Neural Correlates of Parkinsonian Syndromes

The thesis investigated objective neuroimaging biomarkers in parkinsonian syndromes, which could be applied to increase diagnostic accuracy. To find convergence of the literature concerning disease-specific patterns in Parkinson’s disease and progressive supranuclear palsy, we conducted meta-analyses. In Parkinson’s disease glucose hypometabolism was re- vealed in bilateral inferior parietal cortex and left caudate nucleus and focal gray matter atrophy in the middle occipital gyrus. In progressive supranu- clear palsy we identified gray matter atrophy in the midbrain and white mat- ter atrophy in the cerebral/cerebellar pedunculi and midbrain. In sum, in Parkinson’s disease hypometabolism outperforms atrophy and in progres- sive supranuclear palsy we validated pathognomonic markers as disease- specific. Our studies create a novel framework to investigate disease- specific regional alterations for use in clinical routine. Further, we inves- tigated neural correlates by voxel-based morphometry and discriminated disease and clinical syndrome by multivariate pattern recognition in sin- gle patients with corticobasal syndrome and corticobasal syndrome with a unique syndrome - alien/ anarchic limb phenomenon. We found gray matter volume differences between patients and controls in asymmetric frontotem- poral/ occipital regions, motor areas, and insulae. The frontoparietal gyrus including the supplementary motor area contralateral to the side of the af- fected limb was specific for alien/ anarchic limb phenomenon. The predic- tion of the disease among controls was 79.0% accurate. The prediction of the specific syndrome within a disease reached an accuracy of 81.3%. In conclusion, we reliably classified patients and controls by objective pattern recognition. Moreover, we were able to predict a specific clinical syndrome within a disease, paving the way to individualized disease prediction.:SELBSTSTÄNDIGKEITSERKLÄRUNG I ACKNOWLEDGMENTS II SUMMARY III ZUSAMMENFASSUNG VIII BIBLIOGRAPHISCHE DARSTELLUNG XIV CONTENTS XVI 1 GENERAL INTRODUCTION 1 1.1 ParkinsonianSyndromes .................... 2 1.2 Parkinson’sDisease ....................... 2 1.2.1 DiagnosticCriteria .................... 3 1.3 ProgressiveSupranuclearPalsy ................ 4 1.3.1 DiagnosticCriteria .................... 5 1.4 CorticobasalDegeneration ................... 5 1.4.1 DiagnosticCriteria .................... 7 1.5 ImagingBiomarkers ....................... 7 1.6 CurrentThesis .......................... 9 1.6.1 MotivationandFramework ............... 9 1.6.2 ResearchQuestions................... 9 2 GENERAL MATERIALS AND METHODS 12 2.1 MagneticResonanceImaging.................. 12 2.2 AnalyticalMethods........................ 13 2.2.1 Meta-Analysis ...................... 13 2.2.2 Voxel-BasedMorphometry ............... 14 2.2.3 Support-Vector Machine Classification . . . . . . . . . 15 2.3 Multi-CentricData ........................ 16 2.4 ClinicalAssessment ....................... 17 3 Study 1 4 Study 2 5 Study 3 6 Study 4 7 Study 5 8 DISCUSSION 73 8.1 MainFindings........................... 73 8.2 Statistical Approaches to Find Imaging Biomarker . . . . . . 76 8.3 Brain Alterations and their Utility as Imaging Biomarker . . . . 77 8.4 Limitations ............................ 78 8.5 Contributions of the Current Thesis and Future Directions . . 79 9 REFERENCES APPENDIX XVIII LIST OF AUTHORSHIP XXVII CURRICULUM VITÆ XXXVII

CCI-779 (Temsirolimus) exhibits increased anti-tumor activity in low EGFR expressing HNSCC cell lines and is effective in cells with acquired resistance to cisplatin or cetuximab

Background: The mammalian target of rapamycin (mTOR) signaling pathway plays a pivotal role in numerous cellular processes involving growth, proliferation and survival. The purpose of this study was to investigate the anti-tumoral effect of the mTOR inhibitor (mTORi) CCI-779 in HNSCC cell lines and its potency in cisplatin- and cetuximab-resistant cells. Methods: A panel of 10 HNSCC cell lines with differences in TP53 mutational status and basal cisplatin sensitivity and two isogenic models of acquired resistance to cisplatin and cetuximab, respectively were studied. Cell survival after treatment with CCI-779, cisplatin and cetuximab alone or in combination was determined by MTT assays. Potential predictive biomarkers for tumor cell sensitivity to CCI-779 were evaluated. Results: We observed considerable heterogeneity in sensitivity of HNSCC cell lines to CCI-779 monotherapy. Sensitivity was observed in TP53 mutated as well as wild-type cell lines. Total and p-EGFR expression levels but not the basal activity of the mTOR and MAPK signaling pathways were correlated with sensitivity to CCI-779. Resistant cells with increased EGFR activation could be sensitized by the combination of CCI-779 with cetuximab. Interestingly, cell lines with acquired resistance to cisplatin displayed a higher sensitivity to CCI-779 whereas cetuximab-resistant cells were less sensitive to the drug, but could be sensitized to CCI-779 by EGFR blockade. Conclusions: Activity of CCI-779 in HNSCC cells harboring TP53 mutations and displaying a phenotype of cisplatin resistance suggests its clinical potential even in patients with dismal outcome after current standard treatment. Cetuximab/mTORi combinations might be useful for treatment of tumors with high expression of EGFR/p-EGFR and/or acquired cetuximab resistance. This combinatorial treatment modality needs further evaluation in future translational and clinical studies

The Basso-Dixon Formula and Calabi-Yau Geometry

We analyse the family of Calabi-Yau varieties attached to four-point fishnet integrals in two dimensions. We find that the Picard-Fuchs operators for fishnet integrals are exterior powers of the Picard-Fuchs operators for ladder integrals. This implies that the periods of the Calabi-Yau varieties for fishnet integrals can be written as determinants of periods for ladder integrals. The representation theory of the geometric monodromy group plays an important role in this context. We then show how the determinant form of the periods immediately leads to the well-known Basso-Dixon formula for four-point fishnet integrals in two dimensions. Notably, the relation to Calabi-Yau geometry implies that the volume is also expressible via a determinant formula of Basso-Dixon type. Finally, we show how the fishnet integrals can be written in terms of iterated integrals naturally attached to the Calabi-Yau varieties.Comment: 42 page

Photoassociation and coherent transient dynamics in the interaction of ultracold rubidium atoms with shaped femtosecond pulses - I. Experiment

We experimentally investigate various processes present in the photoassociative interaction of an ultracold atomic sample with shaped femtosecond laser pulses. We demonstrate the photoassociation of pairs of rubidium atoms into electronically excited, bound molecular states using spectrally cut femtosecond laser pulses tuned below the rubidium D1 or D2 asymptote. Time-resolved pump-probe spectra reveal coherent oscillations of the molecular formation rate, which are due to coherent transient dynamics in the electronic excitation. The oscillation frequency corresponds to the detun-ing of the spectral cut position to the asymptotic transition frequency of the rubidium D1 or D2 lines, respectively. Measurements of the molecular photoassociation signal as a function of the pulse energy reveal a non-linear dependence and indicate a non-perturbative excitation process. Chirping the association laser pulse allowed us to change the phase of the coherent transients. Furthermore, a signature for molecules in the electronic ground state is found, which is attributed to molecule formation by femtosecond photoassociation followed by spontaneous decay. In a subsequent article [A. Merli et al., submitted] quantum mechanical calculations are presented, which compare well with the experimental data and reveal further details about the observed coherent transient dynamics

Coherent control with shaped femtosecond laser pulses applied to ultracold molecules

We report on coherent control of excitation processes of translationally ultracold rubidium dimers in a magneto-optical trap by using shaped femtosecond laser pulses. Evolution strategies are applied in a feedback loop in order to optimize the photoexcitation of the Rb2 molecules, which subsequently undergo ionization or fragmentation. A superior performance of the resulting pulses compared to unshaped pulses of the same pulse energy is obtained by distributing the energy among specific spectral components. The demonstration of coherent control to ultracold ensembles opens a path to actively influence fundamental photo-induced processes in molecular quantum gases

A hyperelastic model for simulating cells in flow

In the emerging field of 3D bioprinting, cell damage due to large deformations is considered a main cause for cell death and loss of functionality inside the printed construct. Those deformations, in turn, strongly depend on the mechano-elastic response of the cell to the hydrodynamic stresses experienced during printing. In this work, we present a numerical model to simulate the deformation of biological cells in arbitrary three-dimensional flows. We consider cells as an elastic continuum according to the hyperelastic Mooney-Rivlin model. We then employ force calculations on a tetrahedralized volume mesh. To calibrate our model, we perform a series of FluidFM(R) compression experiments with REF52 cells demonstrating that all three parameters of the Mooney-Rivlin model are required for a good description of the experimental data at very large deformations up to 80%. In addition, we validate the model by comparing to previous AFM experiments on bovine endothelial cells and artificial hydrogel particles. To investigate cell deformation in flow, we incorporate our model into Lattice Boltzmann simulations via an Immersed-Boundary algorithm. In linear shear flows, our model shows excellent agreement with analytical calculations and previous simulation data.Comment: 15 pages, 9 figures, Supplementary information included. Unfortunately, the journal version misses an important contributor. The correct author list is the one given in this document. Biomech Model Mechanobiol (2020

A Recovery-Oriented Approach for an Acute Psychiatric Ward: Is It Feasible and How Does It Affect Staff Satisfaction?

To evaluate professionals' attitudes to recovery and coercion, as well their satisfaction with working conditions before and after the implementation of a recovery-oriented ward concept on an admission ward. Longitudinal study design with two measurement times of the study sample, with a control group assessed at study end. Evaluating the implementation of the recovery concept, attitudes towards recovery, coercion, perceptions of the ward and working satisfaction were assessed with questionnaires and computed using Chi square and ANOVA variance analyses. The members of the intervention ward (n=17) did not differ from the control group (n=21), except that control group members were younger. The recovery-orientation of the study ward (ROSE questionnaire) increased significantly (alpha level=0.05) from study begin to study end (p=0.003), and compared to the control group (p=0.002). The attitudes towards coercion did not change significantly in the intervention group, but did so compared to the control group. The contentedness (GMI) and the satisfaction with working conditions (ABB) of the intervention group members compared to control group was significantly higher (GMI: p=0.004, ABB subscale working conditions: p=0.043, satisfaction: p=0.023). The study indicates that recovery-oriented principles can be implemented even in an acute admission ward, increasing team satisfaction with work, while attitudes towards coercion did not change significantly within this single-unit project

Nipple Discharge: Role of Ductoscopy in Comparison with Standard Diagnostic Tests

Background: This study aims to assess the role of ductoscopy for detecting intraductal anomalies in patients with nipple discharge in comparison to conventional tests and to find an effective combination of both approaches. Materials and Methods: Prior to duct excision, ductoscopy was performed in 97 women. Histologic and all other diagnostic results were compared. Sensitivity, specificity, and efficiency were calculated for all methods. These parameters were also calculated for all possible test combinations in 12 patients who had completed all tests. Results: Breast sonography reached the highest sensitivity (64.1%) and efficiency (64%); mammography had the highest specificity (100%). The sensitivity of ductoscopy was 53.2%, its specificity 60%, and its efficiency 55.1%. Among combinations of all methods, the combination ductoscopy + galactography was the most sensitive (80%). Mammography, magnetic resonance imaging, and ductoscopy were each 100% specific. Ductoscopy was the most efficient (75%) single method. Conclusion: Ductoscopy is a valuable test for diagnosing intraductal lesions in patients with nipple discharge. It is more efficient than conventional tests in patients undergoing all tests

Brain Edema Formation and Functional Outcome After Surgical Decompression in Murine Closed Head Injury Are Modulated by Acetazolamide Administration

Acetazolamide (ACZ), carbonic anhydrase inhibitor, has been successfully applied in several neurosurgical conditions for diagnostic or therapeutic purposes. Furthermore, neuroprotective and anti-edematous properties of ACZ have been postulated. However, its use in traumatic brain injury (TBI) is limited, since ACZ-caused vasodilatation according to the Monro-Kellie doctrine may lead to increased intracranial blood volume / raise of intracranial pressure. We hypothesized that these negative effects of ACZ will be reduced or prevented, if the drug is administered after already performed decompression. To test this hypothesis, we used a mouse model of closed head injury (CHI) and decompressive craniectomy (DC). Mice were assigned into following experimental groups: sham, DC, CHI, CHI+ACZ, CHI+DC, and CHI+DC+ACZ (n = 8 each group). 1d and 3d post injury, the neurological function was assessed according to Neurological Severity Score (NSS) and Beam Balance Score (BBS). At the same time points, brain edema was quantified by MRI investigations. Functional impairment and edema volume were compared between groups and over time. Among the animals without skull decompression, the group additionally treated with acetazolamide demonstrated the most severe functional impairment. This pattern was reversed among the mice with decompressive craniectomy: CHI+DC treated but not CHI+DC+ACZ treated animals showed a significant neurological deficit. Accordingly, radiological assessment revealed most severe edema formation in the CHI+DC group while in CHI+DC+ACZ animals, volume of brain edema did not differ from DC-only animals. In our CHI model, the response to acetazolamide treatment varies between animals with decompressive craniectomy and those without surgical treatment. Opening the cranial vault potentially creates an opportunity for acetazolamide to exert its beneficial effects while vasodilatation-related risks are attenuated. Therefore, we recommend further exploration of this potentially beneficial drug in translational research projects