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- Berntsson, Shala Ghaderi, 1964-
(författare)
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Towards Novel Biomarkers for Low-grade Glioma
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Gliomas are common primary brain tumours that occur as low-grade (LGG) and high-grade gliomas (HGG). Typically occurring in younger adults, LGG has an indolent course with a median survival of 5-10 years, but carries an inherent potential for transforming into HGG. The thesis focused on LGG in adults, with the aim of identifying prognostic biomarkers for LGG.Paper I. Epileptic seizures are common symptoms in LGG. In a retrospective study, the correlation between 11C-methionine (MET) uptake, measured by Positron Emission Tomography (PET), and seizure activity was assessed in 101 patients with LGG. Although there was no correlation between MET uptake and seizure activity, survival was longer in patients who were seizure-free before surgery.Paper II. This finding prompted the search for common genetic pathways for both tumour and seizure development and a review of genetic polymorphisms in focal epilepsy and glioma risk. Cell cycle and immune response genes affecting both glioma and seizure risk were identified, and genes involved in synaptic transmission presented potential candidates for future studies.Paper III. The transcription factor PROX1 plays a pivotal role in normal development and carcinogenesis of various organs. The prognostic value of PROX1, together with established clinical and molecular prognostic factors for survival, was retrospectively assessed in 116 patients with LGG. High PROX1 expression in the tumour was associated with shorter survival.Paper IV. DNA repair enzymes, such as ERCC6, are crucial for maintaining genomic stability in glioma response to radiotherapy. An association between the polymorphism rs4253079, mapped to ERCC6, and longer survival in patients with LGG and HGG was identified.Paper V. As LGG typically presented as non-contrast enhancing tumours on morphological MRI (magnetic resonance imaging), the value of combined MET PET with physiological MRI for preoperative diagnosis was assessed in a prospective study of 32 patients with suspected LGG. Representative tumour areas were identified through a combination of perfusion-MRI with MET PET, which can be used as a baseline investigation for follow-up over time.Conclusions: The parameters seizure-freedom before surgery, the polymorphism rs4253079 in ERCC6 and low PROX1 expression in the tumor were identified as favorable prognostic biomarkers.
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| 2. |
- Ek, Lena, 1961-
(författare)
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Cognitive Deficits Reflecting Diffuse and Focal Brain Lesions Caused by Slow Growing Brain Tumors - Low-grade Gliomas
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The overall purpose was to characterize the impact that low-grade glioma (LGG) – a type of slowly growing brain tumor – has on cognitive functions. Paper I was an in-depth analysis of cognitive dysfunction of patients with histological proven LGG. The pattern varied among patients, revealing three subgroups: 1) patients with severe cognitive dysfunction; 2) patients with mild cognitive dysfunction; 3) patients with selective dysfunction due to tumor localization. In the first two subgroups the patients had slowed information-processing speed. Patients with a favorable prognosis performed better than those with unfavorable prognosis. Nonworking patients showed more pronounced dysfunction than working patients. Paper II studied cognitive functions of patients who were in the early stage of the disease and had not yet received any major medical treatments. Patients’ performances ranked at the lower end of normal limits, which contrasted with those of the individually matched controls, whose performances ranked at the upper end. Patients had slower information-processing-speed and less effective executive functions. Patients with frontal tumors had various executive problems due to tumor localization. Paper III investigated cognitive impairment at the individual level in relation to neurological symptoms, radiological characteristics of the tumor, depression, and fatigue. Paper III included the same patients as Paper II. The results showed that the majority of the patients did not have more than selective impairment. One subgroup, consisting of younger patients with large left frontal tumors showed obvious cognitive impairment, including slowed information-processing speed. The thesis showed that diffuse brain injury was closely connected to LGG. A subgroup of patients in the early phase of the disease showed signs of mild diffuse brain injury. The majority of the patients who were in later stage of the disease displayed cognitive signs of diffuse brain injury.
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| 3. |
- Sundblom, Jimmy, 1981-
(författare)
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Autosomal Dominant Leukodystrophy with Autonomic Symptoms and Rippling Muscle Disease : Translational Studies of Two Neurogenetic Diseases
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- There is a large variety of diseases caused by single-gene mutations. Although most of these conditions are rare, together they impose a significant burden to the population. This thesis describes clinical and genetic studies of two single-gene diseases: 1) Adult-onset autosomal dominant leukodystrophy with autonomic symptoms (ADLD) caused by LMNB1 gene duplications, and characterized by autonomic, pyramidal and cerebellar symptoms. Spinal cords of patients with ADLD were studied by MRI and found to be thin, with high signal intensity in white matter. Histopathology showed loss of myelinated fibres with some reactive gliosis. DNA samples from four different families with ADLD were obtained, and the LMNB1 gene was screened for duplications. Single nucleotide polymorphism array revealed LMNB1 duplications in all ADLD families. LMNB1 mRNA and protein levels were assessed in white blood cells using quantitative polymerase chain reaction and Western blot, and increased levels of LMNB1 mRNA and lamin B1 protein could be demonstrated. We concluded that spinal cord atrophy in patients with ADLD is a valuable differential diagnostic sign, and that increased levels of LMNB1 can be detected in peripheral blood. 2) Rippling muscle disease (RMD) is caused by CAV3 gene mutations. Clinical features are percussion-induced muscle mounding, –rapid contractions and undulating muscle contractions (rippling). The CAV3 gene was sequenced in 38 members of a family with RMD. Twenty-two individuals had clinical features of RMD. No muscle weakness was seen. All patients with signs of RMD carried the p.A46T CAV3 mutation, showing that the p.A46T mutation was benign and that the diagnosis can be made clinically. In vitro contracture test results from 10 of the subjects were collected, but no association between pathological test results and RMD was found.
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