Die Rolle der Kynureninsäure bei der Alzheimer Demenz

Die Alzheimer-Erkrankung ist eine neurodegenerative Demenzerkrankung, für die bisher keine kurative Therapie entwickelt werden konnte. Im Jahr 2007 lag die weltweite Prävalenz bei 29 Millionen (Brookmeyer et al. 2007). In der Pathogenese der Erkrankung stehen die Bildung von Aβ Plaques sowie intra-zelluläre Neurofibrillenbündel im Vordergrund. Neben diesen histopatho-logischen Korrelaten spielt vor allem die Neuroinflammation eine bedeutende Rolle (Krause und Muller 2010). Kynureninsäure entsteht im Kynureninstoffwechselweg, welcher eine zentrale Stellung im Tryptophanabbauweg einnimmt. Die Kynureninsäure gilt als endo-gener Antagonist des α7nAChR. Ihr wird in der Literatur eine neuroprotektive Rolle zugewiesen (Gulaj et al. 2010). Zielsetzung dieser Arbeit war es anhand verschiedener in vitro Experimente darzustellen, ob bzw. inwiefern die Kynureninsäure einen Einfluss Aβ-stimulierte Mikrogliazellen ausübt. Zu Beginn der Arbeit wurde eine mögliche Regulierbarkeit der α7nACh Rezeptorexpression durch die Kynureninsäure mit der Western-Blot-Methodik untersucht. Das angewandte Methodenspektrum umfasste zusätzlich MTT-Assays und fluoreszenzmarkierte Durchflusszytometrie zur Untersuchung der Zellviabilität und des Apoptoseverhaltens sowie Zytokin-ELISAs und NO-Assays zur Detektion freigesetzter proinflammatorischer Zytokine und NO. Zudem wurde die mikrogliale Phagozytose von Aβ mit einer fluoreszenz- markierten Durchflusszytometrie untersucht und mittels Western-Blotting verifiziert. Des Weiteren wurde die Konzentration der Kynureninsäure in Serumproben von Patienten mit AD und von einer Kontrollgruppe mit einem Kynureninsäure-ELISA bestimmt. Bei der Auswertung der Ergebnisse konnte in vitro ein protektiver Einfluss der Kynureninsäure auf Aβ-stimulierte Mikrogliazellen detektiert werden. In Bezug auf die Toxizität konnte die Apoptoserate durch Ko-Inkubation mit KA signifikant reduziert werden. Zudem konnte gezeigt werden, dass die KA in der Lage ist, die Aβ-induzierte Freisetzung von TNF-α signifikant und von IL-6 und NO in der Tendenz zu senken. Die mikrogliale Phagozytose von Aβ konnte durch die Ko-Stimulation mit KA signifikant um ein Drittel reduziert werden. Im Kynureninsäure-ELISA konnten keine Unterschiede der KA-Konzentration in den Seren von AD und Kontrollen gesehen werden. Durch die Senkung proinflammatorischer Zytokine und die Reduktion mikroglialer Aβ-Aufnahme greift die KA jedoch wesentlich in den Zellstoffwechsel ein, bedingt somit eine geringere Neuroinflammation und senkt konsekutiv den mikroglialen Zelluntergang. Im Ausblick wäre es interessant die Wirkung der KA auf Aβ-stimulierte primäre Mikrogliazellen zu untersuchen

Rethinking interhemispheric imbalance as a target for stroke neurorehabilitation

© 2019 American Neurological Association Objective: Patients with chronic stroke have been shown to have failure to release interhemispheric inhibition (IHI) from the intact to the damaged hemisphere before movement execution (premovement IHI). This inhibitory imbalance was found to correlate with poor motor performance in the chronic stage after stroke and has since become a target for therapeutic interventions. The logic of this approach, however, implies that abnormal premovement IHI is causal to poor behavioral outcome and should therefore be present early after stroke when motor impairment is at its worst. To test this idea, in a longitudinal study, we investigated interhemispheric interactions by tracking patients’ premovement IHI for one year following stroke. Methods: We assessed premovement IHI and motor behavior five times over a 1-year period after ischemic stroke in 22 patients and 11 healthy participants. Results: We found that premovement IHI was normal during the acute/subacute period and only became abnormal at the chronic stage; specifically, release of IHI in movement preparation worsened as motor behavior improved. In addition, premovement IHI did not correlate with behavioral measures cross-sectionally, whereas the longitudinal emergence of abnormal premovement IHI from the acute to the chronic stage was inversely correlated with recovery of finger individuation. Interpretation: These results suggest that interhemispheric imbalance is not a cause of poor motor recovery, but instead might be the consequence of underlying recovery processes. These findings call into question the rehabilitation strategy of attempting to rebalance interhemispheric interactions in order to improve motor recovery after stroke. Ann Neurol 2019;85:502–513

Comparing a Novel Neuroanimation Experience to Conventional Therapy for High-Dose Intensive Upper-Limb Training in Subacute Stroke: The SMARTS2 Randomized Trial

BACKGROUND Evidence from animal studies suggests that greater reductions in poststroke motor impairment can be attained with significantly higher doses and intensities of therapy focused on movement quality. These studies also indicate a dose-timing interaction, with more pronounced effects if high-intensity therapy is delivered in the acute/subacute, rather than chronic, poststroke period. OBJECTIVE To compare 2 approaches of delivering high-intensity, high-dose upper-limb therapy in patients with subacute stroke: a novel exploratory neuroanimation therapy (NAT) and modified conventional occupational therapy (COT). METHODS A total of 24 patients were randomized to NAT or COT and underwent 30 sessions of 60 minutes time-on-task in addition to standard care. The primary outcome was the Fugl-Meyer Upper Extremity motor score (FM-UE). Secondary outcomes included Action Research Arm Test (ARAT), grip strength, Stroke Impact Scale hand domain, and upper-limb kinematics. Outcomes were assessed at baseline, and days 3, 90, and 180 posttraining. Both groups were compared to a matched historical cohort (HC), which received only 30 minutes of upper-limb therapy per day. RESULTS There were no significant between-group differences in FM-UE change or any of the secondary outcomes at any timepoint. Both high-dose groups showed greater recovery on the ARAT (7.3 ± 2.9 points; P = .011) but not the FM-UE (1.4 ± 2.6 points; P = .564) when compared with the HC. CONCLUSIONS Neuroanimation may offer a new, enjoyable, efficient, and scalable way to deliver high-dose and intensive upper-limb therapy

Die Rolle der Kynureninsäure bei der Alzheimer Demenz

Die Alzheimer-Erkrankung ist eine neurodegenerative Demenzerkrankung, für die bisher keine kurative Therapie entwickelt werden konnte. Im Jahr 2007 lag die weltweite Prävalenz bei 29 Millionen (Brookmeyer et al. 2007). In der Pathogenese der Erkrankung stehen die Bildung von Aβ Plaques sowie intra-zelluläre Neurofibrillenbündel im Vordergrund. Neben diesen histopatho-logischen Korrelaten spielt vor allem die Neuroinflammation eine bedeutende Rolle (Krause und Muller 2010). Kynureninsäure entsteht im Kynureninstoffwechselweg, welcher eine zentrale Stellung im Tryptophanabbauweg einnimmt. Die Kynureninsäure gilt als endo-gener Antagonist des α7nAChR. Ihr wird in der Literatur eine neuroprotektive Rolle zugewiesen (Gulaj et al. 2010). Zielsetzung dieser Arbeit war es anhand verschiedener in vitro Experimente darzustellen, ob bzw. inwiefern die Kynureninsäure einen Einfluss Aβ-stimulierte Mikrogliazellen ausübt. Zu Beginn der Arbeit wurde eine mögliche Regulierbarkeit der α7nACh Rezeptorexpression durch die Kynureninsäure mit der Western-Blot-Methodik untersucht. Das angewandte Methodenspektrum umfasste zusätzlich MTT-Assays und fluoreszenzmarkierte Durchflusszytometrie zur Untersuchung der Zellviabilität und des Apoptoseverhaltens sowie Zytokin-ELISAs und NO-Assays zur Detektion freigesetzter proinflammatorischer Zytokine und NO. Zudem wurde die mikrogliale Phagozytose von Aβ mit einer fluoreszenz- markierten Durchflusszytometrie untersucht und mittels Western-Blotting verifiziert. Des Weiteren wurde die Konzentration der Kynureninsäure in Serumproben von Patienten mit AD und von einer Kontrollgruppe mit einem Kynureninsäure-ELISA bestimmt. Bei der Auswertung der Ergebnisse konnte in vitro ein protektiver Einfluss der Kynureninsäure auf Aβ-stimulierte Mikrogliazellen detektiert werden. In Bezug auf die Toxizität konnte die Apoptoserate durch Ko-Inkubation mit KA signifikant reduziert werden. Zudem konnte gezeigt werden, dass die KA in der Lage ist, die Aβ-induzierte Freisetzung von TNF-α signifikant und von IL-6 und NO in der Tendenz zu senken. Die mikrogliale Phagozytose von Aβ konnte durch die Ko-Stimulation mit KA signifikant um ein Drittel reduziert werden. Im Kynureninsäure-ELISA konnten keine Unterschiede der KA-Konzentration in den Seren von AD und Kontrollen gesehen werden. Durch die Senkung proinflammatorischer Zytokine und die Reduktion mikroglialer Aβ-Aufnahme greift die KA jedoch wesentlich in den Zellstoffwechsel ein, bedingt somit eine geringere Neuroinflammation und senkt konsekutiv den mikroglialen Zelluntergang. Im Ausblick wäre es interessant die Wirkung der KA auf Aβ-stimulierte primäre Mikrogliazellen zu untersuchen

Aspirin versus anticoagulation in cervical artery dissection (TREAT-CAD): an open-label, randomised, non-inferiority trial

Background Cervical artery dissection is a major cause of stroke in young people (aged <50 years). Historically, clinicians have preferred using oral anticoagulation with vitamin K antagonists for patients with cervical artery dissection, although some current guidelines—based on available evidence from mostly observational studies—suggest using aspirin. If proven to be non-inferior to vitamin K antagonists, aspirin might be preferable, due to its ease of use and lower cost. We aimed to test the non-inferiority of aspirin to vitamin K antagonists in patients with cervical artery dissection. Methods We did a multicentre, randomised, open-label, non-inferiority trial in ten stroke centres across Switzerland, Germany, and Denmark. We randomly assigned (1:1) patients aged older than 18 years who had symptomatic, MRI-verified, cervical artery dissection within 2 weeks before enrolment, to receive either aspirin 300 mg once daily or a vitamin K antagonist (phenprocoumon, acenocoumarol, or warfarin; target international normalised ratio [INR] 2·0–3·0) for 90 days. Randomisation was computer-generated using an interactive web response system, with stratification according to participating site. Independent imaging core laboratory adjudicators were masked to treatment allocation, but investigators, patients, and clinical event adjudicators were aware of treatment allocation. The primary endpoint was a composite of clinical outcomes (stroke, major haemorrhage, or death) and MRI outcomes (new ischaemic or haemorrhagic brain lesions) in the per-protocol population, assessed at 14 days (clinical and MRI outcomes) and 90 days (clinical outcomes only) after commencing treatment. Non-inferiority of aspirin would be shown if the upper limit of the two-sided 95% CI of the absolute risk difference between groups was less than 12% (non-inferiority margin). This trial is registered with ClinicalTrials.gov, NCT02046460. Findings Between Sept 11, 2013, and Dec 21, 2018, we enrolled 194 patients; 100 (52%) were assigned to the aspirin group and 94 (48%) were assigned to the vitamin K antagonist group. The per-protocol population included 173 patients; 91 (53%) in the aspirin group and 82 (47%) in the vitamin K antagonist group. The primary endpoint occurred in 21 (23%) of 91 patients in the aspirin group and in 12 (15%) of 82 patients in the vitamin K antagonist group (absolute difference 8% [95% CI −4 to 21], non-inferiority p=0·55). Thus, non-inferiority of aspirin was not shown. Seven patients (8%) in the aspirin group and none in the vitamin K antagonist group had ischaemic strokes. One patient (1%) in the vitamin K antagonist group and none in the aspirin group had major extracranial haemorrhage. There were no deaths. Subclinical MRI outcomes were recorded in 14 patients (15%) in the aspirin group and in 11 patients (13%) in the vitamin K antagonist group. There were 19 adverse events in the aspirin group, and 26 in the vitamin K antagonist group. Interpretation - Our findings did not show that aspirin was non-inferior to vitamin K antagonists in the treatment of cervical artery dissection

Rethinking interhemispheric imbalance as a target for stroke neurorehabilitation

OBJECTIVE Patients with chronic stroke have been shown to have failure to release interhemispheric inhibition (IHI) from the intact to the damaged hemisphere before movement execution (premovement IHI). This inhibitory imbalance was found to correlate with poor motor performance in the chronic stage after stroke and has since become a target for therapeutic interventions. The logic of this approach, however, implies that abnormal premovement IHI is causal to poor behavioral outcome and should therefore be present early after stroke when motor impairment is at its worst. To test this idea, in a longitudinal study, we investigated interhemispheric interactions by tracking patients' premovement IHI for one year following stroke. METHODS We assessed premovement IHI and motor behavior five times over a 1-year period after ischemic stroke in 22 patients and 11 healthy participants. RESULTS We found that premovement IHI was normal during the acute/subacute period and only became abnormal at the chronic stage; specifically, release of IHI in movement preparation worsened as motor behavior improved. In addition, premovement IHI did not correlate with behavioral measures cross-sectionally, whereas the longitudinal emergence of abnormal premovement IHI from the acute to the chronic stage was inversely correlated with recovery of finger individuation. INTERPRETATION These results suggest that interhemispheric imbalance is not a cause of poor motor recovery, but instead might be the consequence of underlying recovery processes. These findings call into question the rehabilitation strategy of attempting to rebalance interhemispheric interactions in order to improve motor recovery after stroke. Ann Neurol 2019;85:502-513

Differential Poststroke Motor Recovery in an Arm Versus Hand Muscle in the Absence of Motor Evoked Potentials

. After stroke, recovery of movement in proximal and distal upper extremity (UE) muscles appears to follow different time courses, suggesting differences in their neural substrates. . We sought to determine if presence or absence of motor evoked potentials (MEPs) differentially influences recovery of volitional contraction and strength in an arm muscle versus an intrinsic hand muscle. We also related MEP status to recovery of proximal and distal interjoint coordination and movement fractionation, as measured by the Fugl-Meyer Assessment (FMA). . In 45 subjects in the year following ischemic stroke, we tracked the relationship between corticospinal tract (CST) integrity and behavioral recovery in the biceps (BIC) and first dorsal interosseous (FDI) muscle. We used transcranial magnetic stimulation to probe CST integrity, indicated by MEPs, in BIC and FDI. We used electromyography, dynamometry, and UE FMA subscores to assess muscle-specific contraction, strength, and inter-joint coordination, respectively. . Presence of MEPs resulted in higher likelihood of muscle contraction, greater strength, and higher FMA scores. Without MEPs, BICs could more often volitionally contract, were less weak, and had steeper strength recovery curves than FDIs; in contrast, FMA recovery curves plateaued below normal levels for both the arm and hand. . There are shared and separate substrates for paretic UE recovery. CST integrity is necessary for interjoint coordination in both segments and for overall recovery. In its absence, alternative pathways may assist recovery of volitional contraction and strength, particularly in BIC. These findings suggest that more targeted approaches might be needed to optimize UE recovery