Erinnerung bei Menschen mit Down Syndrom

Das Thema dieser Arbeit handelt von der Analyse des Erinnerungsvermögens bei Menschen mit Down Syndrom. Aufgrund meiner Arbeit mit Menschen mit Trisomie 21 kam die Vermutung, dass diese eine besondere Art haben, sich an Vergangenes zu erinnern. Dies führte zur leitenden Fragestellung dieser Arbeit: Lassen sich Besonderheiten in der Art und Weise, wie Menschen mit Down Syndrom sich an Vergangenes erinnern, erkennen? Einige in dieser Arbeit relevanten Thesen befassen sich damit, inwieweit Menschen mit Down Syndrom ein besonderes Empfinden von Zeitspannen aufweisen, ein präzises Datengedächtnis haben und wie sie sich an spezifische Episoden aus ihrem Leben erinnern. Zur Erforschung dieser Fragestellung wurde die Methode der Grounded Theory gewählt. Die Datensammlung wurde durch leicht modifizierte, narrative Interviews erlangt. In dieser Arbeit wird das Gedächtnis im Zusammenhang mit dem Gehirn als Medium beleuchtet und die Gedächtnistheorie nach Welzer beschrieben. Nach der Auswertung der Interviews wurde das Datenmaterial, anhand Welzers Gedächtnissystems, auf Besonderheiten in der Erinnerung von Menschen mit Down Syndrom untersucht. Schlussfolgernd machte sich jedoch bemerkbar, dass sich nicht einheitlich bei allen interviewten Personen Besonderheiten in den befragten Bereichen feststellen ließen. Im Allgemeinen zeigte sich, dass Zeitspannen unter- oder überschätzt wurden, verwandte Personen in Vergessenheit gerieten, Daten und besonders auch emotional verankerte Ereignisse aber gut in Erinnerung gerufen werden konnten, jedoch die Zeit der schulischen Ausbildung und das Geburtsjahr oft realitätsfern von den befragten Personen beschrieben wurden. Aufgrund des geringen Datenmaterials und der inhomogenen Resultate kann die Annahme nicht in Verallgemeinerung gesetzt werden.This thesis deals with the analysis of memory in people with Down syndrome. The work with people with Down syndrome indicated that they have a special way to remember the past. This led to the key question of this work: Can characteristics be identified in the way how people with Down syndrome remember the past? Some hypotheses of this study act on the extent of people with Down syndrome have a special feeling for time spans specific time periods, have an accurate memory of data and how they remember specific episodes from their lives. To investigate these questions, the method of Grounded Theory was chosen. The data collection was obtained by slightly modified, narrative interviews. In this work, the connection between the memory and the brain used a medium and theory of memory by Welzer described. After analyzing the interviews, the obtained data sets were analyzed according to Welzer’s memory system to identify specific memory-features of people with Down syndrome. In conclusion, however, no commonality of the interviewed persons in the in the special areas surveyed could be identified. In general, it seemed that time periods are under-or overestimated, relatives were oblivioned, data- and especially emotionally-anchored events could be properly well-remembered, however, concerning school education, it seemed that the people surveyed, display a biased reality. Due to the limited data material and the inhomogenous results, these phenomena can't be generalized

Current treatment of comorbid insomnia and obstructive sleep apnea with CBTI and PAP-therapy : a systematic review

Insomnia and obstructive sleep apnea (OSA) are often both present in patients with sleep- disordered-breathing. The coexistence of the two disorders shows an increase in cumulative morbidity and an overall greater illness severity. There is still considerable controversy regarding management decisions in this group of patients. This systematic review focused on more recent evidence regarding treatment of patients presenting with both clinical entities of comorbid insomnia and obstructive sleep apnea in terms of their management, especially using combinations of positive airway pressure (PAP, namely aPAP, cPAP, adaptive servo-ventilation[ASV]) and CBTi as well as each one of these two modalities alone. As a conclusion it is necessary to specifically target distinct combinations of both insomnia (initial, middle, late) and OSA (mild, moderate, severe) phenotypes. The present review gives reason to assume that both CBTi and PAP-therapy are necessary. However, it appears that distinct treatment patterns may suit different COMISA phenotypes

An AI-supported diagnostic tool for obstructive sleep apnea patients based on delta-alpha connectivity at the sensorimotor cortex [Abstract]

Background: The modulation of delta-alpha phase-amplitude cross-frequency coupling (PACFC) may influence information processing throughout the human cerebral cortex. We investigated whether this frequency band-specific modulation is impaired in patients with obstructive sleep apnea (OSA). Patients & Methods: In this study, the C3- and C4- electroencephalographic recordings of 170 participants (86 in main dataset: age 27-84 years, 44 subjects had moderate or severe OSA with respiratory disturbance index RDI>15/h; 84 in validation dataset: age 35 -75 years, 42 subjects with RDI>15/h) who underwent full-night polysomnography (PSG) were evaluated. We tested if the delta-alpha PACFC modulation index (MI) at the sensorimotor cortex differs between OSA patients with RDI>15/h and those with RDI≤15/h in distinct sleep stages. Further, by making use of a Support Vector Machine (SVM) algorithm, we tested if the sleep stage – specific MIs could predict RDI values of OSA patients. Results: In both datasets, in OSA patients with RDI >15/h, the delta-alpha CFC-MI was significantly (p< 0.05) reduced at the sensorimotor cortex during REM and NREM1 stages, while increased during NREM2 compared to patients with RDI ≤15/h. In addition, the delta-alpha MI in REM sleep stage could provide with use of an SVM algorithm a quite reliable (82% accuracy) prediction of the RDI in OSA patients. Conclusions: This increase in disconnection at the cortical sensorimotor areas with increasing respiratory distress during sleep further supports the concept of a cortical sensorimotor dysfunction in OSA patients. Additionally, the delta – alpha MI during REM sleep may provide an objective neurophysiologic surrogate marker of respiratory distress in OSA patients

Intensity of respiratory cortical arousals is a distinct pathophysiologic feature and is associated with disease severity in obstructive sleep apnea patients

Background: We investigated whether the number, duration and intensity of respiratory arousals (RA) on C3-electroencephalographic (EEG) recordings correlate with polysomnography (PSG)-related disease severity in obstructive sleep apnea (OSA) patients. We also investigated if every patient might have an individual RA microstructure pattern, independent from OSA-severity. Methods: PSG recordings of 20 OSA patients (9 female; age 27–80 years) were analyzed retrospectively. Correlation coefficients were calculated between RA microstructure (duration, EEG-intensity) and RA number and respiratory disturbance index (RDI), oxygen desaturation index (ODI) and arousal index (AI). Intraclass correlations (ICC) for both RA duration and intensity were calculated. Sleep stage-specific and apnea- and hypopnea-specific analyses were also done. The probability distributions of duration and intensity were plotted, interpolated with a kernel which fits the distribution. A Bayesian posterior distribution analysis and pair-wise comparisons of each patient with all other 19 patients were performed. Results: Of the analyzed 2600 RA, strong positive correlations were found between average RA intensity and both RDI and AI. The number of PSG-recorded RA was strongly positively correlated with RDI. Significant correlations between average RA intensity in REM, NREM2 and NREM3 sleep stages and total ODI were identified. No sleep stage-specific correlations of arousal microstructure with age, sex, RDI or AI were identified. Although between-subjects ICC values were 0.7 (all p < 0.05). While apnea-related RA duration did not differ from hypopnea-related RA duration, RA intensity was significantly higher (p = 0.00135) in hypopneas than in apneas. A clear individual pattern of arousal duration for each patient was made distinct. For arousal intensity, a Gaussian distribution was identified in most patients. The Bayesian statistics regarding the arousal microstructure showed significant differences between each pair of patients. Conclusions: Each individual patient with OSA might have an individual pattern of RA intensity and duration indicating a distinct individual pathophysiological feature. Arousal intensity was significantly higher in hypopneic than in apneic events and may be related causally to the diminished (compared to apneas) respiratory distress associated with hypopneas. RA intensity in REM, NREM2 and NREM3 strongly correlated with ODI

A very mild phenotype in six individuals of a three-generation family with the novel HRAS variant c.176C > G p.(Ala59Gly): Emergence of a new HRAS-related RASopathy distinct from Costello syndrome

Costello syndrome is a clinically recognizable, severe neurodevelopmental disorder caused by heterozygous activating variants in HRAS. The vast majority of affected patients share recurring variants affecting HRAS codons 12 and 13 and a relatively uniform phenotype. Here, we report the unique and attenuated phenotype of six individuals of an extended family affected by the HRAS variant c.176C>T p.(Ala59Gly), which, to our knowledge, has never been reported as a germline variant in patients so far. HRAS Alanine 59 has been previously functionally investigated as an oncogenic hotspot and the p.Ala59Gly substitution was shown to impair intrinsic GTP hydrolysis. All six individuals we report share a phenotype of ectodermal anomalies and mild features suggestive of a RASopathy, reminiscent of patients with Noonan syndrome-like disorder with loose anagen hair. All six are of normal intelligence, none have a history of failure to thrive or malignancy, and they have no known cardiac or neurologic pathologies. Our report adds to the previous reports of patients with rare variants affecting amino acids located in the SWITCH II/G3 region of HRAS and suggests a consistent, attenuated phenotype distinct from classical Costello syndrome. We propose the definition of a new distinct HRAS-related RASopathy for patients carrying HRAS variants affecting codons 58, 59, 60

Corticoperipheral neuromuscular disconnection in obstructive sleep apnoea

The roles of central nervous mechanisms and cortical output in obstructive sleep apnea remain unclear. We addressed corticomuscular coupling between cortical sensorimotor areas and lower facial motor units as a mechanistic pathway and as a possible surrogate marker of cortico-peripheral motor control in obstructive sleep apnea. In this exploratory cross-sectional retrospective study we analysed EEG (C3- and C4-leads) and chin EMG from polysomnography recordings in 86 participants (22 females; age range: 26-81 years), 27 with mild (respiratory disturbance index = 5-15 events/hour), 21 with moderate (15-30 events/h) and 23 with severe obstructive sleep apnea (> 30 events/h) and 15 control subjects (<5 events/h). By computing C3-/C4-EEG- chin EMG coherence of signal dynamics in time and frequency domains we investigated corticomuscular coupling between cortical sensorimotor areas and lower facial motor units with increasing obstructive sleep apnea severity during the entire sleeping time, during different sleep stages and during obstructive respiratory events, including 5 seconds before (stable breathing) and after events (breathing resumption). Additionally, we studied a possible influence of body-mass-index and autonomic nervous system activation. We found that both average and respiratory event-specific corticomuscular coupling between cortical sensorimotor areas and lower facial motor units weakened significantly with increasing obstructive sleep apnea severity, was strongest during N3 and weakened in N1, N2 and rapid-eye-movement stages (in decreasing order). Coupling increases significantly during the obstructive respiratory events compared with coupling just before and following them. Results were independent of body-mass-index or autonomic nervous system activation. We conclude that obstructive respiratory events in obstructive sleep apnea are very strongly associated both quantitatively and temporally with the degree of disconnection within the cortical sensorimotor areas - lower facial motor units pathway. This quite coordinated activity pattern suggests a cortical sensorimotor area-driven obstructive respiratory event pattern generator and a central motor output disorder in obstructive sleep apnea

KI-gestützte Diagnostik der obstruktiven Schlafapnoe mittels delta – alpha Konnektivität am sensorimotorischen Cortex [Abstract]

Fragestellung: Die Modulation der delta-alpha Phasenamplituden-Kreuzfrequenzkopplung (PAKFK) kann die cerebro-corticale Informationsverarbeitung beeinflussen. Wir haben untersucht, ob diese frequenzband-spezifische Modulation bei Patienten mit obstruktiver Schlafapnoe (OSA) beeinträchtigt wird. Patienten und Methoden: Es wurden die C3- und C4- elektroencephalographischen Aufnahmen der Polysomnographien von 170 Teilnehmern (86 im Hauptdatensatz, 27 - 84 Jahre alt, 44 Teilnehmer mit Respiratorischen Disturbance Index RDI>15/h und 84 im Validierungsdatensatz, 35 - 75 Jahre alt, 42 davon mit RDI>15/h) ausgewertet. Der delta-alpha KFK-Modulationsindex (MI) wurde bei Patienten mit unterschiedlichem OSA-Schweregrad in den unterschiedlichen Schlafstadien am sensorimotorischen Cortex berechnet. Auch die Möglichkeit der Vorhersage des RDI mit Hilfe der Schlafstadien-spezifischen MIs unter Verwendung eines Support Vector Machine (SVM) - Algorithmus wurde getestet. Ergebnisse: In beiden Datensätzen wurde der delta-alpha KFK-MI an den kortikalen sensorimotorischen Bereichen bei Patienten mit RDI>15/h im Vergleich zu Patienten mit RDI≤15/h im Stadium NREM1 und REM signifikant (p15/h signifikant erhöht im Vergleich zu Patienten mit RDI≤15/h. Delta-alpha MI im REM-Stadium konnte mittels SVM zuverlässig (82% Genauigkeit) den RDI vorhersagen. Schlussfolgerungen: Diese Frequenzband- und Schlafstadien-spezifische sensorimotorische Diskonnektion unterstützt das Konzept einer kortikalen sensorimotorischen Dysfunktion bei OSA-Patienten. Zudem, bietet der delta-alpha MI im REM–Schlaf einen potenziellen objektiven neurophysiologischen Ersatzmarker der respiratorischen Störung bei OSA-Patienten an

Assessing clinical utility of preconception expanded carrier screening regarding residual risk for neurodevelopmental disorders

The magnitude of clinical utility of preconception expanded carrier screening (ECS) concerning its potential to reduce the risk of affected offspring is unknown. Since neurodevelopmental disorders (NDDs) in their offspring is a major concern of parents-to-be, we addressed the question of residual risk by assessing the risk-reduction potential for NDDs in a retrospective study investigating ECS with different criteria for gene selection and definition of pathogenicity. We used exome sequencing data from 700 parents of children with NDDs and blindly screened for carrier-alleles in up to 3046 recessive/X-linked genes. Depending on variant pathogenicity thresholds and gene content, NDD-risk-reduction potential was up to 43.5% in consanguineous, and 5.1% in nonconsanguineous couples. The risk-reduction-potential was compromised by underestimation of pathogenicity of missense variants (false-negative-rate 4.6%), inherited copy-number variants and compound heterozygosity of one inherited and one de novo variant (0.9% each). Adherence to the ACMG recommendations of restricting ECS to high-frequency genes in nonconsanguineous couples would more than halve the detectable inherited NDD-risk. Thus, for optimized clinical utility of ECS, screening in recessive/X-linked genes regardless of their frequency (ACMG Tier-4) and sensible pathogenicity thresholds should be considered for all couples seeking ECS

PD-L1 Expression and Immune Cell Infiltration in Gastroenteropancreatic (GEP) and Non-GEP Neuroendocrine Neoplasms With High Proliferative Activity

The potential of neuroendocrine neoplasms (NEN) to respond to checkpoint inhibitors is largely unknown and full of great expectations. Immunohistochemical (IHC) studies of programmed cell death ligand 1 (PD-L1) expression in the tumor microenvironment and its implications in predicting the response to checkpoint inhibition is a very active subject. Currently, the combined analysis of PD-L1 expression and tumor-associated immune cell (TAIC) infiltration is considered the best predictive marker of therapeutic response. Here we investigated the expression of PD-L1 on tumor cells (TC) and tumor-infiltrating immune cells (IC) by IHC in 68 NEN samples with a high proliferation rate (Ki-67 &gt;20%) from 57 patients and in 22 samples we correlated it with TAIC density by assessing intratumoral infiltration of CD3+, CD8+, and CD68+ cells. Furthermore, the tumor microenvironment was evaluated according to the classification of Teng et al. We detected PD-L1 expression in 31.6% of NEN G3. Its expression usually was weak and more IC than TC expressed PD-L1. The proportion of tumors positive for PD-L1 was comparable in NEN from different sites of origin but varied depending on tumor differentiation and disease extension. No positive IHC staining was found in 3 well-differentiated neuroendocrine tumors (NETs) with a proliferation rate above 20% (NET G3). When analyzing TAIC, we rarely (18.2%) detected intratumoral CD8+ cells, whereas infiltration by CD3+ and CD68+ cells was more common (45.5 and 59.1%, respectively). By combining CD3+ cells and PD-L1 status, we identified the immune ignorant phenotype of tumor microenvironment as being the most common phenotype, supporting the concept of a preferably combined immunotherapeutic approach in neuroendocrine carcinoma (NEC)

Loss-of-function and missense variants in NSD2 cause decreased methylation activity and are associated with a distinct developmental phenotype

PURPOSE: Despite a few recent reports of patients harboring truncating variants in NSD2, a gene considered critical for the Wolf–Hirschhorn syndrome (WHS) phenotype, the clinical spectrum associated with NSD2 pathogenic variants remains poorly understood. METHODS: We collected a comprehensive series of 18 unpublished patients carrying heterozygous missense, elongating, or truncating NSD2 variants; compared their clinical data to the typical WHS phenotype after pooling them with ten previously described patients; and assessed the underlying molecular mechanism by structural modeling and measuring methylation activity in vitro. RESULTS: The core NSD2-associated phenotype includes mostly mild developmental delay, prenatal-onset growth retardation, low body mass index, and characteristic facial features distinct from WHS. Patients carrying missense variants were significantly taller and had more frequent behavioral/psychological issues compared with those harboring truncating variants. Structural in silico modeling suggested interference with NSD2’s folding and function for all missense variants in known structures. In vitro testing showed reduced methylation activity and failure to reconstitute H3K36me2 in NSD2 knockout cells for most missense variants. CONCLUSION: NSD2 loss-of-function variants lead to a distinct, rather mild phenotype partially overlapping with WHS. To avoid confusion for patients, NSD2 deficiency may be named Rauch–Steindl syndrome after the delineators of this phenotype