Einfluss von Vasopressin-Rezeptoren und Aquaporinen auf den sekundären Hirnschaden nach experimentellem Schädel-Hirntrauma

Das Schädel-Hirntrauma (SHT) ist bei Kindern und jungen Erwachsen bis zum 45. Lebensjahr mit einer Inzidenz von 332 Verletzten pro 100.000 Einwohner in Deutschland die häufigste Krankheits- und Todesursache. Neben dem persönlichen Leiden und der hohen Rate an posttraumatischer Pflegebedürftigkeit, sollte auch die sozioökonomische Tragweite mit, allein in Deutschland, gesamtgesellschaftlichen Kosten von 2,8 Milliarden Euro pro Jahr berücksichtigt werden. Zwei wesentliche Verletzungsmuster des SHT werden unterschieden: die fokale Kontusion sowie der diffuse Axonschaden. Beide Mechanismen führen zum posttraumatischen Hirnödem und intrakraniellem Druckanstieg, Hauptprädiktoren für ein schlechtes Ergebnis der Patienten. Die daraus resultierende zerebrale Minderperfusion und Hirnischämie münden in einen Circulus vitiosus mit Progredienz des Hirnödems. Ca. 50% des Hirnödems entsteht sekundär und wäre daher einer Behandlung prinzipiell zugänglich. Trotz intensiver Forschung fehlt weiterhin eine kausale und anti-ödematöse Therapie. Vasopressin und V1a-Rezeptoren scheinen eine wesentliche Rolle in der Pathophysiologie von Hirnschädigungen zu spielen, da einerseits die Höhe des Vasopressin-Serumspiegels positiv mit der Schwere von verschiedenen Hirnläsionen korreliert und andererseits eine pharmakologische Hemmung des V1a-Rezeptors das Hirnödem und den sekundären Hirnschaden nach experimentellem Schädel-Hirntrauma mindert. Während die systemische Regulation der Wasserhomöostase in der Niere über den antidiuretischen Effekt von Vasopressin sehr gut bekannt ist, vermittelt über V2-Rezeptoren und Aquaporin 2 (AQP2), ist sowohl die zentrale Funktion von Vasopressin als auch die Regulation zerebraler AQP noch unzureichend verstanden. Ziel der vorliegenden Arbeit war es daher 1. den Einfluss von Vasopressin V1a-Rezeptoren auf den sekundären Hirnschaden nach experimentellem SHT an einem hochspezifischen V1a-Rezeptor knock-out Mausmodell zu untersuchen, 2. die Bedeutung der zerebralen AQP 1, 4 & 9 für den Hirnwassertransport und die post-traumatische Hirnödem Entstehung zu erforschen sowie 3. die Frage zu klären, ob die gezeigten anti-ödematösen Effekte des V1a-Rezeptors über zerebrale AQP nach Controlled Cortical Impact (CCI) im Mausmodell vermittelt werden. An tief anästhesierten Wildtyp und V1a-Rezeptor knock-out Mäusen wurde nach mikrochirurgischer Präparation ein standardisiertes und mittelschweres CCI ausgelöst. Die Hirnentnahme erfolgte je nach Zielparameter jeweils von unbehandelten Mäusen sowie 15 Minuten, 1, 3, 6, 12, 24 h oder 7 Tage nach Trauma. Für die Validierung des knock-out Modells wurden die physiologischen Parameter intrakranieller Druck, mittlerer arterieller Druck und die zerebrale Durchblutung vor und über 30 Minuten nach CCI bestimmt. Für die Untersuchung der neuroprotektiven Effekte des V1a Rezeptors waren die Zielparameter: Hirnwassergehalt, sekundäres Nekrosevolumen, die neurologische Funktion, Gewichtsänderung sowie die Mortalität. Die Entwicklung von maushirnspezifischen Primern war wesentliche Voraussetzung für die Quantifizierung von AQP1, 4 & 9 mRNA durch quantitative Real-Time PCR. Immunhistochemisch wurden mit der Fluorchrom-Methode und dem Infrarot Scan AQP1 & 4 lokalisiert und quantifiziert. Wesentliche Ergebnisse waren der Nachweis der neuroprotektiven Effekte durch die Deletion des V1a-Rezeptors, wodurch das posttraumatische Hirnödem und der sekundäre Hirnschaden 24 h nach Trauma um knapp 30% reduziert wurde, der posttraumatische Gewichtsverlust über 7 Tage verringert sowie die neurologische Funktion über 7 Tage nach experimentellem SHT signifikant verbessert war. Die murinen AQP1, 4 & 9 Primer waren spezifisch und für die quantitative RT-PCR geeignet. Auf Transkriptionsebene wurde AQP1 V1a-Rezeptor-abhängig 24 h nach CCI hochreguliert. AQP4 mRNA wurde konstitutiv exprimiert. AQP9 unterlag auf Transkriptionsebene keiner posttraumatischen Regulation. Auf Proteinebene wurde AQP1 nicht nur auf dem Ependym des Plexus choroideus, sondern erstmals auf kortikalen Neuronen im Maushirn detektiert. AQP4 war ubiquitär auf kortikalen und subkortikalen Astrozyten lokalisiert. Posttraumatisch wurde AQP1 kontralateral und AQP4 periläsional V1a-Rezeptor-abhängig sowohl kurz- als auch langfristig reguliert. Zusammenfassend ist zu sagen, dass Vasopressin an der Entstehung des sekundären Hirnschadens über V1a Rezeptoren nach experimentellem SHT im Mausmodell beteiligt ist. Die gezeigten anti-ödematösen Effekte werden im V1a-Rezeptor knock-out Mausmodell über Aquaporine vermittelt. Die kurz- und langfristige V1a-Rezeptor-abhängige AQP1 & 4 Regulation im Hirnparenchym korreliert dabei mit der Bildung des posttraumatischen Hirnödems. Somit sind der V1a-Rezeptor sowie AQP1 & 4 ein möglicher pharmakologischer Angriffspunkt für die Prävention und Reduktion des posttraumatischen, sekundären Hirnödems

Psychopathological Symptom Load and Distinguishable Cerebral Blood Flow Velocity Patterns in Patients With Schizophrenia and Healthy Controls: A Functional Transcranial Doppler Study

Introduction: Schizophrenia is a severe psychiatric disorder, with executive dysfunction and impaired processing speed playing a pivotal role in the course of the disease. In patients with schizophrenia, neurocognitive deficits appear to be related to alterations in cerebral hemodynamics. It is not fully understood if psychopathological symptom load (i.e., presence and severity of symptoms) is also related to alterations in cerebral hemodynamics. We aim to study the relationship between psychopathological symptom load and cerebral hemodynamics in the Middle Cerebral Artery (MCA) during a cognitive task in patients with schizophrenia and healthy controls. Methodology: Cerebral hemodynamics in the MCA were examined in 30 patients with schizophrenia and 15 healthy controls using functional Transcranial Doppler (fTCD) during the Trail Making Test (TMT). Psychopathological symptoms were measured using the Brief Psychiatric Rating Scale (BPRS). Patients were dichotomized according to BPRS scores: mild-moderate (BPRS < 41, n = 15) or marked-severe (BPRS ≧ 41, n = 15). Mean blood flow velocity (MFV) in the MCA and processing speed of the TMT were analyzed. Cerebral hemodynamics were analyzed using the general additional model (GAM) with a covariate analysis of variance (ANCOVA) for group comparisons. Results: Patients and healthy controls were comparable regarding demographics. Patients had a slower processing speed for the TMT-A (patients-severe: 52s, patients-moderate: 40s, healthy-controls: 32s, p = 0.019) and TMT-B [patients-severe: 111s, patients-moderate: 76s, healthy-controls: 66s, p < 0.001)]. Patients demonstrated differing hemodynamic profiles in both TMTs: TMT- A [F(6, 1,792) = 17, p < 0.000); TMT-B [F(6, 2,692) = 61.93, p < 0.000], with a delay in increase in MFV and a failure to return to baseline values. Conclusions: Patients with schizophrenia demonstrated slower speeds of processing during both the TMT-A and TMT-B. The speed of processing deteriorated with increasing psychopathological symptom load, additionally a distinct cerebral hemodynamic pattern in the MCA was observed. Our results further support the view that severity of schizophrenia, particularly psychopathological symptom load, influences performance in neurocognitive tasks and is related to distinct patterns of brain hemodynamics

Decompressive Craniectomy Is Associated With Good Quality of Life Up to 10 Years After Rehabilitation From Traumatic Brain Injury

OBJECTIVES Traumatic brain injury is the number one cause of death in children and young adults and has become increasingly prevalent in the elderly. Decompressive craniectomy prevents intracranial hypertension but does not clearly improve physical outcome 6 months after traumatic brain injury. However, it has not been analyzed if decompressive craniectomy affects traumatic brain injury patients' quality of life in the long term. DESIGN Therefore, we conducted a cross-sectional study assessing health-related quality of life in traumatic brain injury patients with or without decompressive craniectomy up to 10 years after injury. SETTING Former critical care patients. PATIENTS Chronic traumatic brain injury patients having not (n = 37) or having received (n = 98) decompressive craniectomy during the acute treatment. MEASUREMENTS AND MAIN RESULTS The Quality of Life after Brain Injury questionnaire was used as outcome measure with a total score from zero to 100, representing lowest and best health-related quality of life, respectively. Health-related quality of life was compared between patients with or without decompressive craniectomy for the entire cohort, for the traumatic brain injury severity (mild, moderate, severe) measured by the initial Glasgow Coma Scale, for age and time variables (age at traumatic brain injury, age at survey, elapsed time since traumatic brain injury) using the Mann-Whitney U test. Differences were considered significant at a p value of less than 0.05.Decompressive craniectomy was necessary in all initial traumatic brain injury severity groups. Eight percent more decompressive craniectomy patients reported good health-related quality of life with a Quality of Life after Brain Injury total score greater than or equal to 60 compared with the no decompressive craniectomy patients up to 10 years after traumatic brain injury (p = 0.004). Initially, mild classified traumatic brain injury patients had a median Quality of Life after Brain Injury total score of 83 (decompressive craniectomy) versus 62 (no decompressive craniectomy) (p = 0.028). Health-related quality of life regarding physical status was better in decompressive craniectomy patients (p = 0.025). Decompressive craniectomy showed a trend toward better health-related quality of life in the 61-85-year-old reflected by median Quality of Life after Brain Injury total scores of 62 (no decompressive craniectomy) versus 79 (decompressive craniectomy) (p = 0.06). CONCLUSIONS Our results suggest that decompressive craniectomy is associated with good health-related quality of life up to 10 years after traumatic brain injury. Thus, decompressive craniectomy may have an underestimated therapeutic potential after traumatic brain injury

Influence of footwear on postural sway: A systematic review and meta-analysis on barefoot and shod bipedal static posturography in patients and healthy subjects

Background Bipedal static posturography is widely used to assess postural control. However, standardized methods and evidence on the influence of footwear on balance in comparison to barefoot stance is sparse. Research questions Is bipedal static posturography applied in a standardized way with respect to demographics and the experimental set-up (systematic review)? Does habitual footwear influence postural control in comparison to barefoot condition during bipedal static posturography in adult patients and healthy subjects (meta-analysis)? Methods For this systematic review and meta-analysis, a comprehensive follow-up literature search was conducted from March 2009 until January 2020 according to the PRISMA guidelines. Original, research articles reporting on bipedal, unsupported, static posturography in adults (≥18 years) were included according to inclusion criteria (age, sex, height, weight, duration, repetitions, visual/foot condition, sampling frequency). Studies comparing habitual footwear with barefoot condition during bipedal static posturography were included for the meta-analysis. Center of pressure parameters (sway velocity, range, root mean square, paths lengths) with subjects having eyes closed (EC) or open (EO) were analyzed using random effects models. Results For this systematic review and meta-analysis, 207 and eight out of 5189 studies with 12'341 and 156 subjects, respectively, were eligible. Most studies (89%) reported barefoot, 5% shod, and 6% barefoot and shod measurements. Less than half of studies (44%) included patients of which the minority (13%) suffered from neurological disease. Sway velocity in the anterior-posterior direction was higher in habitual shoes compared to barefoot with EC (SMD: 1.08; 95% CI: 0.68–1.48; p < 0.01; I2 = 0%), with EO (SMD: 0.68; 95% CI: 0.11–1.26; p = 0.02; I2 = 1%), and in the medio-lateral direction with EC (SMD: 1.30; 95% CI: 0.76–1.85, p < 0.01; I2 = 37%). Significance Methodical heterogeneity of bipedal static posturography hampers studies’ comparability. Thus, we provide a standardized approach to increase knowledge whether habitual footwear decrease postural control in comparison to barefoot stance

Sensitivity of outcome instruments in a priori selected patient groups after traumatic brain injury:Results from the CENTER-TBI study

Traumatic brain injury (TBI) can negatively impact patients' lives on many dimensions. Multiple instruments are available for evaluating TBI outcomes, but it is still unclear which instruments are the most sensitive for that purpose. This study examines the sensitivity of nine outcome instruments in terms of their ability to discriminate within and between specific patient groups, selected a priori as identified from the literature, at three different time points within a year after TBI (i.e., 3, 6, and 12 months post injury). The sensitivity of the instruments to sociodemographic (sex, age, education), premorbid (psychological health status), and injury-related (clinical care pathways, TBI and extracranial injury severity) factors was assessed by means of cross-sectional multivariate Wei-Lachin analyses. The Glasgow Outcome Scale Extended (GOSE)-the standard in the field of TBI for measuring functional recovery-demonstrated the highest sensitivity in most group comparisons. However, as single functional scale, it may not be able to reflect the multidimensional nature of the outcome. Therefore, the GOSE was used as a reference for further sensitivity analyses on more specific outcome scales, addressing further potential deficits following TBI. The physical component summary score (PCS) of the generic health-related quality of life (HRQOL) instruments (SF-36v2/-12v2) and the TBI-specific HRQOL instruments (QOLIBRI/-OS) were most sensitive in distinguishing recovery after TBI across all time points and patient groups, followed by the RPQ assessing post-concussion symptoms and the PHQ-9 measuring depression. The SF-36v2/-12v2 mental component summary score and the GAD-7 measuring anxiety were less sensitive in several group comparisons. The assessment of the functional recovery status combined with generic HRQOL (the PCS of the SF-12v2), disease-specific HRQOL (QOLIBRI-OS), and post-concussion symptoms (RPQ) can provide a sensitive, comprehensive, yet time-efficient evaluation of the health status of individuals after TBI in different patient groups.</p

Accelerometric Trunk Sensors to Detect Changes of Body Positions in Immobile Patients

Mobilization, verticalization and position change are mandatory for severely affected neurological patients in early neurorehabilitation in order to improve neurological status and prevent complications. However, with the exception of hospitals and rehabilitation facilities, this activity is not usually monitored and so far the automated monitoring of position changes in immobile patients has not been investigated. Therefore, we investigated whether accelerometers on the upper trunk could reliably detect body position changes in immobile patients. Thirty immobile patients in early neurorehabilitation (Barthel Index 30) were enrolled. Two tri-axial accelerometers were placed on the upper trunk and on the thigh. Information on the position and position changes of the subject were derived from accelerometer data and compared to standard written documentation in the hospital over 24 h. Frequency and duration of different body positions (supine, sidelying, sitting) were measured. Data are presented as mean +/- SEM. Groups were compared using one-way ANOVA or Kruskal-Wallis-test. Differences were considered significant if p < 0.05. Trunk sensors detected 100% and thigh sensors 66% of position changes (p = 0.0004) compared to standard care documentation. Furthermore, trunk recording also detected additional spontaneous body position changes that were not documented in standard care (81.8 +/- 4.4% of all position changes were documented in standard care documentation) (p < 0.0001). We found that accelerometric trunk sensors are suitable for recording position changes and mobilization of severely affected patients. Our findings suggest that using accelerometers for care documentation is useful for monitoring position changes and mobilization frequencies in and outside of hospital for severely affected neurological patients. Accelerometric sensors may be valuable in monitoring continuation of care plans after intensive neurorehabilitation

Traumatic Encephalopathy Syndrome and Tauopathy in a 19-Year-Old With Child Abuse

The majority of traumatic encephalopathy syndrome (TES) cases have been reported in former contact sport athletes. This is the first case with TES in a 19-year-old male patient with progressive cognitive decline after daily domestic physical violence through repeated hits to the head for 15 years. The patient presented with a moderate depressive episode and progressive cognitive decline. Tau positron emission tomography (PET) with 220 MBq of [18F]PI-2620 revealed increased focal signal at the frontal and parietal white/gray matter border. Brain magnetic resonance imaging (MRI) showed a cavum septum pellucidum, reduced left-sided hippocampal volume, and a left midbrain lesion. Cerebrospinal fluid results showed elevated total and p-tau. Neurocognitive testing at admission showed memory deficits clearly below average, and hampered dysfunctions according to the slow processing speed with a low mistake rate, indicating the acquired, thus secondary, attentional deficits. We diagnosed the patient with a TES suggestive of chronic traumatic encephalopathy and classified him as having subtle/mild functional limitation with a most likely transition to mild dementia within the TES criteria. This report underlines child abuse as a relevant criterion in diagnosing TES in cases with repetitive hits to the head. In addition to clinical markers, we show the relevance of fluid tau biomarkers and tau-PET to support the diagnosis of TES according to the recently published diagnosis criteria for TES

Explaining variability in early stages of [18F]-flortaucipir tau-PET binding: Focus on sex differences

INTRODUCTION Female sex is associated with increased [18F]-flortaucipir signal, which may be affected by amyloid pathology, age, and off-target binding in skull and meninges. METHODS In this cross-sectional study comprising 52 females and 52 matched males, we examined sex-related differences in regional tau-positron emission tomography (PET) with and without considering off-target binding. We assessed the respective contributions of sex, age, amyloid-PET burden, and off-target binding to tau-PET signal. We explored associations between age at menopause and hormone replacement therapy (HRT) use with regional tau-PET signals. RESULTS Female sex was associated with increased regional tau both independently and interactively with amyloid, but amyloid-independent associations were largely reduced when controlling for off-target binding. Age but not age*sex interactions explained a small but significant amount of tau-PET signal in temporoparietal regions. Considering the sample size and limited range of amyloid-PET burden, no clear associations between regional tau-PET signals and age at menopause or HRT use could be found. DISCUSSION Female sex is associated with increased [18F]-flortaucipir signal mainly through its interaction with amyloid

Internet Cognitive Behavioral Therapy With or Without Face-to-Face Psychotherapy: A 12-Weeks Clinical Trial of Patients With Depression

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Relationship Between Time of Admission, Help-Seeking Behavior, and Psychiatric Outcomes: “From Dusk Till Dawn”

Introduction: Day and time of admission influence treatment outcomes and prognosis in several medical specialties; this seems related to resources' ability. It is largely unknown whether this also applies to mental health services. We investigate the relationship between time of admission, patients' demographic and clinical profile, and treatment outcomes. Methods: Demographic and clinical profiles of admitted and discharged patients to a general psychiatric ward between January 1st, 2013 and December 31st, 2020, were analyzed. In addition, we used the last year (i.e., 2020) to monitor rehospitalization. Time of admission was defined as weekdays (working day, weekend) and dayshifts (daytime, dusk, and dawn). Results: During the study period, 12,449 patient admissions occurred. The mean age of the sample was 48.05 ± 20.90 years, with 49.32% (n = 6,140) females. Most admissions (n = 10,542, 84%) occurred on working days. Two-fifths of admissions (39.7%, n = 4,950) were compulsory, with a higher rate outside daytime hours. Patients had slight differences in the clinical profile, resulting from evaluating the different items of the Health of Nation Outcome Scale (HoNOS). Patients admitted on night shifts, weekends, and holidays showed a shorter length of stay; patients compulsorily admitted during daytime (disregarding the day of the week) had a longer length of stay. All patient groups achieved a robust clinical improvement (i.e., an HoNOS score reduction of around 50%), with similar readmission rates. Discussion: The main finding of our study is the relationship between "daytime hours" and fewer compulsory admissions, a result of the interplay between demographics, clinical characteristics, and out-of-clinic service availability (such as ambulatory psychiatric- psychological praxis; day-clinic; home-treatment). The differing clinical profile, in turn, determines differences in treatment selection, with patients admitted after office hours experiencing a higher rate of coercive measures. The shorter length of stay for out-of-office admissions might result from the hospitalization as an intervention. These results should encourage the implementation of outpatient crisis-intervention services, available from dusk till dawn. Keywords: coercive measures; day and time of admission; help-seeking behavior; psychiatric outcomes; service use