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Coming dissertations at MedFak

  • Lika men ändå olika : Språkscreening av enspråkiga och flerspråkiga barn vid 2,5-3 år på BVC Author: Laleh Nayeb Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-482165 Publication date: 2022-09-21 14:04

    Children who do not develop their language as expected are at risk of difficulties in school and with peer relations. The Swedish Child Health Services (CHS) offer preventive health surveillance, including language screening, at 2.5-3 years. However, the screening has only been validated for monolingual children. 

    The aims of the thesis were to explore CHS nurses’ experiences of language screening of bilingual children, to evaluate the 3-year screening for language disorder for use at 2.5 years, and to assess the stability of the children’s diagnoses and the classification accuracy of the screening after 6 months.  

    In Study I, 863 nurses answered a web-based survey. Half of the nurses simplified the screening processes for bilingual children, and 74% postponed referrals to speech and language services. About 80% believed that language development was slower in bilingual children which was the strongest predictor of simplified screening practices. In Studies II and III, 105 monolingual and 111 bilingual children were screened and clinically assessed at age 2.5. The screening classification accuracy for monolinguals vs bilinguals screened in both their languages was: sensitivity 91% vs 88%, specificity 91% vs 82%, PPV 56% vs 67%, and NPV 99% vs 94%, respectively. Study IV reassessed 141 children (48 mono- and 93 bilinguals) at age 3, i.e. all children with a positive outcome at age 2.5 from studies II and III, and matched children from the same studies with negative outcomes. The number of new cases with language disorder (n=4) was about the same as the number who had recovered (n=5) at age 3. These few changes were statistically significant, but not considered to be of clinical relevance since the classification accuracy of the screening was still within 95 CI after 6 months. The screening classification accuracy for monolinguals vs bilinguals was: sensitivity 71% vs 81%, specificity 93% vs 82%, PPV 39% vs 67%, and NPV 98% vs 90%. 

    In conclusion, the modified language screening can be recommended for use at age 2.5. Bilingual children who don’t pass the screening in Swedish, should be screened in their mother tongue using a standard procedure. The wait-and-see strategy reported by the nurses in Study I was not supported as screening results remained stable between 2.5 and 3 years. There is a need to implement new evidence-based routines in child health services to equitably screen both monolingual and bilingual children for language disorder. 

  • Ex‘PLA’ining the progression of pathological proteins in Alzheimer’s and Parkinson’s diseases : see(d)ing is believing Author: Anish Behere Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-482999 Publication date: 2022-09-20 13:48

    Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the two most common forms of neurodegenerative disorders affecting approximately 50 million people worldwide. The underlying neuropathological processes leading to AD and PD share many similarities, i.e. aberrant protein aggregation of tau and alpha-synuclein (αSyn) in the brain. Monitoring tau and αSyn aggregation is challenging, due to morphological heterogeneity of the aggregating species and problems in preserving the antigen conformation ex vivo.

    In paper-I, we validated the usefulness of proximity ligation assay (PLA), a technique that enabled us to visualize previously undetected early αSyn pathology in the A30P-tg mouse model of PD. We observed an age-progressive increase in the levels of phosphorylated αSyn (pSynS129) and the compactness of aggregates in the brain. Although loss of dopaminergic neurons was not found, a subtle dysregulation of other catecholamines was recorded in the older mice.

    In paper-II, we revealed a wide distribution of pSynS129 aggregates in alpha-synucleinopathy-patient brains. By using a PLA setup with certain antibody pair combinations on brain sections, we observed unique staining patterns, which could not be visualized using regular immunohistochemistry (IHC). In A30P-tg mice, the morphological pattern of the PLA signals indicated an intracellular shift of pSynS129  from the periphery towards the neuronal soma.

    In Paper-III, we demonstrated that multiplex pTauS202,T205-pTauT231, singleplex pTauT231 and singleplex pSynS129 PLAs can recognize an extensive tau and αSyn pathology compared to regular IHC. We found that using our PLA approach we could differentiate between pTauS202,T205 and pTauT231 pathology in AD brains, whereas IHC could not. Similarly, in the PD brain, singleplex pSynS129 PLA detected novel structures, i.e. apparent thick intercellular tunnelling nanotubes and early aggregates; whereas pSynS129 IHC was limited to the detection of mature pathology. Lastly, we demonstrated that our multiplex PLA approach detected co-aggregates of pSynS129-pTau.

    In Paper-IV, in an αSyn seeding mouse model we observed pSynS129 immunoreactivity close to the striatal injection site one day post-injection (dpi). Intriguingly, this type of staining disappeared with the concurrent formation of peri-nuclear pSynS129 inclusions in specific brain regions after 14 dpi. In parallel, astrocytic activation prior to pSynS129 inclusion formation was observed.

    In conclusion, we have developed several novel PLAs that detect both tau and αSyn pathology with a higher ex vivo sensitivity and specificity than currently used immunostaining methods. This thesis work provides valuable insights that potentially could be used for the development of future biomarkers for tauopathies and synucleinopathies.

  • Evaluation of Intracranial Arteriovenous Malformations with Magnetic Resonance Imaging Author: Maria Correia de Verdier Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-481797 Publication date: 2022-09-15 12:02

    Intracranial arteriovenous malformations (AVMs) are characterized by feeding arteries, a tangle of abnormal vessels (nidus) and draining veins. Radiological evaluation methods are used in diagnosing AVMs, treatment planning, post-treatment evaluation and monitoring stability. The general aim of our studies reviewed in this thesis was to develop and evaluate magnetic resonance imaging (MRI) techniques for the evaluation of AVMs. 

    Methods

    Paper I – In 30 patients treated with proton radiation therapy, radiation-induced MRI changes (vasogenic edema, contrast enhancement and cavitation) and their association with development of neurological symptoms and nidus obliteration were assessed. 

    Paper II – We evaluated the effect of acquisition parameters (voxel size, number of signal averages and velocity encoding) on the accuracy and precision of phase-contrast MRI (PC-MRI)-measured flow and velocity in a small-lumen vessel phantom with constant flow. 

    Paper III – Normal ranges and test-retest reproducibility of flow and velocity in the anterior, middle and posterior cerebral arteries were measured with PC-MRI in 30 healthy volunteers.

    Paper IV – We studied PC-MRI-measured flow and velocity in feeding arteries in 10 patients with AVMs and compared the values obtained with the results from paper III. We also assessed post-treatment changes in flow and velocity in three patients.  

    Results 

    Paper I – Radiation-induced MRI changes were found in 87% of patients after proton radiation treatment of AVMs. MRI changes were associated with neurological symptoms but not with nidus obliteration. 

    Paper II – PC-MRI overestimated flow in a small-lumen vessel phantom. Accuracy for flow measurements improved by decreasing voxel size. Precision for both flow and velocity measurements improved by increasing voxel size. Precision for flow measurements improved by increasing the number of signal averages.

    Paper III – We reported normal ranges and test-retest reproducibility for PC-MRI-measured flow and velocity in the main intracranial arteries. Reproducibility was overall quite low, but higher for the middle cerebral arteries than for the anterior and posterior cerebral arteries.

    Paper IV – Patients with a large nidus have increased velocity measured with PC-MRI in feeding arteries compared to intracranial arteries in healthy individuals. There is a reduction in PC-MRI-measured flow and velocity after treatment.  

    Conclusion

    Radiation-induced MRI changes are common after proton radiation treatment of AVMs. The accuracy and precision of PC-MRI measurements in a phantom depend on acquisition parameter settings. In patients with AVMs with a large nidus, increased velocity is observed in feeding arteries, and a decrease in flow and velocity is observed after treatment. PC-MRI can potentially be used as a clinical tool to aid treatment planning and post-treatment evaluation.  

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