchungen nach therapeutischer Intervention ergaben die Zeigeübungen eine signifikante Verbesserung der BIG-Gruppe im Zeitverlauf. Die Untersuchungen zu Feinmotorik und MDS-UPDRS III ergaben zwar eine tendenzielle Verbesserung durch die LSVT-BIG-Therapie, waren jedoch statistisch nicht signifikant.
Die Lebensqualität der PmIPS in der BIG-Gruppe verbesserte sich signifikant nach Intervention.
Die Ergebnisse sprechen für die Hypothese der fehlerhaften propriozeptiven Integration beim Morbus Parkinson. Dies zeigte sich für aktive sensomotorische Tasks, nicht hingegen in der passiv-sensiblen propriozeptiven Testung.
Auch wenn weitere Studien mit größeren Kohorten benötigt werden, legt unsere Studie nahe, dass die LSVT-BIG-Therapie mit einer propriozeptiven Rekalibrierung einhergeht. Damit erklärt sich möglicherweise der nachhaltige Erfolg der Therapie.
High-mobility group box 1 protein (HMGB1) is a damage-associated molecular pattern (DAMP) involved in neutrophil extracellular trap (NET) formation and thrombosis. NETs are regularly found in cerebral thromboemboli. We here analyzed associated HMGB1 expression in human thromboemboli retrieved via mechanical thrombectomy from 37 stroke patients with large vessel occlusion. HMGB1 was detected in all thromboemboli, accounting for 1.7% (IQR 0.6–6.2%) of the total thromboemboli area and was found to be colocalized with neutrophils and NETs and in spatial proximity to platelets. Correlation analysis revealed that the detection of HMGB1 was strongly related to the number of neutrophils (r = 0.58, p = 0.0002) and platelets (r = 0.51, p = 0.001). Our results demonstrate that HMGB1 is a substantial constituent of thromboemboli causing large vessel occlusion stroke.
Inflammation is crucial in the pathophysiology of stroke and thus a promising therapeutic target. High-frequency stimulation (HFS) of the mesencephalic locomotor region (MLR) reduces perilesional inflammation after photothrombotic stroke (PTS). However, the underlying mechanism is not completely understood. Since distinct neural and immune cells respond to electrical stimulation by releasing acetylcholine, we hypothesize that HFS might trigger the cholinergic anti-inflammatory pathway via activation of the α7 nicotinic acetylcholine receptor (α7nAchR). To test this hypothesis, rats underwent PTS and implantation of a microelectrode into the MLR. Three hours after intervention, either HFS or sham-stimulation of the MLR was applied for 24 h. IFN-γ, TNF-α, and IL-1α were quantified by cytometric bead array. Choline acetyltransferase (ChAT)\(^+\) CD4\(^+\)-cells and α7nAchR\(^+\)-cells were quantified visually using immunohistochemistry. Phosphorylation of NFĸB, ERK1/2, Akt, and Stat3 was determined by Western blot analyses. IFN-γ, TNF-α, and IL-1α were decreased in the perilesional area of stimulated rats compared to controls. The number of ChAT\(^+\) CD4\(^+\)-cells increased after MLR-HFS, whereas the amount of α7nAchR\(^+\)-cells was similar in both groups. Phospho-ERK1/2 was reduced significantly in stimulated rats. The present study suggests that MLR-HFS may trigger anti-inflammatory processes within the perilesional area by modulating the cholinergic system, probably via activation of the α7nAchR.
Patients with atrial fibrillation and previous ischemic stroke (IS) are at increased risk of cerebrovascular events despite anticoagulation. In these patients, treatment with non-vitamin K oral anticoagulants (NOAC) such as edoxaban reduced the probability and severity of further IS without increasing the risk of major bleeding. However, the detailed protective mechanism of edoxaban has not yet been investigated in a model of ischemia/reperfusion injury. Therefore, in the current study we aimed to assess in a clinically relevant setting whether treatment with edoxaban attenuates stroke severity, and whether edoxaban has an impact on the local cerebral inflammatory response and blood–brain barrier (BBB) function after experimental IS in mice. Focal cerebral ischemia was induced by transient middle cerebral artery occlusion in male mice receiving edoxaban, phenprocoumon or vehicle. Infarct volumes, functional outcome and the occurrence of intracerebral hemorrhage were assessed. BBB damage and the extent of local inflammatory response were determined. Treatment with edoxaban significantly reduced infarct volumes and improved neurological outcome and BBB function on day 1 and attenuated brain tissue inflammation. In summary, our study provides evidence that edoxaban might exert its protective effect in human IS by modulating different key steps of IS pathophysiology, but further studies are warranted.
Skin alpha-synuclein deposition is considered a potential biomarker for Parkinson's disease (PD). Real-time quaking-induced conversion (RT-QuIC) is a novel, ultrasensitive, and efficient seeding assay that enables the detection of minute amounts of alpha-synuclein aggregates. We aimed to determine the diagnostic accuracy, reliability, and reproducibility of alpha-synuclein RT-QuIC assay of skin biopsy for diagnosing PD and to explore its correlation with clinical markers of PD in a two-center inter-laboratory comparison study. Patients with clinically diagnosed PD (n = 34), as well as control subjects (n = 30), underwent skin punch biopsy at multiple sites (neck, lower back, thigh, and lower leg). The skin biopsy samples (198 in total) were divided in half to be analyzed by RT-QuIC assay in two independent laboratories. The a-synuclein RT-QuIC assay of multiple skin biopsies supported the clinical diagnosis of PD with a diagnostic accuracy of 88.9% and showed a high degree of inter-rater agreement between the two laboratories (92.2%). Higher alpha-synuclein seeding activity in RT-QuIC was shown in patients with longer disease duration and more advanced disease stage and correlated with the presence of REM sleep behavior disorder, cognitive impairment, and constipation. The alpha-synuclein RT-QuIC assay of minimally invasive skin punch biopsy is a reliable and reproducible biomarker for Parkinson's disease. Moreover, alpha-synuclein RT-QuIC seeding activity in the skin may serve as a potential indicator of progression as it correlates with the disease stage and certain non-motor symptoms.
Based on recent findings that show that depletion of factor XII (FXII) leads to better posttraumatic neurological recovery, we studied the effect of FXII-deficiency on post-traumatic cognitive and behavioral outcomes in female and male mice. In agreement with our previous findings, neurological deficits on day 7 after weight-drop traumatic brain injury (TBI) were significantly reduced in FXII\(^{−/−}\) mice compared to wild type (WT) mice. Also, glycoprotein Ib (GPIb)-positive platelet aggregates were more frequent in brain microvasculature of WT than FXII\(^{−/−}\) mice 3 months after TBI. Six weeks after TBI, memory for novel object was significantly reduced in both female and male WT but not in FXII\(^{−/−}\) mice compared to sham-operated mice. In the setting of automated home-cage monitoring of socially housed mice in IntelliCages, female WT mice but not FXII\(^{−/−}\) mice showed decreased exploration and reacted negatively to reward extinction one month after TBI. Since neuroendocrine stress after TBI might contribute to trauma-induced cognitive dysfunction and negative emotional contrast reactions, we measured peripheral corticosterone levels and the ration of heart, lung, and spleen weight to bodyweight. Three months after TBI, plasma corticosterone levels were significantly suppressed in both female and male WT but not in FXII\(^{−/−}\) mice, while the relative heart weight increased in males but not in females of both phenotypes when compared to sham-operated mice. Our results indicate that FXII deficiency is associated with efficient post-traumatic behavioral and neuroendocrine recovery.
The differentiation of human induced pluripotent stem cells (hiPSCs) into specific cell types for disease modeling and restorative therapies is a key research agenda and offers the possibility to obtain patient-specific cells of interest for a wide range of diseases. Basal forebrain cholinergic neurons (BFCNs) play a particular role in the pathophysiology of Alzheimer’s dementia and isolated dystonias. In this work, various directed differentiation protocols based on monolayer neural induction were tested for their effectiveness in promoting a ventral telencephalic phenotype and generating BFCN. Ventralizing factors [i.e., purmorphamine and Sonic hedgehog (SHH)] were applied at different time points, time intervals, and concentrations. In addition, caudal identity was prevented by the use of a small molecule XAV-939 that inhibits the Wnt-pathway. After patterning, gene expression profiles were analyzed by quantitative PCR (qPCR). Rostro-ventral patterning is most effective when initiated simultaneously with neural induction. The most promising combination of patterning factors was 0.5 μM of purmorphamine and 1 μM of XAV-939, which induces the highest expression of transcription factors specific for the medial ganglionic eminence, the source of GABAergic inter- and cholinergic neurons in the telencephalon. Upon maturation of cells, the immune phenotype, as well as electrophysiological properties were investigated showing the presence of marker proteins specific for BFCN (choline acetyltransferase, ISL1, p75, and NKX2.1) and GABAergic neurons. Moreover, a considerable fraction of measured cells displayed mature electrophysiological properties. Synaptic boutons containing the vesicular acetylcholine transporter (VACHT) could be observed in the vicinity of the cells. This work will help to generate basal forebrain interneurons from hiPSCs, providing a promising platform for modeling neurological diseases, such as Alzheimer’s disease or Dystonia.
Objective: In light of the ongoing COVID-19 pandemic and the associated hospitalization of an overwhelming number of ventilator-dependent patients, medical and/or ethical patient triage paradigms have become essential. While guidelines on the allocation of scarce resources do exist, such work within the subdisciplines of intensive care (e.g., neurocritical care) remains limited.
Methods: A 16-item questionnaire was developed that sought to explore/quantify the expert opinions of German neurointensivists with regard to triage decisions. The anonymous survey was conducted via a web-based platform and in total, 96 members of the Initiative of German Neurointensive Trial Engagement (IGNITE)-study group were contacted via e-mail. The IGNITE consortium consists of an interdisciplinary panel of specialists with expertise in neuro-critical care (i.e., anesthetists, neurologists and neurosurgeons).
Results: Fifty members of the IGNITE consortium responded to the questionnaire; in total the respondents were in charge of more than 500 Neuro ICU beds throughout Germany. Common determinants reported which affected triage decisions included known patient wishes (98%), the state of health before admission (96%), SOFA-score (85%) and patient age (69%). Interestingly, other principles of allocation, such as a treatment of “youngest first” (61%) and members of the healthcare sector (50%) were also noted. While these were the most accepted parameters affecting the triage of patients, a “first-come, first-served” principle appeared to be more accepted than a lottery for the allocation of ICU beds which contradicts much of what has been reported within the literature. The respondents also felt that at least one neurointensivist should serve on any interdisciplinary triage team.
Conclusions: The data gathered in the context of this survey reveal the estimation/perception of triage algorithms among neurointensive care specialists facing COVID-19. Further, it is apparent that German neurointensivists strongly feel that they should be involved in any triage decisions at an institutional level given the unique resources needed to treat patients within the Neuro ICU.
Diabetic polyneuropathy (DPN) is the most common complication in diabetes and can be painful in up to 26% of all diabetic patients. Peripheral nerves are shielded by the blood-nerve barrier (BNB) consisting of the perineurium and endoneurial vessels. So far, there are conflicting results regarding the role and function of the BNB in the pathophysiology of DPN. In this study, we analyzed the spatiotemporal tight junction protein profile, barrier permeability, and vessel-associated macrophages in Wistar rats with streptozotocin-induced DPN. In these rats, mechanical hypersensitivity developed after 2 weeks and loss of motor function after 8 weeks, while the BNB and the blood-DRG barrier were leakier for small, but not for large molecules after 8 weeks only. The blood-spinal cord barrier remained sealed throughout the observation period. No gross changes in tight junction protein or cytokine expression were observed in all barriers to blood. However, expression of Cldn1 mRNA in perineurium was specifically downregulated in conjunction with weaker vessel-associated macrophage shielding of the BNB. Our results underline the role of specific tight junction proteins and BNB breakdown in DPN maintenance and differentiate DPN from traumatic nerve injury. Targeting claudins and sealing the BNB could stabilize pain and prevent further nerve damage.
Dermal and cardiac autonomic fiber involvement in Parkinson's disease and multiple system atrophy
(2021)
Pathological aggregates of alpha-synuclein in peripheral dermal nerve fibers can be detected in patients with idiopathic Parkinson's disease and multiple system atrophy. This study combines skin biopsy staining for p-alpha-synuclein depositions and radionuclide imaging of the heart with [\(^{123}\)I]-metaiodobenzylguanidine to explore peripheral denervation in both diseases. To this purpose, 42 patients with a clinical diagnosis of Parkinson's disease or multiple system atrophy were enrolled. All patients underwent a standardized clinical workup including neurological evaluation, neurography, and blood samples. Skin biopsies were obtained from the distal and proximal leg, back, and neck for immunofluorescence double labeling with anti-p-alpha-synuclein and anti-PGP9.5. All patients underwent myocardial [\(^{123}\)I]-metaiodobenzylguanidine scintigraphy. Dermal p-alpha-synuclein was observed in 47.6% of Parkinson's disease patients and was mainly found in autonomic structures. 81.0% of multiple system atrophy patients had deposits with most of cases in somatosensory fibers. The [\(^{123}\)I]-metaiodobenzylguanidine heart-to-mediastinum ratio was lower in Parkinson's disease than in multiple system atrophy patients (1.94 +/- 0.63 vs. 2.91 +/- 0.96; p < 0.0001). Irrespective of the diagnosis, uptake was lower in patients with than without p-alpha-synuclein in autonomic structures (1.42 +/- 0.51 vs. 2.74 +/- 0.83; p < 0.0001). Rare cases of Parkinson's disease with p-alpha-synuclein in somatosensory fibers and multiple system atrophy patients with deposits in autonomic structures or both fiber types presented with clinically overlapping features. In conclusion, this study suggests that alpha-synuclein contributes to peripheral neurodegeneration and mediates the impairment of cardiac sympathetic neurons in patients with synucleinopathies. Furthermore, it indicates that Parkinson's disease and multiple system atrophy share pathophysiologic mechanisms of peripheral nervous system dysfunction with a clinical overlap.
Purpose
Over the course of COVID-19 pandemic, evidence has accumulated that SARS-CoV-2 infections may affect multiple organs and have serious clinical sequelae, but on-site clinical examinations with non-hospitalized samples are rare. We, therefore, aimed to systematically assess the long-term health status of samples of hospitalized and non-hospitalized SARS-CoV-2 infected individuals from three regions in Germany.
Methods
The present paper describes the COVIDOM-study within the population-based cohort platform (POP) which has been established under the auspices of the NAPKON infrastructure (German National Pandemic Cohort Network) of the national Network University Medicine (NUM). Comprehensive health assessments among SARS-CoV-2 infected individuals are conducted at least 6 months after the acute infection at the study sites Kiel, Würzburg and Berlin. Potential participants were identified and contacted via the local public health authorities, irrespective of the severity of the initial infection. A harmonized examination protocol has been implemented, consisting of detailed assessments of medical history, physical examinations, and the collection of multiple biosamples (e.g., serum, plasma, saliva, urine) for future analyses. In addition, patient-reported perception of the impact of local pandemic-related measures and infection on quality-of-life are obtained.
Results
As of July 2021, in total 6813 individuals infected in 2020 have been invited into the COVIDOM-study. Of these, about 36% wished to participate and 1295 have already been examined at least once.
Conclusion
NAPKON-POP COVIDOM-study complements other Long COVID studies assessing the long-term consequences of an infection with SARS-CoV-2 by providing detailed health data of population-based samples, including individuals with various degrees of disease severity.
Trial registration
Registered at the German registry for clinical studies (DRKS00023742).
Tetrahydroisoquinolines (TIQs) such as salsolinol (SAL), norsalsolinol (NSAL) and their methylated derivatives N-methyl-norsalsolinol (NMNSAL) and N-methyl-salsolinol (NMSAL), modulate dopaminergic neurotransmission and metabolism in the central nervous system. Dopaminergic neurotransmission is thought to play an important role in the pathophysiology of chronic tic disorders, such as Tourette syndrome (TS). Therefore, the urinary concentrations of these TIQ derivatives were measured in patients with TS and patients with comorbid attention-deficit/hyperactivity disorder (TS + ADHD) compared with controls. Seventeen patients with TS, 12 with TS and ADHD, and 19 age-matched healthy controls with no medication took part in this study. Free levels of NSAL, NMNSAL, SAL, and NMSAL in urine were measured by a two-phase chromatographic approach. Furthermore, individual TIQ concentrations in TS patients were used in receiver-operating characteristics (ROC) curve analysis to examine the diagnostic value. NSAL concentrations were elevated significantly in TS [434.67 ± 55.4 nmol/l (standard error of mean = S.E.M.), two-way ANOVA, p < 0.0001] and TS + ADHD patients [605.18 ± 170.21 nmol/l (S.E.M.), two-way ANOVA, p < 0.0001] compared with controls [107.02 ± 33.18 nmol/l (S.E.M.), two-way ANOVA, p < 0.0001] and NSAL levels in TS + ADHD patients were elevated significantly in comparison with TS patients (two-way ANOVA, p = 0.017). NSAL demonstrated an AUC of 0.93 ± 0.046 (S.E.M) the highest diagnostic value of all metabolites for the diagnosis of TS. Our results suggest a dopaminergic hyperactivity underlying the pathophysiology of TS and ADHD. In addition, NSAL concentrations in urine may be a potential diagnostic biomarker of TS.
Hintergrund und Ziel
Telemedizinische Schlaganfall-Netzwerke tragen dazu bei, die Schlaganfallversorgung und insbesondere den Zugang zu zeitkritischen Schlaganfalltherapien in vorrangig strukturschwachen, ländlichen Regionen zu gewährleisten. Ziel ist eine Darstellung der Nutzungsfrequenz und regionalen Verteilung dieser Versorgungsstruktur.
Methoden
Die Kommission „Telemedizinische Schlaganfallversorgung“ der Deutschen Schlaganfall-Gesellschaft führte eine Umfragestudie in allen Schlaganfall-Netzwerken durch.
Ergebnisse
In Deutschland sind 22 telemedizinische Schlaganfall-Netzwerke aktiv, welche insgesamt 43 Zentren (pro Netzwerk: Median 1,5, Interquartilsabstand [IQA] 1–3) sowie 225 Kooperationskliniken (pro Netzwerk: Median 9, IQA 4–17) umfassen und an einem unmittelbaren Zugang zur Schlaganfallversorgung für 48 Mio. Menschen teilhaben. Im Jahr 2018 wurden 38.211 Telekonsile (pro Netzwerk: Median 1340, IQA 319–2758) durchgeführt. Die Thrombolyserate betrug 14,1 % (95 %-Konfidenzintervall 13,6–14,7 %), eine Verlegung zur Thrombektomie wurde bei 7,9 % (95 %-Konfidenzintervall 7,5–8,4 %) der ischämischen Schlaganfallpatienten initiiert. Das Finanzierungssystem ist uneinheitlich mit einem Vergütungssystem für die Zentrumsleistungen in nur drei Bundesländern.
Diskussion
Etwa jeder 10. Schlaganfallpatient wird telemedizinisch behandelt. Die telemedizinischen Schlaganfall-Netzwerke erreichen vergleichbar hohe Lyseraten und Verlegungen zur Thrombektomie wie neurologische Stroke-Units und tragen zur Sicherstellung einer flächendeckenden Schlaganfallversorgung bei. Eine netzwerkübergreifende Sicherstellung der Finanzierung und einheitliche Erhebung von Qualitätssicherungsdaten haben das Potenzial diese Versorgungsstruktur zukünftig weiter zu stärken.
Objectives: Deep brain stimulation (DBS) programming is based on clinical response testing. Our clinical pilot trial assessed the feasibility of image-guided programing using software depicting the lead location in a patient-specific anatomical model.
Methods: Parkinson's disease patients with subthalamic nucleus-DBS were randomly assigned to standard clinical-based programming (CBP) or anatomical-based (imaging-guided) programming (ABP) in an 8-week crossover trial. Programming characteristics and clinical outcomes were evaluated.
Results: In 10 patients, both programs led to similar motor symptom control (MDS-UPDRS III) after 4 weeks (medicationOFF/stimulationON; CPB: 18.27 ± 9.23; ABP: 18.37 ± 6.66). Stimulation settings were not significantly different, apart from higher frequency in the baseline program than CBP (p = 0.01) or ABP (p = 0.003). Time spent in a program was not significantly different (CBP: 86.1 ± 29.82%, ABP: 88.6 ± 29.0%). Programing time was significantly shorter (p = 0.039) with ABP (19.78 ± 5.86 min) than CBP (45.22 ± 18.32).
Conclusion: Image-guided DBS programming in PD patients drastically reduces programming time without compromising symptom control and patient satisfaction in this small feasibility trial.
Background: Recently, attention has grown toward cerebellar neuromodulation in motor learning using transcranial direct current stimulation (tDCS). An important point of discussion regarding this modulation is the optimal timing of tDCS, as this parameter could significantly influence the outcome. Hence, this study aimed to investigate the effects of the timing of cerebellar anodal tDCS (ca-tDCS) on motor learning using a sequential finger-tapping task (FTT).
Methods: One hundred and twenty two healthy young, right-handed subjects (96 females) were randomized into four groups (During\(_{sham}\), Before, During\(_{real}\), After). They performed 2 days of FTT with their non-dominant hand on a custom keyboard. The task consisted of 40 s of typing followed by 20 s rest. Each participant received ca-tDCS (2 mA, sponge electrodes of 25 cm\(^{2}\), 20 min) at the appropriate timing and performed 20 trials on the first day (T1, 20 min). On the following day, only 10 trials of FTT were performed without tDCS (T2, 10 min). Motor skill performance and retention were assessed.
Results: All participants showed a time-dependent increase in learning. Motor performance was not different between groups at the end of T1 (p = 0.59). ca-tDCS did not facilitate the retention of the motor skill in the FTT at T2 (p = 0.27). Thus, our findings indicate an absence of the effect of ca-tDCS on motor performance or retention of the FTT independently from the timing of stimulation.
Conclusion: The present results suggest that the outcome of ca-tDCS is highly dependent on the task and stimulation parameters. Future studies need to establish a clear basis for the successful and reproducible clinical application of ca-tDCS.
Background and purpose
Improving understanding of study contents and procedures might enhance recruitment into studies and retention during follow-up. However, data in stroke patients on understanding of the informed consent (IC) procedure are sparse.
Methods
We conducted a cross-sectional study among ischemic stroke patients taking part in the IC procedure of an ongoing cluster-randomized secondary prevention trial. All aspects of the IC procedure were assessed in an interview using a standardized 20-item questionnaire. Responses were collected within 72 h after the IC procedure and analyzed quantitatively and qualitatively. Participants were also asked their main reasons for participation.
Results
A total of 146 stroke patients (65 ± 12 years old, 38% female) were enrolled. On average, patients recalled 66.4% (95% confidence interval = 65.2%–67.5%) of the content of the IC procedure. Most patients understood that participation was voluntary (99.3%) and that they had the right to withdraw consent (97.1%); 79.1% of the patients recalled the study duration and 56.1% the goal. Only 40.3% could clearly state a benefit of participation, and 28.8% knew their group allocation. Younger age, higher graduation, and allocation to the intervention group were associated with better understanding. Of all patients, 53% exclusively stated a personal and 22% an altruistic reason for participation.
Conclusions
Whereas understanding of patient rights was high, many patients were unable to recall other important aspects of study content and procedures. Increased attention to older and less educated patients may help to enhance understanding in this patient population. Actual recruitment and retention benefit of an improved IC procedure remains to be tested in a randomized trial.
It remains unclear if principal components of the local cerebral stroke immune response can be reliably and reproducibly observed in patients with acute large-vessel-occlusion (LVO) stroke. We prospectively studied a large independent cohort of n = 318 consecutive LVO stroke patients undergoing mechanical thrombectomy during which cerebral blood samples from within the occluded anterior circulation and systemic control samples from the ipsilateral cervical internal carotid artery were obtained. An extensive protocol was applied to homogenize the patient cohort and to standardize the procedural steps of endovascular sample collection, sample processing, and laboratory analyses. N = 58 patients met all inclusion criteria. (1) Mean total leukocyte counts were significantly higher within the occluded ischemic cerebral vasculature (I) vs. intraindividual systemic controls (S): +9.6%, I: 8114/µL ± 529 vs. S: 7406/µL ± 468, p = 0.0125. (2) This increase was driven by neutrophils: +12.1%, I: 7197/µL ± 510 vs. S: 6420/µL ± 438, p = 0.0022. Leukocyte influx was associated with (3) reduced retrograde collateral flow (R\(^2\) = 0.09696, p = 0.0373) and (4) greater infarct extent (R\(^2\) = 0.08382, p = 0.032). Despite LVO, leukocytes invade the occluded territory via retrograde collateral pathways early during ischemia, likely compromising cerebral hemodynamics and tissue integrity. This inflammatory response can be reliably observed in human stroke by harvesting immune cells from the occluded cerebral vascular compartment.
Targeting neuroinflammation in models for infantile and juvenile forms of neuronal ceroid lipofuscinosis (NCL, CLN disease) with the clinically established immunomodulators fingolimod and teriflunomide significantly attenuates the neurodegenerative phenotype when applied preventively, i.e. before the development of substantial neural damage and clinical symptoms. Here, we show that in a mouse model for the early onset and rapidly progressing CLN1 form, more complex clinical phenotypes like disturbed motor coordination and impaired visual acuity are also ameliorated by immunomodulation. Moreover, we show that the disease outcome can be attenuated even when fingolimod and teriflunomide treatment starts after disease onset, i.e. when neurodegeneration is ongoing and clinical symptoms are detectable. In detail, treatment with either drug led to a reduction in T-cell numbers and microgliosis in the CNS, although not to the same extent as upon preventive treatment. Pharmacological immunomodulation was accompanied by a reduction of axonal damage, neuron loss and astrogliosis in the retinotectal system and by reduced brain atrophy. Accordingly, the frequency of myoclonic jerks and disturbed motor coordination were attenuated. Overall, disease alleviation was remarkably substantial upon therapeutic treatment with both drugs, although less robust than upon preventive treatment. To test the relevance of putative immune-independent mechanisms of action in this model, we treated CLN1 mice lacking mature T- and B-lymphocytes. Immunodeficient CLN1 mice showed, as previously reported, an improved neurological phenotype in comparison with genuine CLN1 mice which could not be further alleviated by either of the drugs, reflecting a predominantly immune-related therapeutic mechanism of action. The present study supports and strengthens our previous view that repurposing clinically approved immunomodulators may alleviate the course of CLN1 disease in human patients, even though diagnosis usually occurs when symptoms have already emerged.
Treatment-induced neuropathy in diabetes (TIND) — Developing a disease model in type 1 diabetic rats
(2021)
Treatment-induced neuropathy in diabetes (TIND) is defined by the occurrence of an acute neuropathy within 8 weeks of an abrupt decrease in glycated hemoglobin-A1c (HbA1c). The underlying pathogenic mechanisms are still incompletely understood with only one mouse model being explored to date. The aim of this study was to further explore the hypothesis that an abrupt insulin-induced fall in HbA1c may be the prime causal factor of developing TIND. BB/OKL (bio breeding/OKL, Ottawa Karlsburg Leipzig) diabetic rats were randomized in three groups, receiving insulin treatment by implanted subcutaneous osmotic insulin pumps for 3 months, as follows: Group one received 2 units per day; group two 1 unit per day: and group three 1 unit per day in the first month, followed by 2 units per day in the last two months. We serially examined blood glucose and HbA1c levels, motor- and sensory/mixed afferent conduction velocities (mNCV and csNCV) and peripheral nerve morphology, including intraepidermal nerve fiber density and numbers of Iba-1 (ionized calcium binding adaptor molecule 1) positive macrophages in the sciatic nerve. Only in BB/OKL rats of group three, with a rapid decrease in HbA1c of more than 2%, did we find a significant decrease in mNCV in sciatic nerves (81% of initial values) after three months of treatment as compared to those group three rats with a less marked decrease in HbA1c <2% (mNCV 106% of initial values, p ≤ 0.01). A similar trend was observed for sensory/mixed afferent nerve conduction velocities: csNCV were reduced in BB/OKL rats with a rapid decrease in HbA1c >2% (csNCV 90% of initial values), compared to those rats with a mild decrease <2% (csNCV 112% of initial values, p ≤ 0.01). Moreover, BB/OKL rats of group three with a decrease in HbA1c >2% showed significantly greater infiltration of macrophages by about 50% (p ≤ 0.01) and a decreased amount of calcitonin gene related peptide (CGRP) positive nerve fibers as compared to the animals with a milder decrease in HbA1c. We conclude that a mild acute neuropathy with inflammatory components was induced in BB/OKL rats as a consequence of an abrupt decrease in HbA1c caused by high-dose insulin treatment. This experimentally induced neuropathy shares some features with TIND in humans and may be further explored in studies into the pathogenesis and treatment of TIND.
Second hit hypothesis in dystonia: Dysfunctional cross talk between neuroplasticity and environment?
(2021)
One of the great mysteries in dystonia pathophysiology is the role of environmental factors in disease onset and development. Progress has been made in defining the genetic components of dystonic syndromes, still the mechanisms behind the discrepant relationship between dystonic genotype and phenotype remain largely unclear. Within this review, the preclinical and clinical evidence for environmental stressors as disease modifiers in dystonia pathogenesis are summarized and critically evaluated. The potential role of extragenetic factors is discussed in monogenic as well as adult-onset isolated dystonia. The available clinical evidence for a "second hit" is analyzed in light of the reduced penetrance of monogenic dystonic syndromes and put into context with evidence from animal and cellular models. The contradictory studies on adult-onset dystonia are discussed in detail and backed up by evidence from animal models. Taken together, there is clear evidence of a gene-environment interaction in dystonia, which should be considered in the continued quest to unravel dystonia pathophysiology.
This expert opinion paper on cardiac imaging after acute ischemic stroke or transient ischemic attack (TIA) includes a statement of the "Heart and Brain" consortium of the German Cardiac Society and the German Stroke Society. The Stroke Unit-Commission of the German Stroke Society and the German Atrial Fibrillation NETwork (AFNET) endorsed this paper. Cardiac imaging is a key component of etiological work-up after stroke. Enhanced echocardiographic tools, constantly improving cardiac computer tomography (CT) as well as cardiac magnetic resonance imaging (MRI) offer comprehensive non- or less-invasive cardiac evaluation at the expense of increased costs and/or radiation exposure. Certain imaging findings usually lead to a change in medical secondary stroke prevention or may influence medical treatment. However, there is no proof from a randomized controlled trial (RCT) that the choice of the imaging method influences the prognosis of stroke patients. Summarizing present knowledge, the German Heart and Brain consortium proposes an interdisciplinary, staged standard diagnostic scheme for the detection of risk factors of cardio-embolic stroke. This expert opinion paper aims to give practical advice to physicians who are involved in stroke care. In line with the nature of an expert opinion paper, labeling of classes of recommendations is not provided, since many statements are based on expert opinion, reported case series, and clinical experience.
Regional iron accumulation and α‐synuclein (α‐syn) spreading pathology within the central nervous system are common pathological findings in Parkinson's disease (PD). Whereas iron is known to bind to α‐syn, facilitating its aggregation and regulating α‐syn expression, it remains unclear if and how iron also modulates α‐syn spreading. To elucidate the influence of iron on the propagation of α‐syn pathology, we investigated α‐syn spreading after stereotactic injection of α‐syn preformed fibrils (PFFs) into the striatum of mouse brains after neonatal brain iron enrichment. C57Bl/6J mouse pups received oral gavage with 60, 120, or 240 mg/kg carbonyl iron or vehicle between postnatal days 10 and 17. At 12 weeks of age, intrastriatal injections of 5‐µg PFFs were performed to induce seeding of α‐syn aggregates. At 90 days post‐injection, PFFs‐injected mice displayed long‐term memory deficits, without affection of motor behavior. Interestingly, quantification of α‐syn phosphorylated at S129 showed reduced α‐syn pathology and attenuated spreading to connectome‐specific brain regions after brain iron enrichment. Furthermore, PFFs injection caused intrastriatal microglia accumulation, which was alleviated by iron in a dose‐dependent way. In primary cortical neurons in a microfluidic chamber model in vitro, iron application did not alter trans‐synaptic α‐syn propagation, possibly indicating an involvement of non‐neuronal cells in this process. Our study suggests that α‐syn PFFs may induce cognitive deficits in mice independent of iron. However, a redistribution of α‐syn aggregate pathology and reduction of striatal microglia accumulation in the mouse brain may be mediated via iron‐induced alterations of the brain connectome.
Inflammatory mechanisms in the pathophysiology of diabetic peripheral neuropathy (DN) — new aspects
(2021)
The pathogenesis of diabetic neuropathy is complex, and various pathogenic pathways have been proposed. A better understanding of the pathophysiology is warranted for developing novel therapeutic strategies. Here, we summarize recent evidence from experiments using animal models of type 1 and type 2 diabetes showing that low-grade intraneural inflammation is a facet of diabetic neuropathy. Our experimental data suggest that these mild inflammatory processes are a likely common terminal pathway in diabetic neuropathy associated with the degeneration of intraepidermal nerve fibers. In contrast to earlier reports claiming toxic effects of high-iron content, we found the opposite, i.e., nutritional iron deficiency caused low-grade inflammation and fiber degeneration while in normal or high non-heme iron nutrition no or only extremely mild inflammatory signs were identified in nerve tissue. Obesity and dyslipidemia also appear to trigger mild inflammation of peripheral nerves, associated with neuropathy even in the absence of overt diabetes mellitus. Our finding may be the experimental analog of recent observations identifying systemic proinflammatory activity in human sensorimotor diabetic neuropathy. In a rat model of type 1 diabetes, a mild neuropathy with inflammatory components could be induced by insulin treatment causing an abrupt reduction in HbA1c. This is in line with observations in patients with severe diabetes developing a small fiber neuropathy upon treatment-induced rapid HbA1c reduction. If the inflammatory pathogenesis could be further substantiated by data from human tissues and intervention studies, anti-inflammatory compounds with different modes of action may become candidates for the treatment or prevention of diabetic neuropathy.
Genetic deficiency for acid sphingomyelinase or its pharmacological inhibition has been shown to increase Foxp3\(^+\) regulatory T-cell frequencies among CD4\(^+\) T cells in mice. We now investigated whether pharmacological targeting of the acid sphingomyelinase, which catalyzes the cleavage of sphingomyelin to ceramide and phosphorylcholine, also allows to manipulate relative CD4\(^+\) Foxp3\(^+\) regulatory T-cell frequencies in humans. Pharmacological acid sphingomyelinase inhibition with antidepressants like sertraline, but not those without an inhibitory effect on acid sphingomyelinase activity like citalopram, increased the frequency of Foxp3\(^+\) regulatory T cell among human CD4\(^+\) T cells in vitro. In an observational prospective clinical study with patients suffering from major depression, we observed that acid sphingomyelinase-inhibiting antidepressants induced a stronger relative increase in the frequency of CD4\(^+\) Foxp3\(^+\) regulatory T cells in peripheral blood than acid sphingomyelinase-non- or weakly inhibiting antidepressants. This was particularly true for CD45RA\(^-\) CD25\(^{high}\) effector CD4\(^+\) Foxp3\(^+\) regulatory T cells. Mechanistically, our data indicate that the positive effect of acid sphingomyelinase inhibition on CD4\(^+\) Foxp3\(^+\) regulatory T cells required CD28 co-stimulation, suggesting that enhanced CD28 co-stimulation was the driver of the observed increase in the frequency of Foxp3+ regulatory T cells among human CD4\(^+\) T cells. In summary, the widely induced pharmacological inhibition of acid sphingomyelinase activity in patients leads to an increase in Foxp3+ regulatory T-cell frequencies among CD4\(^+\) T cells in humans both in vivo and in vitro.