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- Syk, Mikaela, 1990-
(författare)
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Immunometabolic patterns in psychiatric disease
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Many forms of immune system dysregulation are linked to psychiatric disorders. This thesis examines specific types of immune dysregulation in broad cohorts with psychiatric disease. The first section focuses on adipokines and other immunometabolic biomarkers and their interaction with state vs. trait symptoms. Direct-acting autoantibodies are an increasingly recognized mechanism for causing psychosis and obsessive-compulsive disorder, but it is unclear how prevalent this patient group is. To identify which patients to investigate more extensively, superior methods are needed. Therefore, the second section addresses the value of clinical red flags in predicting elevated central nervous system (CNS) damage biomarkers and other CNS pathology.In paper I-III, a psychiatric cohort of young adults was examined for plasma immunometabolic biomarkers, depressive symptom severity, bulimia nervosa and neurotic traits. Psychiatric diagnoses were based on diagnostic interviews while depressive symptom severity was assessed with the self-rating version of the Montgomery-Åsberg Depression Rating Scale. Personality traits were evaluated using the Swedish universities Scales of Personality. Young adults with higher leptin levels self-reported more severe depressive symptoms (paper I) and leptin levels were independently linked to neuroticism (paper III). Neuroticism was also linked to other immunometabolic alterations. Women with bulimia nervosa had elevated plasma adiponectin levels that remained stable over time (paper II), suggesting long-term metabolic changes.In paper IV, a psychiatric patient cohort enriched for clinical signs of suspected autoimmune psychiatric disease was investigated for psychiatric symptoms, neurological findings and signs of CNS pathology in radiological, neurophysiological, blood and CSF analyses. In this cohort, 27% had CSF signs of CNS tissue damage and 21% had CSF signs of neuroinflammation or blood-brain barrier dysfunction. Six percent had known anti-neuronal autoantibodies in serum and 2% in CSF. CNS damage biomarkers in CSF were also linked to red flags and specific psychiatric features.In summary, the thesis confirms different patterns of immunometabolic biomarkers and associations with trait and state symptoms in a psychiatric patient cohort that may have important implications for the future health of young adults with psychiatric morbidity. The final study supports clinical red flags in previous guidelines, indicating that a more comprehensive inclusion of patients with diverse psychiatric symptoms (not restricted to purely psychosis) is necessary to find all psychiatric patients requiring further investigation for immune system involvement.
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| 3. |
- Wikgren, Mikael, 1981-
(författare)
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Telomeres and the brain : an investigation into the relationships of leukocyte telomere length with functional and structural attributes of the brain
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Telomeres are the outermost parts of linear chromosomes. They consist of tandemly repeated non-coding short nucleotide sequences (TTAGGG in all vertebrates), in humans spanning over the last 2 to 15 kilobase pairs of the chromosome. Due to the end-replication problem, telomeres shorten with each cellular division. A critically short telomere will trigger the cell to enter a state of cellular senescence or to apoptose. The rate of telomere shortening can be accelerated by factors such as oxidative stress and inflammation. Taken together, this contributed to making telomere length a candidate biomarker of health and aging. Studies have shown that leukocyte telomere length progressively shortens with age, and that it independent of age is associated with age-related morbidity, lifestyle factors, and mortality. This thesis was aimed at exploring the relationships of leukocyte telomere length with various functional and structural attributes of the brain. In Paper I, telomere length was shown to be longer among non-demented carriers of the apolipoprotein E (APOE) ε4 allele, a well-established risk factor for Alzheimer’s disease. However, the rate of telomere shortening was greater among the ε4 carriers, possibly due to the higher levels of oxidative stress and inflammation associated with this allele. Furthermore, performance on episodic memory tests was inversely related to telomere length among ε4 carriers. The results may contribute to a better understanding of the pathophysiology related to the APOE ε4 allele. The volume of the hippocampus, a structure in the brain critical for episodic memory function, was in Paper II found to be inversely related to telomere length among non-demented APOE ε3/ε3 carriers. No correlation between hippocampal volume and telomere length was discernible among ε4 carriers, but they fit the pattern exhibited by the ε3/ε3 carriers as they tended to have smaller hippocampi and longer telomere length compared with the ε3/ε3 carriers. The results are possibly explained by a low proliferative activity among subjects with smaller hippocampi, which might also explain the inverse association between telomere length and episodic memory performance in Paper I. In Paper III, we describe results corroborating earlier findings of shorter telomere length among individuals suffering from depression. Moreover, we found that the shorter telomere length among the patients to a large extent could be linked to a hypocortisolemic state; a state which has been associated with chronic stress. The findings corroborate the link between telomere length and stress, and underline the role of stress in depressive illness. Two prominent manifestations of the aging brain are atrophy and white matter hyperintensities. In Paper IV, we report that white matter hyperintensities and cerebral subcortical atrophy were associated with shorter telomere length in aged non-demented individuals. Cortical atrophy was not associated with telomere length. Inflammation may be the underlying cause of the associations, as it is linked to telomere attrition, subcortical atrophy, and white matter hyperintensities. Taken together, these results show that leukocyte telomere length has the potential of being used as a biomarker for structural and functional attributes of the brain. Furthermore, the findings can provide new insights into mechanisms of disease and aging of the brain
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