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Coming dissertations at MedFak

  • Timed Up-and-Go Dual-Task Tests for Early Detection of Dementia Disorder Author: Hanna Bozkurt Åhman Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-451233 Publication date: 2021-09-20 14:34

    Dementia constitutes an important and growing public health concern. There is a need for new, simple, and inexpensive methods to detect dementia disorders early in the disease progression. For this purpose, dual-tasking, i.e., simultaneous performance of two tasks, has been proposed.

    The overall aim of this thesis was to explore if Timed Up-and-Go (TUG) dual-task (TUGdt) tests can be used for early detection of dementia disorder. Cross-sectional and longitudinal designs were used. Participants were recruited when undergoing memory assessment at memory clinics (patients) and through advertisements (controls). The TUGdt tests involved TUG combined with the cognitive tasks a) naming animals (TUGdt NA) and b) reciting months in reverse order (TUGdt MB). The tests were video recorded. Test outcomes were calculated using time scores and/or verbal performances. Additionally, the data collection comprised clinical tests and medical record reviews. 

    Paper I included 90 patients who had carried out lumbar puncture as part of the memory assessment. By Spearman’s rank correlation, the TUGdt NA test outcomes “number of animals” and “animals/10 s” correlated negatively to the cerebrospinal fluid biomarkers t-tau and p-tau, suggesting that neurodegeneration is associated with dual-task performance. In Paper II, 298 patients and 166 controls participated. Logistic regression models showed that “animals/10 s” and “months/10 s” discriminated significantly between dementia, mild cognitive impairment (MCI), subjective cognitive impairment (SCI), and controls. Thus, TUGdt testing could be useful in diagnostic assessments. Paper III involved 172 patients, initially diagnosed with MCI or SCI, for whom diagnostic information was available after 2.5 years. Logistic regression showed inverse associations between “animals/10 s” and dementia incidence, particularly for patients <72 years (median age). For these younger patients, the predictive capacity of “animals/10 s” was excellent. Hence, TUGdt NA has potential for predicting dementia from SCI or MCI, particularly among younger patients. Paper IV included 166 controls for presenting TUGdt reference values in age- and sex-specific groups, and 43 controls for test-retest reliability. Reference values were calculated with quantile regression and may be useful in clinic and research. Intra-class correlation coefficients showed excellent reliability for time scores, while the other test outcomes were poor to good. “Animals/10 s” showed fair to good reliability despite being a ratio of other variables, which negatively affects reliability. 

    In summary, TUGdt NA has the potential to be used for early detection of dementia disorder, and the test outcome “animals/10 s” merits further evaluation.

  • Oxygen Metabolism in Experimental Kidney Disease Author: Ebba Sivertsson Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-450561 Publication date: 2021-09-16 13:12

    Tubulointerstitial hypoxia has been proposed a unifying mechanism behind the development of chronic kidney disease (CKD), regardless of primary diagnosis. Important factors that contribute to the development of hypoxia are reduced bioavailability of nitric oxide (NO), oxidative stress and mitochondria uncoupling. Diabetes and hypertension are the leading causes of CKD. Once established, CKD is a progressive disease and there is no curative treatment. This thesis aimed to investigate the in vivo kidney oxygen metabolism and in vitro mitochondria function in animal models of pathological conditions known to cause kidney injury.

    The immunosuppressant drug rapamycin has been suggested to counteract diabetic nephropathy by reducing kidney hypertrophy and proteinuria. In a rat model of diabetes type 1, we demonstrate that rapamycin induced intrarenal hypoxia, oxidative stress and mitochondria leak respiration. In diabetic animals, these changes, together with diabetes induced tubular injury, were further aggravated by rapamycin. Proteinuria was decreased by rapamycin in diabetic animals, due to altered glomerular permeability of large molecules. When investigating the role of hypoxia in development of nephropathy there are often confounding factors such as concomitant hyperglycemia, hypertension and oxidative stress to consider. In rats, we demonstrate that increased kidney metabolism, induced by increased thyroid hormone signaling, induced kidney hypoxia, proteinuria and mitochondria leak respiration. Importantly blood glucose, blood pressure and oxidative stress was unchanged. This provides further evidence that hypoxia per se can induce kidney injury. The role of mitochondria dysfunction in hypertensive kidney disease is unclear and angiotensin II (Ang II) has been shown to inhibit mitochondria respiration. In a mouse model of hypertension, we demonstrate that Ang II regulation of mitochondria respiration was dose-dependent. Low Ang II signaling increased leak respiration without compromising efficiency of oxidative phosphorylation. In contrast, high Ang II signaling inhibited mitochondria respiration and decreased efficiency of oxidative phosphorylation. Finally, uremic toxins accumulate in patients with CKD and correlate with the degree of decline in kidney function. In a rat model of CKD, we demonstrate that treatment to reduce plasma levels of protein bound uremic toxins improves cardiac output and kidney oxygenation. 

    In summary, the common denominator for pathological conditions investigated in this thesis is the occurrence of intrarenal hypoxia. This thesis demonstrates that increased mitochondria oxygen consumption via leak respiration as an important contributing factor. Further, targeting plasma levels of circulating uremic toxins may be a potential treatment strategy to slow the rate of progression of CKD.

  • Biomarkers for Peripartum Depression : Focusing on aspects of the immune system and the metabolome Author: Emma Bränn Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-450037 Publication date: 2021-09-15 13:44

    Peripartum depression is a common, multifactorial, and potentially devastating disease among new mothers. A biological marker for peripartum depression would facilitate early detection, better understanding of the pathophysiology, and identification of targets for treatment. Evidence is growing for a potential role of the immune system in depression outside the peripartum period. Major adaptations of the immune system occur during pregnancy, justifying the search for immunological markers for peripartum depression. The immune system is very complex and dynamic during pregnancy, complicating the study of associations with depression. The metabolome is also affected by pregnancy and is linked to the immune system via, e.g., the microbiota. Hence, metabolomic profiling could increase the understanding of peripartum depression. 

    This thesis aimed to explore inflammatory markers and metabolic profiles in the peripartum period, in order to discover possible biomarkers, and to increase the understanding of the pathophysiology of peripartum depression.

    All studies were conducted within the Biology, Affect, Stress, Imaging, and Cognition (BASIC) study. The Edinburgh Postnatal Depression Scale and the Mini International Neuropsychiatric Interview were used to assess depressive symptoms. Multiplex Proximity Extension assays were used to analyze inflammatory markers in pregnancy and postpartum. Luminex Bio-Plex Pro Human Cytokine Assays were used to analyze cytokine levels across the peripartum period, and gas chromatography-mass spectrometry metabolomics were used for metabolic profiling. 

    No marker was discriminative enough to be used on its own as a biomarker for peripartum depression. However, several inflammatory markers (such as STAM-BP, TRANCE, HGF, IL-18, FGF-23, and CXCL1) were identified as possible candidates for more advanced diagnostic algorithms. The results further pointed towards the importance of adaptation of the immune system during pregnancy and postpartum, where levels of cytokines such as VEGF-A might have an important role in antenatal and postpartum depression. The results even highlight the importance of examination timing. Lastly, the metabolic profiling suggested different subgroups of women with postpartum depressive symptoms, supporting theories of peripartum depression being a heterogeneous disease in need of subgroup definition. 

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