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Einfluss örtlicher und zeitlicher Auflösung auf die Analyse von Strain- und Strainrate-Parametern und deren Reproduzierbarkeit in der Feature-Tracking-basierten Deformationsanalyse in der kardialen MRT
No full textDeutsche Herzstiftung e.V.Background: Myocardial deformation assessment using cardiac magnetic resonance feature tracking (CMR-FT) provides prognostic insights beyond conventional volumetric analyses. While ventricular CMR-FT is well-established, atrial deformation analysis has gained increasing interest. However, optimal spatial and temporal resolution parameters for reliable functional assessment of both atria and ventricles remain undefined.
Methods: CMR-FT was performed in 12 healthy volunteers and 9 ischemic heart failure (HF) patients. Cine sequences were acquired using different temporal (20, 30, 40 and 50 frames/cardiac cycle) and spatial resolution parameters (high 1.5 × 1.5 mm in plane and 5 mm slice thickness, standard 1.8 × 1.8 × 8 mm and low 3.0 × 3.0 × 10 mm). Inter- and intra-observer reproducibility were calculated.
Results: Temporal resolution significantly influenced both atrial and ventricular strain and strain rate (SR) values. Increasing temporal resolution is associated with higher absolute strain and SR values.
Significant changes in strain assessment for left atrial (LA) total strain occurred between 20 and 30 frames/cycle amounting to 2,5-4,4% in absolute changes depending on spatial resolution settings. From 30 frames/cycle onward, absolute strain values remained unchanged. Significant changes of LA strain rate assessment were observed up to the highest temporal resolution of 50 frames/cycle. Effects of spatial resolution on strain assessment were smaller. For LA total strain a general trend emerged for a mild decrease in strain values obtained comparing the lowest to the highest spatial resolution at temporal resolutions of 20, 40 and 50 frames/cycle (p = 0.006-0.046) but not at 30 frames/cycle (p = 0.140).
Maximum absolute changes in ventricles between lowest and highest temporal resolution were as follows: 1.8% and 0.3%/s for LV GLS and SR, 2.5% and 0.6%/s for GCS and SR as well as 1.4% for RV GLS. Changes of strain values occurred comparing 20 and 30 frames/cardiac cycle including LV and RV GLS and GCS (p < 0.001-0.046). In contrast, SR values (LV GLS/GCS SR) changed significantly comparing all successive temporal resolutions (p < 0.001-0.013). LV strain and SR reproducibility was not affected by either temporal or spatial resolution, whilst RV strain variability decreased with augmentation of temporal resolution.
Conclusion: Temporal resolution affect boths atrial and ventricular strain and SR in CMR-FT deformation analyses. Spatial resolution only affects atrial functional assessment. Consistent strain assessment requires a standard spatial resolution and a temporal resolution of 30 frames/cycle, whilst SR assessment requires even higher settings of at least 50 frames/cycle.2025-09-0
Deformations of Ideals in Lie Algebroids
No full textIn this dissertation, we address the deformation problem of ideals in Lie algebras and its generalization(s) in the context of Lie algebroids. Lie ideals lie at the heart of the representation theory of Lie algebras, as well as their classification theory. The upshot of deformation theory, as the infinitesimal study of moduli spaces, is to better understand the local geometry of the space of algebro-geometric objects of a specific kind. We attach to every Lie ideal a differential graded Lie algebra such that its Maurer-Cartan elements are in one-to-one correspondence with the (small) deformations of the ideal. Furthermore, we investigate how this theory is related to other well-known deformation theories, and, in addition, we attach to each Lie ideal a Lie-infinity algebra that controls the deformations of both the ideal and the ambient Lie bracket simultaneously. Under appropriate assumptions regarding the low levels of the deformation cohomology of a Lie ideal, we obtain (topological) rigidity and stability results. By translating the main technique used to solve the deformation problem of a Lie ideal inside a Lie algebra into differential graded geometric terms, we pave the way towards a generalization of this theory to bundles of Lie ideals within Lie algebroids. Finally, given that the most general (and appropriate) notion of an ideal in a Lie algebroid is equivalent to that of a double Lie subalgebroid of its tangent double bundle, we discuss the corresponding deformation problem, explain the necessary ingredients to tackle it, and describe the progress that has been made thus far.2025-08-0
Automated Capillary Electrophoresis Immunoblot for the Detection of Alpha-Synuclein in Mouse Tissue
No full textBackground: Alpha-synuclein (aSyn) is a key player in neurodegenerative diseases such as Parkinson’s disease (PD), dementia with Lewy bodies, or multiple system atrophy. aSyn is expressed throughout the brain, and can also be detected in various peripheral tissues. In fact, initial symptoms of PD are non-motoric and include autonomic dysfunction, suggesting that the periphery might play an important role in early development of the disease. aSyn is expressed at relatively low levels in non-central tissues, which brings challenges for its detection and quantification in different tissues.
Objective: Our goal was to assess the sensitivity of aSyn detection in central and peripheral mouse tissues through capillary electrophoresis (CE) immunoblot, considering the traditional SDS-PAGE immunoblot as the current standard.
Methods: Tissues from central and non-central origin from wild type mice were extracted, and included midbrain, inner ear, and esophagus/stomach. aSyn detection was assessed through immunoblotting using Simple Western size-based CE and SDS-PAGE.
Results: CE immunoblots show a consistent detection of aSyn in central and peripheral tissues. Through SDS-PAGE, immunoblots revealed a reliable signal corresponding to aSyn, particularly following membrane fixation.
Conclusion: Our results suggest a reliable detection of aSyn in central and peripheral tissues using the CE Simple Western immunoblot system. These observations can serve as preliminary datasets when aiming to formally compare CE with SDS- PAGE, as well as for further characterization of aSyn using this technique.2026-01-1
Intraoperative navigated marking of tumor resection margins for planning target volumes in adjuvant radiotherapy
No full textMundhöhlenkarzinome gehören zu den häufigsten Tumorentitäten weltweit. Neben der Chirurgie ist die adjuvante Radiatio wesentlicher Bestandteil der onkologischen Therapie. Die intensitätsmodulierte Radiotherapie (IMRT) erreicht eine hochkonformale Bestrahlung von Risikobereichen, während gesundes Gewebe geschont wird. Eine präzise Konturierung des Clinical target volume (CTV) ist für eine optimale Tumorkontrolle und die Risikominimierung von Nebenwirkungen somit entscheidend. Die Festlegung des CTV ist im postoperativen Setting jedoch aufgrund der veränderten Anatomie, des Gewebsverlusts und der entsprechenden plastischen Rekonstruktionstechniken erschwert. Ein Lösungsansatz besteht in der intraoperativen Markierung der Tumorresektionsgrenzen mithilfe spezieller Navigationssysteme. In der vorliegenden Arbeit wurde untersucht, ob die Nutzung solcher intraoperativen, digitalen Markierungen eine Reduktion des CTV ermöglicht. Dabei erfolgte bei Patienten mit ausgedehnten Resektionen der Mundhöhle eine navigierte Markierung der Resektionsgrenzen. Postoperativ wurden diese digitalen Koordinaten in die Bestrahlungsplanungssoftware importiert und mit der postoperativen Bildgebung gematched. Anschließend wurden die CTVs mithilfe der Marker konturiert und mit den unabhängig davon erstellten konventionell konturierten Zielvolumina verglichen. Die Arbeit zeigt, dass die Nutzung intraoperativ navigierter Tumorbettmarkierungen zur Zielvolumenkonturierung eine signifikante Reduktion des CTV ermöglicht. Wir etablierten einen personalisierten digitalen Workflow zum Informationsaustausch zwischen den beteiligten Fachdisziplinen in unserer Klinik.Oral squamous cell carcinoma is among the most common tumor entities worldwide. In addition to surgery, adjuvant radiation therapy is an important element of oncological treatment. Intensity-modulated radiation therapy (IMRT) achieves intensified irradiation of risk areas while preserving healthy tissue. Precise contouring of the clinical target volume (CTV) is therefore essential for optimal tumor control and minimizing the risk of side effects. However, defining the CTV in the postoperative setting is difficult due to changes in anatomy, tissue loss and the plastic reconstruction techniques used. One approach is to mark the tumor resection margins intraoperatively using special navigation systems. This study examines whether the use of such intraoperative digital markings allows a reduction of the CTV. In patients with extensive resections of the oral cavity, resection margins were marked using intraoperative navigation. After surgery, these digital coordinates were imported into the radiation planning software and matched with postoperative imaging. The CTVs were then contoured using the markers and compared with the conventional contoured target volumes. The study demonstrates that the use of intraoperative navigated tumor bed markings for contouring target volumes enables a significant reduction of the CTV. We established a personalized digital workflow for the exchange of information between the involved disciplines in our clinic.2025-09-2
Radial velocity search for extrasolar planets around late M dwarfs
No full textThe radial velocity (RV) method has revealed the presence of rocky exoplanets in the habitable zones of M dwarf stars in the Solar neighborhood. Some of the potentially most Earth-like exoplanets have been found orbiting late-type M dwarfs. The search for exoplanets around late-type M dwarfs is challenging because these stars are often faint and exhibit high levels of stellar activity. Stellar activity refers to phenomena causally connect to stellar magnetic fields and gives rise to RV excess noise (RV jitter). Consequently, only few exoplanets have been discovered around late-type M dwarfs so far. The focus of this thesis is the characterization of the RV jitter in M dwarfs and the search for exoplanets around late-type M dwarfs with the RV method.
We investigated the RV jitter in M dwarfs as a function of stellar equatorial rotation velocity and average magnetic fields based on a sample of 239 M dwarfs from the Calar Alto high-Resolution search for M dwarfs with Exoearths with Near-infrared and optical Échelle Spectrographs (CARMENES) survey. The RV jitter in our sample is primarily a function of stellar equatorial rotation velocity for stars with equatorial rotation velocities greater than 1 km/s. We observed an elevated RV jitter in a series of stars with distinctive distributions of magnetic filling factors, which could be related to their magnetic fields.
We conducted an RV survey of ten late-type M dwarfs with the near-infrared Habitable Zone Planet Finder (HPF) spectrograph to search for exoplanets. Our measurements achieved a precision down to 3.4 m/s per RV epoch. After completing half of the anticipated total of 50 RV epochs per star, our measurements indicate a possible Neptune-mass planet candidate with an orbital period of 2.9 d and a second, tentative planet candidate. A third candidate is likely an equal-mass binary as indicated by archival imaging data. Further measurements and analysis are needed to reveal the true nature of these objects. Once completed, the survey will contribute to uncover the planet population of late-type M dwarfs.2025-09-0
Impact of transplacentally transferred thyroid antibodies on neonatal and infant health
No full textAutoimmune Schilddrüsenerkrankungen bei Schwangeren können über transplazentar übertragene Antikörper zu Schilddrüsenfunktionsstörungen beim Neugeborenen führen. Diese zeigen sich mitunter erst verzögert und entgehen somit dem regulären Neugeborenen-Screening, wenn der Anstieg des Thyrotropins (TSH) nach dem üblichen Abnahmezeitpunkt erfolgt. Ziel dieser retrospektiven Datenanalyse war es, die Häufigkeit sowie den Verlauf von Schilddrüsenfunktionsstörungen bei Neugeborenen mit maternalen Schilddrüsenantikörpern anhand von Laborwerten zu untersuchen und die auxologischen Unterschiede zwischen den Gruppen mit und ohne postnatale Antikörper mittels deskriptiver Statistik zu analysieren. Zudem wurde die Qualität des Screening-Programms kritisch bewertet.
Die im Zeitraum vom 01.01.1999 – 28.02.2004 im Klinikum Bremen-Nord entbundenen Neugeborenen wurden bei anamnestisch erhobener bestehender Schilddrüsenerkrankung der Mutter dem Screening auf Schilddrüsen-Antikörper (Thyroidperoxidase-Antikörper (TPO-AK) und TSH-Rezeptor-Antikörper (TRAK), nachrangig Thyreoglobulin-Antikörper (TAK)) mit Bestimmung der Funktionsparameter zugeführt. Die Durchführung der nach drei Monaten empfohlenen Kontrollen der positiven Antikörperwerte durch die Kinderärzte wurde abgefragt und ausgewertet. Von 7709 Geburten im Untersuchungszeitraum war bei 325 Neugeborenen (4,2%) eine maternale Schilddrüsenerkrankung dokumentiert. Bei 99 Kindern wurden postnatal Schilddrüsenantikörper nachgewiesen (71 mit TPO-AK (darunter 14 Zwillinge), 16 mit TRAK, 7 mit TPO-AK und TRAK, 4 mit TPO-AK und TAK und ein Kind war isoliert TAK positiv). Die Inzidenz für die subklinische permanente connatale Hypothyreose betrug 2/7709 (0,03%). Für Kinder mit postnatal positiven Antiköpern schilddrüsenerkrankter Mütter betrug diese 2/85 (2,4%), für Zwillinge 2/99 (2,0%). Bei beiden betroffenen Kindern waren ausschließlich TPO-AK nachweisbar. Ein Kind wurde nach konsequenten postnatalen Kontrolluntersuchungen ab dem 42. Lebenstag therapiert, das andere Kind wurde erst im Alter von dreieinhalb Jahren diagnostiziert. Bei den postnatalen Kontrollen waren spätestens nach sechs Monaten die Antikörper im Serum nicht mehr nachweisbar. Bei 3 von 21 Müttern (14,3%) gab es eine Diskrepanz bezogen auf die Präsenz von postnatalen Schilddrüsen-Antikörpern zwischen der ersten und zweiten Schwangerschaft.
Auxologisch zeigten Antikörper-positive Kinder im Mittel signifikant niedrigere Geburtsgewichts-Standard Deviation Scores (SDS) als die Antikörper-negativ Gruppe (p = 0,025). Beide Gruppen waren im Mittel signifikant kleiner, (p < 0,001 Antikörper-positive-Gruppe, p = 0,001 Antikörper-negative-Gruppe), als der Median der zur Berechnung der Perzentilenkurven zugrunde gelegten Neugeborenen gleichen Alters. Bei fast der Hälfte der Kinder wurde keine Nachkontrolle der Schilddrüsenfunktion durchgeführt.
Die Ergebnisse unterstreichen, dass das bestehende Neugeborenen-Screening allein nicht ausreicht, um alle Fälle frühzeitig zu erfassen. Bei Nachweis von transplazentar übertragenen Thyroidperoxidase- und TSH-Rezeptor-Antikörper ist ein zweiter Abnahmezeitpunkt zur Bestimmung des TSH und der Antikörper zwei – vier Wochen nach der Geburt und eine Kontrolle bis zum Verschwinden der Antikörper sinnvoll. Zudem ist eine direkte Ansprache der weiter betreuenden Kinderärzte empfehlenswert. Weitere prospektive Studien sind notwendig, um das Risiko für eine connatale Hypothyreose bei maternaler Autoimmunthyreoiditis besser abschätzen zu können.Autoimmune thyroid diseases in pregnant women can lead to thyroid dysfunction in the newborn due to transplacentally transferred antibodies. These dysfunctions may present with a delay and can therefore be missed by routine newborn screening if the rise in thyroid-stimulating hormone (TSH) occurs after the standard sampling time. The aim of this retrospective data analysis was to investigate the frequency and course of thyroid dysfunction in newborns with maternal thyroid antibodies based on laboratory findings, and to analyze auxological differences between groups with and without postnatally detectable antibodies using descriptive statistics. In addition, the quality of the current screening program was critically evaluated. Neonates born between January 1, 1999, and February 28, 2004, at the Bremen-Nord Hospital were screened for thyroid antibodies (thyroid peroxidase antibodies (TPO-Ab), TSH receptor antibodies (TRAb), and secondarily thyroglobulin antibodies (TgAb)) along with assessment of functional parameters, if there was a documented maternal history of thyroid disease. The recommended follow-up of positive antibody levels after three months by pediatricians was assessed and evaluated.
Out of 7,709 births during the study period, 325 neonates (4.2%) had a documented maternal thyroid disorder. Thyroid antibodies were detected postnatally in 99 children (71 newborns had TPO-Ab, including 14 twins; 16 had TRAb; 7 had both TPO-Ab and TRAb; 4 had TPO-Ab and TgAb; and a single case showed isolated TgAb positivity). The incidence of subclinical permanent congenital hypothyroidism was 2/7,709 (0.03%). Among children with postnatally positive antibodies from mothers with thyroid disease, the incidence was 2/85 (2.4%), or 2/99 (2.0%) when including twins. In both affected children, only TPO antibodies were detectable. One child received treatment starting on the 42nd day of life following consistent postnatal monitoring, the other was diagnosed only at the age of three and a half years. Postnatal controls showed that antibodies were no longer detectable in the serum after six months. In 3 out of 21 mothers (14.3%), there was a discrepancy in the presence of postnatal thyroid antibodies between the first and second pregnancies. Auxologically, antibody-positive children had significantly lower mean birth weight standard deviation scores (SDS) compared to the antibody-negative group (p = .025). Both groups were significantly shorter on average than the median of newborns of the same age used to create the percentile curves (p < .001 for the antibody-positive group, p = .001 for the antibody-negative group). Nearly half of the children did not receive follow-up for thyroid function.
These findings underscore that the existing newborn screening alone is insufficient to detect all cases early. In the presence of transplacentally transferred thyroid peroxidase or TSH receptor antibodies, a second sampling for TSH and antibody levels two to four weeks after birth, and monitoring until antibody disappearance, is advisable. Furthermore, direct communication with the child’s pediatrician is recommended. Additional prospective studies are needed to better assess the risk of congenital hypothyroidism in cases of maternal autoimmune thyroiditis.2025-11-2
Wirksamkeitsuntersuchungen von Levetiracetam in der Epilepsietherapie
No full textDie Epilepsie ist eine weltweit verbreitete Erkrankung und spielt auch in Deutschland eine wichtige Rolle. Zur medikamentösen Therapie wird Levetiracetam (LEV) als gut verträgliches Medikament eingesetzt und zählt mittlerweile zu einem der am weitesten verbreiteten Anfallssuppressiva. Allerdings gibt es aktuell keine klaren Erkenntnisse darüber, mit welchen Charakteristika die Wirksamkeit von LEV bei unterschiedlichen Charakteristika der Patient*innen vorhergesagt werden könnte. Auch fehlt es an ausreichenden Daten darüber, welche der zahlreichen Medikamentenkombinationen bei welchen Patient*innen die beste Wirksamkeit aufweisen. In dieser Arbeit wurde untersucht, wie sich die LEV-Effektivität in einem Studienkollektiv aus 226 randomisiert ausgewählten Patient*innen der Universitätsmedizin Göttingen darstellte. Dabei wurde überprüft, ob sich ein Einfluss der Faktoren Geschlecht, Alter, Epilepsieart, Ätiologie der Epilepsie sowie der medikamentösen Kombinationspartner und der Dosis auf die Effektivität von LEV und das Auftreten von Nebenwirkungen nachweisen ließ. Hieraus sollten geeignete Vorhersagemodelle für die LEV-Effektivität erstellt werden.
Es ließ sich kein signifikanter Zusammenhang zwischen dem Geschlecht oder dem Alter und der LEV-Effektivität nachweisen. Allerdings führte LEV bei Pat. mit generalisierter Epilepsie deutlich häufiger zu Anfallsfreiheit als bei Pat. mit fokaler Epilepsie. Hinsichtlich der Ätiologie der Epilepsie wurde bei Patient*innen mit genetischer Epilepsieursache die beste Wirksamkeit nachgewiesen, jedoch ohne statistisch signifikanten Zusammenhang. Hinsichtlich der Medikamentenkombinationen trat die beste Effektivitätsbeurteilung unter „LEV + Valproat“ auf. Als negativer Einfluss zeigte sich, dass bei einer Kombination von LEV mit Natriumkanalinhibitoren geringere Wahrscheinlichkeiten für eine gebesserte Anfallssituation bestanden. Eine verlässliche Vorhersage der LEV-Effektivität anhand der verabreichten Tagesdosis gelang nicht.
In Hinblick auf die Nebenwirkungen unter LEV zeigten diese sich bei jungen Patienten milder ausgeprägt. Bei ≥60-jährigen Patient*innen kamen signifikant häufiger neurotoxische Nebenwirkungen vor als bei den übrigen Patient*innen. Zwischen der LEV-Dosis und dem Schweregrad der Nebenwirkungen konnte ein schwacher signifikanter Zusammenhang belegt werden.
Insgesamt ließen sich anhand der hier vorliegenden Daten noch keine signifikanten Prognosemodelle zur LEV-Effektivität erstellen; weitere Studien bleiben hierzu abzuwarten.Epilepsy is a widely prevalent condition and holds significant relevance in Germany as well. Levetiracetam (LEV) is a well-tolerated medication commonly used in pharmacological therapy and has become one of the most frequently prescribed anticonvulsants. However, there is currently insufficient evidence regarding which patient characteristics could predict the effectiveness of LEV. Additionally, there is a lack of sufficient data on which of the numerous drug combinations are most effective for specific patient subgroups.
This study investigated the effectiveness of LEV in a cohort of 226 patients, which were randomly selected from the Clinic of Neurology at the Universitätsmedizin Göttingen. The analysis focused on determining whether factors such as gender, age, type of epilepsy, etiology, as well as the specific combinations and dosages, influenced the effectiveness of LEV and the occurrence of adverse effects. The goal was to develop potential predictive models for LEV effectiveness.
No significant correlation was found between gender or age and LEV effectiveness. However, LEV was significantly more effective in achieving seizure freedom in patients with generalized epilepsy compared to those with focal epilepsy. Regarding the etiology, the best efficacy was observed in patients with a genetic cause of epilepsy, although this finding was not statistically significant. Among the various drug combinations, the combination of LEV and valproate demonstrated the best efficacy. On the contrary, the combination of LEV with sodium channel blockers was associated with lower probabilities of improved seizure control. No reliable prediction of LEV effectiveness was possible based on the administered daily dose.
Regarding side effects, these were generally milder in younger patients, whereas neurotoxic side effects occurred significantly more frequently in patients aged ≥60 compared to younger individuals. A weak but significant correlation was found between the LEV dose and the severity of side effects.
In conclusion, the data presented in this study did not allow for the development of reliable predictive models for LEV effectiveness. Further studies are needed to address these gaps and provide clearer insights.2025-11-2
Mathematical Background of Parallel Magnetic Resonance Imaging
No full textWe provide mathematical analyses of reconstruction methods in parallel Magnetic Resonance Imaging (pMRI). We start with a discussion of the mathematical model and then discuss multiple methods such as SENSE, (AUTO-)SMASH, GRAPPA, ESPIRiT and the new MOCCA method. The methods ESPIRiT and MOCCA are shown to be equivalent to the assumption of coil sensitivities modelled by trigonometric polynomials of a low degree.2025-10-1
Retrospektive Analyse der Patienten mit chronischem Subduralem Hämatom nach Embolisation der Arterie meningea media versus offene Operation
No full textiese Dissertation analysiert retrospektiv die Behandlungsergebnisse von Patientinnen und Patienten mit chronischem Subduralhämatom (cSDH), die entweder mittels Embolisation der Arteria meningea media (EAMM) oder durch konventionelle operative Verfahren therapiert wurden. Insgesamt wurden 196 Patientinnen und Patienten, die zwischen 2015 und 2018 an der Asklepios Klinik Schildautal Seesen behandelt wurden, eingeschlossen. 54 erhielten eine EAMM, 142 eine operative Therapie (Bohrlochtrepanation oder Kraniotomie). Ziel war der Vergleich von Rezidiv- und Komplikationsraten beider Behandlungsansätze. Die statistische Analyse zeigte eine signifikant niedrigere Rezidivrate in der Embolisationsgruppe (9 %) im Vergleich zur chirurgischen Gruppe (32 %). Die logistische Regressionsanalyse ergab, dass die EAMM das Rezidivrisiko um das Sechsfache senkte, während die Kraniotomie dieses signifikant erhöhte. Die Komplikationsraten unterschieden sich nicht signifikant. Die Ergebnisse sprechen für die Embolisation der Arteria meningea media als effektive und sichere Ergänzung bzw. Alternative zur offenen Operation, insbesondere bei älteren oder multimorbiden Patientinnen und Patienten.This dissertation presents a retrospective analysis comparing outcomes of patients with chronic subdural hematoma (cSDH) treated either by middle meningeal artery embolization (MMAE) or conventional surgical evacuation. A total of 196 patients treated between 2015 and 2018 at Asklepios Klinik Schildautal Seesen were included. Fifty-four patients underwent MMAE, while 142 received traditional surgical management such as burr-hole trepanation or craniotomy. The study aimed to evaluate recurrence and complication rates between both approaches. Statistical analysis demonstrated a significantly lower recurrence rate in the embolization group (9%) compared to the surgical group (32%). Logistic regression revealed that MMAE reduced recurrence risk six-fold, while craniotomy increased it fifteen-fold. Complication rates did not differ significantly between groups. These results support MMAE as an effective and safe adjunct or alternative to open surgery for chronic subdural hematoma, especially in elderly or multimorbid patients.2025-12-0
Amyloid-β and phospho-Tau biomarkers immunoassay development and optimization to support the blood-based early and differential diagnosis of Alzheimer’s disease
No full textThe recent emergence of anti-amyloid treatments for early symptomatic Alzheimer’s disease (AD) require biomarker confirmation of amyloid pathology, increasing the need for biomarker testing. In the last few years, there has been enormous progress in the development of new ultrasensitive blood based biomarker assays with great analytical and clinical performances. Compared to amyloid PET or cerebrospinal fluid (CSF) tests, blood tests are less costly, more accessible and more scalable for widespread use than. The most promising tests consist of low Aβ42/Aβ40 ratio and phosphorylated Tau (pTau) in particular Tau phosphorylated at Threonine 217 (pTau217) that reflect brain Aβ-amyloid pathology.
The overall goal of this thesis was to develop and validate blood-based biomarkers tests for the AD amyloid pathology. The thesis was divided in 3 independent parts, covering biomarker development, assay development and analytical/technical validation and clinical validation.
Pre-analytical immunoprecipitation of Aβ peptides from blood plasma was previously shown to improve the diagnostic performance of MSD and Elecsys plasma Aβ assays for detecting amyloid pathology. In order to tentatively improve the previous stablished immunoprecipitation-immunoassay approach, this thesis investigated different antibody selection and immunoassay platforms in detecting low-abundant brain-derived biomarkers in blood plasma in proof of concept case-control cohorts. For extending the use of pre-analytical IP to additional AD biomarkers, the protocol was modified for the immunoprecipitation of Tau proteins for the subsequent quantification of plasma pTau181 and pTau217. Aβ- and Tau-IP were shown to be compatible with the Lumipulse G System, the currently best performing immunoassay platform for the measurement of plasma biomarkers Aβ1-
42/1-40, pTau217 and pTau181. However, as it turned out, the pre-analytical IP did not statistically significantly improve the diagnostic performance of the plasma AD biomarkers Aβ42/40 ratio and pTau217 compared to direct measurements in EDTA-plasma and following the manufacturer’s recommendations. In contrast, the proposed IP protocol worked reasonably well in improving the performance of plasma pTau181 in a small pre-selected sample.
A clinical validation study was performed to demonstrate the clinical diagnostic value of the protocols developed in the first part of this thesis in samples from the DELCODE study of the German Center for Neurodegenerative Diseases (DZNE). This study cohort was assumed to have demographic characteristics representative of the patients presenting at memory clinics. Results indicated plasma pTau217 as the leading single plasma biomarker to detect brain amyloid pathology, supporting published findings. A novel composite biomarker was proposed, that combines the plasma measurements of Aβ1-40, Aβ1-42 and pTau in a single biomarker for detecting amyloid pathology. The Aβ1-40/Aβ1-42∗ pTau217 ratio showed an added diagnostic value relative to the more straightforward pTau217 but additional studies are needed to confirm these observations.
Biomarkers results are often interpreted using a binary system with a single cut-off value, indicating either the presence (+) or absence (−) of specific pathogenic processes. With the aim to optimize the overall test accuracy, a previously proposed two-cut-point (three-category) approach was investigated. The results suggest that, for future use in clinical trials and routine, a two-cut-point approach provides a particularly useful way for the interpretation of biomarker measurements for predicting amyloid status, and thus decreasing the risk of patient misclassification.
Finally, this thesis aimed to assess a novel blood biomarker candidate that was hypothesized to reflect brain amyloid deposition. The presence of N-terminally elongated Aβ-3-42 was confirmed for the first time in human CSF. In order to investigate the potential diagnostic value of the Aβ-3-42/-3-40 ratio, an ultra-sensitive 2-step immunoprecipitation-immunoassay approach was developed for blood plasma and CSF samples. On a small pilot study, the CSF Aβ-3-42/-3-40 ratio seemed to offer the same information as the well established CSF Aβ42/40 ratio. Moreover, the novel Aβ ratio was significantly altered in plasma samples of AD patients. Nevertheless, larger patient cohorts are needed to validate these results and investigate whether the Aβ-3-42/-3-40 ratio offers an added diagnostic information for the differential diagnosis of early diagnosis.2025-10-2