Bipolar disorder (BD) is a chronic and often progressive illness that has a significant impact on quality of life and functioning. Pharmacological treatments are not effective for all patients, emphasizing the need to better understand the pathophysiology of the disorder. It is well known that patients with BD present with increased levels of inflammatory markers during mood episodes and often exhibit chronic low grade inflammation, implicating the immune system in the etiology of the disorder. Furthermore, patients with BD show deficits in neurotrophic factors suggesting that alterations in neurogenesis may precipitate clinical features. Recent evidence indicates that accelerated aging processes may underlie the pathophysiological changes observed in BD, implicating biomarkers related to aging. The chemokine C-C motif chemokine 11 (CCL11) and the cytokine growth differentiation factor 11 (GDF11) have been identified as proteins that increase and decrease with age, respectively. As such, this thesis presents research examining serum levels of these proteins in drug-naive young adults with BD and a matched healthy control group. We analyzed serum levels of CCL11 and GDF11 using enzyme linked immunosorbent assay (ELISA). Our results indicate that serum levels of CCL11 and GDF11 do not differ between the BD group and the healthy control group, however CCL11 levels were elevated in males and in individuals with tobacco abuse/dependence when considering the entire sample. Our results suggest that serum levels of these proteins do not differ between drug-naive young adults with BD and healthy controls, but that alterations may be due to demographic and lifestyle factors. Small sample size and low power should be considered when interpreting these results. / Thesis / Master of Science (MSc)

A Thesis Submitted to the School of Graduate Studies in Partial Fulfilment of the Requirements for the Degree Doctor of Philosophy in Neuroscience / Bipolar disorder (BD) is increasingly being recognized as a neuroprogressive illness characterized by progressively worsening cognitive function and structural brain changes. Although lithium remains the gold standard treatment for BD, its ability to halt neuroprogression is a crucial, yet not fully understood aspect of its therapeutic benefit. Accumulating evidence suggests that lithium may be neuroprotective through alleviating ER stress, a feature highly implicated in the pathogenesis of BD. Over the last 20 years, Mesencephalic Astrocyte-Derived Neurotrophic Factor (MANF), an ER resident protein, has gained significant attention due to its ability to alleviate ER stress, reduce inflammation, and enhance cellular survival. In this thesis, we investigated the relationship between lithium and MANF using in vitro cellular models and in vivo rodent models. We establish that lithium upregulates MANF expression via the AP-1 signalling pathway. Moreover, we show that MANF plays a crucial functional role in lithium’s neuroprotective effects, as inhibiting the AP-1 pathway negated lithium’s protection against ER stress-induced neurotoxicity and reduced MANF expression. Furthermore, we demonstrate that MANF deficiency increases striatal cell susceptibility to amphetamine-induced neurotoxicity, highlighting its protective function in preclinical models of mania. In vivo experiments further showed that overexpressing MANF in amphetamine-treated rats reduced hyperlocomotion, prevented the upregulation of ER stress markers, and prevented amphetamine-associated death. Collectively, these findings suggest that MANF may be a critical mediator of lithium’s ability to halt neuroprogression in BD and advance our understanding of BD pathophysiology. Importantly, we present MANF as a promising therapeutic candidate for future therapeutic interventions aimed at halting neuroprogression in BD and preventing fatality due to amphetamine overdose. / Dissertation / Doctor of Philosophy (PhD) / Bipolar disorder (BD) is a psychiatric condition characterized by extreme episodic mood swings of highs (mania) and severe lows (depression). Over time, BD patients can experience changes in the brain, worsening symptoms, and cognitive decline – a process understood as neuroprogression. Lithium, a common treatment for BD, has been shown to slow down this detrimental progression, although exactly how it is accomplished is not fully understood. This thesis focused on a protein called MANF, which has been shown to protect and keep brain cells healthy by reducing stress within cells. We found that lithium increases MANF levels in brain cells, and this increase is crucial for lithium’s neuroprotective effects. Furthermore, we show that MANF is protective against the toxic drug amphetamine in brain cells and stops overdose- mediated death from occurring. By understanding how MANF works, we propose a new treatment intended to prevent the progression of BD and potential treatment for amphetamine overdose.

No description available.

Large family studies of complex disorders can be used to detect a genomic region linked with a particular illness. Where multiple families are found with common regions of linkage, this could be due to an ancestral mutation common to these families. In this thesis, I describe a method for studying allele sharing in families that share a linkage region, to identify a common founder mutation, thus maximising the results of replicated linkage studies. The method tests the hypothesis that the evidence for shared linkage is derived from the sharing of a common affected ancestor. By comparing the allelic similarity of haplotypes across common linkage regions, it is possible to identify any regions that are identical by descent between the families. A method of permutation analysis followed by a nested permutation technique have been developed to assess the statistical significance of allele sharing scores. Chapter 3 describes the proof of principle of the method through its application to known cystic fibrosis mutations and through simulated datasets. This provides both a real dataset and a much more diverse range of simulated conditions on which to test the method. The range of simulated data was also used to develop a set of criteria for the effective us of the method. In Chapter 4, the allele sharing method was applied to two replicated linkage regions on chromosome 4p15-16 that segregate with bipolar affective disorder. This was done over two phases, first taking in markers covering the genic regions of the shared linkage region and then followed up with a complete coverage of the region. This analysis identified a 200kb region with significant confidence within the 8Mb of the two linkage regions. The study of this region presents a clear example of how replicated linkage results that are caused by some founder effect, can be examined, and refined using this allele sharing method to vastly reduce the region under investigation.

ABSTRACT Over the last few years Bipolar Disorder has been associated with chronic neuropsychological deficits that remain even when episodes of depression, mania or hypomania remit. Furthermore Bipolar Disorder has been associated with progressive cognitive impairment, leading to the description of the illness as chronic and deteriorating, rather than as an illness with discreet episodes from which patients can fully recover. The results of neuropsychological studies have been criticized for methodological weaknesses however. The present study attempted to address these weaknesses. The aim was primarily to establish whether neuropsychological impairment exists in euthymic patients, and secondarily, to establish if neuropsychological functioning deteriorates with illness severity. Sixteen euthymic Bipolar I disordered patients were matched for age and sex to 16 controls and subjected to a battery of neuropsychological tests. Matched pair T-tests were used to identify if significant differences in neuropsychological functioning existed between the two groups. The ANOVA technique was used to determine if neuropsychological functioning deteriorated with illness severity. Markers of illness severity utilised in this study were number of depressive episodes, number of manic episodes, number of suicide attempts and number of hospitalisations. The results indicated that neuropsychological differences between the patient and control group were minimal and not clinically significant. The present study sample was medically and psychologically well managed and enjoyed good support structures and their neuropsychological functioning did not deteriorate with illness severity. It was concluded that the sample size and the nature of the sample selected could perhaps have affected the study outcome. It was therefore hypothesized that bipolar disorder is not a homogenous group and that protective factors may exist which affect the course and outcome of the illness. These protective factors should be the subject of further investigation as they are likely to significantly impact on the natural history of this disease process.

Thesis (doctoral)--University of Uppsala, 1981. / Bibliography: p. 47-56.

Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgico / O transtorno afetivo bipolar (TAB) à um transtorno psiquiÃtrico multifatorial, progressivo, que se caracteriza por uma oscilaÃÃo entre episÃdios manÃacos ou hipomanÃacos e depressivos. Estima-se que o transtorno afete cerca de 1 â 2 % da populaÃÃo mundial. O diagnÃstico definitivo e o tratamento adequado podem demorar 10 anos para se concretizar. Leva a grande prejuÃzo à qualidade de vida dos pacientes, gerando altas taxas de incapacidade funcional, comorbidades clÃnicas, como hipertensÃo e alta prevalÃncia de suicÃdio. A fisiopatologia do transtorno ainda permanece obscura, porÃm muitos esforÃos sÃo empregados em pesquisas para tentar elucidar os possÃveis mecanismos envolvidos no TAB, bem como para melhorar seu tratamento. As hipÃteses para explicar a fisiopatologia do TAB incluem: desregulaÃÃo da dopamina, alteraÃÃes mitocondriais, aumento do estresse oxidativo, reduÃÃo dos nÃveis de neurotrofinas, dentre outras. Diante deste cenÃrio, buscou-se investigar os possÃveis efeitos antimanÃacos do carvedilol (CVD), um beta-bloqueador nÃo seletivo usado amplamente no tratamento da hipertensÃo arterial com comprovada aÃÃo antioxidante e neuroprotetora. Para tanto, se utilizou um modelo animal de mania induzido por dimesilado de lisdexanfetamina (LDX), recentemente validado por nosso grupo de pesquisa. O LDX à um prÃ-fÃrmaco que se converte a D-anfetamina, a qual possui efeito psicoestimulante. O CVD foi avaliado em dois protocolos de tratamento, prevenÃÃo (simulando a fase de manutenÃÃo do TAB) e reversÃo (simulando a fase de crise do TAB), em ambos o valproato (VAL) foi utilizado como estabilizante do humor padrÃo. Foram avaliadas no presente estudo alteraÃÃes comportamentais e de estresse oxidativo. Os animais submetidos aos protocolos de prevenÃÃo (animais prÃ-tratados durante 7 dias com CVD, VAL e Salina e por mais 7 dias com LDX 10 mg/kg) e reversÃo (prÃ-tratados durante 7 dias com LDX e posteriormente tratados com CVD, VAL e Salina) tiveram os nÃveis de glutationa reduzida (GSH) e de peroxidaÃÃo lipÃdica (TBARS) determinados nas Ãreas cerebrais do cÃrtex prÃ-frontal (PFC) e corpo estriado (CE) e o fator neurotrÃfico derivado do cÃrebro (BDNF) no hipocampo (HC). Os resultados indicaram que o CVD preveniu e reverteu a hiperlocomoÃÃo e comprometimento da interaÃÃo social induzidas por LDX. Na avaliaÃÃo neuroquÃmica o CVD foi capaz de aumentar prevenir e reverter as alteraÃÃes nos nÃveis de GSH, BDNF e peroxidaÃÃo lipÃdica dos animais submetidos ao modelo de mania com resultados comparÃveis aos dos animais tratados com VAL e controles. Em conclusÃo, os resultados deste estudo revelaram que o CVD à um fÃrmaco em potencial para o tratamento da mania, sendo indicados, portanto, estudos clÃnicos que comprovem a aÃÃo deste fÃrmaco. / Bipolar disorder (BD) is a psychiatric disorder with multifactorial development and neuroprogressive characterized by oscillation between periods of manic and depressive episodes. It is estimated that the disease affects about 1 - 2% of the worldwide population and it takes about 10 years to a definitive diagnosis and appropriate treatment. BD brings many impairment of quality of life of patients, generating high rates of functional disability, comorbidities such as hypertension during the clinical course of the disease and presenting a high prevalence of suicide. The pathophysiology of the disease remains unclear, but many efforts are employed in research to try to elucidate the possible mechanisms involved in BD. The pathways hypothesized to take part of BD pathophysiology includes: dopamine deregulation, increased oxidative stress, decreased levels of neurotrophins such as BDNF, mitochondrial dysfunction among others. Based on the described above we sought to investigate the effects of carvedilol, (CVD), a nonseletive beta-blocker widely used in the treatment of hypertension with antioxidant properties, in a model of mania induced by dimesilate of lisdexamfetamine (LDX) a prodrug metabolized to D-amphetamine, in rats. The experimental design of the study consisted evaluation of CVD against behavioral changes and oxidative stress alterations in two protocols of treatment, prevention and reversal using valproate (VAL) a humor stabilizer as standard drug to assess the effectiveness of CVD. In the prevention protocol the animals were pre-treated for 7 days with CVD, saline or VAL). In the reversal protocol the animals were pre-treated for 7 days with LDX and for further 7 days received CVD, saline or VAL plus LDX. The behavioral determinations of locomotor activity and social interaction were conducted 2 h after the last administration of LDX. Reduced glutathione (GSH) and lipid peroxidation (TBARS) levels were determined in brain areas of the prefrontal cortex (PFC) and striatum (EC) and brain-derived neurotrophic factor (BDNF) in the hippocampus (HC) rats. The results indicated that CVD prevented and reversed the hyperlocomotion and deficit in social contacts induced by LDX. In the neurochemical determinations CVD significantly prevented and reversed the alterations in BDNF, GSH and MDA levels induced by LDX presenting results comparable to those of saline and VAL groups. Therefore, the results of the present study indicates that CVD prevents reverts the behavioral and neurochemical alterations induced by LDX used as an animal model of mania being, thus, a potential drug for the treatment of BD.

No description available.

Bipolar disorder (BD), previously known as manic depressive disorder, is associated with recurring episodes of depression and mania/hypomania. Currently, no definitive biological mechanisms have been pinpointed with regards to the origin and progression of BD, however, inflammation and oxidative stress have been shown to present in the brains of individuals with BD. Notably, other neurodegenerative disorders which also contain an inflammatory component including Alzheimer’s disease and Multiple Sclerosis display with disruption of the brain blood barrier (BBB). We thus propose a model of BD wherein BBB disruption facilitates inflammation and oxidative stress induced neural damage. This study looked to utilize amphetamine (AMPH) induced mania model and lipopolysaccharide (LPS) induced inflammatory model to represent BD like conditions in rats and to assess BBB permeability. We observed elevated locomotor data in response to AMPH administration and a trend of increased BBB permeability across regions following low dose chronic AMPH injections. In the LPS induced BBB permeability model, we did not detect any elevated serum C-reactive protein (CRP) or tumour necrosis factor alpha (TNF-α) levels but did see significantly elevated BBB permeability in the LPS group and lithium pre-treatment providing some protection against BBB permeability in one of our cohorts. These trends were further corroborated by a follow-up study and thus warrant further investigation into the mechanistic nature of BBB breakdown in this model. This may provide a breakthrough in understanding the pathophysiology of BD and the underlying mechanistic effects of lithium, paving the way for new more target therapeutic remedies to combat this debilitating disorder. / Thesis / Master of Science (MSc)

No description available.