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- Berginström, Nils, 1984-
(författare)
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Fatigue after traumatic brain injury : exploring novel methods for diagnosis and treatment
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Traumatic brain injury (TBI) is one of the most common causes of disability and mortality. While some patients recover quickly, especially at the mild side of the injury severity continuum, many will experience symptoms for years to come. In this chronic phase, patients report a wide array of symptoms, where fatigue is one the most common. This fatigue makes huge impact in several areas of these patients’ lives. Despite the prevalence of fatigue after TBI, the underlying mechanisms are unclear. Further, there are no standardized way for assessment and diagnosis, and there are no treatments with satisfying empirical support. The aim of this thesis was to examine the effects of the novel compound OSU6162 on fatigue in patients with TBI, and to explore functional and structural brain imaging correlates of fatigue after TBI.Methods: Studies I and III were based on a placebo-controlled, double-blinded clinical trial examining the effects of the monoaminergic stabilizer OSU6162 on fatigue in patients in the chronic phase of traumatic brain injury. In study I, self-assessment scales of fatigue and neuropsychological tests were used as outcomes, while functional magnetic resonance imaging (fMRI) blood-oxygen-level dependent (BOLD) signal was the primary outcome in study III. Studies II and IV used cross-sectional designs, comparing patients with TBI with age- and gender matched healthy controls. Study II examined whether fMRI BOLD signal could be used to detect and diagnose fatigue in patients with TBI, and study IV whether white matter hyperintensities (WMH) contribute to lower cognitive functioning and presence of fatigue after TBI.Results: Study I revealed no effects of OSU6162 during 28 days of treatment at maximum doses of 15 mg twice daily on measures of fatigue or any other outcome. The results from study II indicated that fatigue after TBI is linked to alterations in striato-thalamic-cortical loops, and suggested that fMRI could be a promising technique to use in the diagnosis of fatigue after TBI. In study III the results revealed effects of treatment in the right occipitotemporal and orbitofrontal cortex. In these areas, the BOLD response was normalized in the OSU6162 group as compared to healthy controls, while the placebo group showed a steady low activity in these areas. The regional effects were located outside the network shown to be linked to fatigue in study II, which might explain why there were no effects on fatigue after treatment with OSU6162 in study I. Study IV showed that WMH lesions increased with increased TBI severity, but the presence and extent of lesions did not explain lower neuropsychological functioning or fatigue in subjects with previous TBI.Conclusions: In summary, although no effects on fatigue after treatment with OSU6162 were seen, the results provide support to the theory that fatigue after TBI is linked to alterations in striato-thalamic-cortical loops, and on how fatigue after TBI could be assessed or diagnosed using fMRI. Structural damage within white matter was however not related to fatigue.
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| 2. |
- Boström, Gustaf
(författare)
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Depression in older people with and without dementia : non-pharmacological interventions and associations between psychotropic drugs and mortality
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The aim of this thesis was to investigate associations between psychotropic drug use and death, associations between functional capacity, dependency in ADL and depression, and to evaluate a non-pharmacological intervention to reduce depressive symptoms, among older people with and without dementia.There is limited knowledge about the risk of death associated with psychotropic drug use among those aged ≥85 years, those with dementia, or those living in residential care facilities; groups that have a higher intake of psychotropic drugs and who are also more prone to adverse drug reactions. In a representative sample of people ≥85 years (n = 992), baseline antidepressant use was not associated with an increased 5-year mortality risk when adjusting for confounding factors. A significant interaction between gender and antidepressant use was found, with a higher mortality risk in women, than in men. When analyzing men and women separately, no significant associations were found. In a sample of older people (i.e. ≥65 years) with dementia (n = 1037), there was a significant gender difference in 2-year mortality associated with the baseline use of antidepressant drugs, with a lower mortality risk in men, than in women. In men, the mortality risk was significantly reduced with antidepressant use, while there was no significant association in women. The association between baseline use of benzodiazepines and mortality had a tendency toward an increased risk during the first year of follow-up, although this became non-significant after adjustments. In this time period, the interaction term for sex was significant, with a higher mortality risk among men than women. When the sexes were analyzed separately, no significant associations were found. No significant associations were found between baseline use of antipsychotic drugs and mortality.Drug treatment for depression seems to have a limited effect in older people and may have no effect in people with dementia. In order to find alternative ways of treating or preventing depression in older age, it is important to increase our knowledge about factors associated with this condition. Functional capacity and dependency in activities of daily living (ADL) are associated with depression in community-dwelling older people. However, it is uncertain whether the same associations are to be found in very old people (i.e. ≥80 years), including those with severe cognitive or physical impairments. In a heterogeneous sample (n = 392) with a high mean age, a large range of cognitive and functional capacity, a wide spectrum of dependency in ADL, and a high prevalence of comorbidities, depressive symptoms were significantly associated with functional balance capacity, but not with overall dependency in ADL. Among individual ADL tasks, dependency in transfer and dressing were associated with depressive symptoms.Physical exercise has shown effect sizes similar to those of antidepressants in reducing depressive symptoms among older people without dementia, with moderate–high-intensity exercise being more effective than low-intensity exercise. However, these effects are unclear among older people with dementia. Care-facility residents with dementia (n = 186) were cluster-randomized to a high-intensity functional exercise program or a non-exercise control activity conducted for 45 minutes every other weekday for 4 months. No significant difference between the exercise and control activity was found in depressive symptoms at 4 or 7 months. Among participants with high levels of depressive symptoms, reductions were observed in both the exercise and control groups at 4 and 7 months.In conclusion, ongoing treatment at baseline with any of the three psychotropic drug classes antidepressants, antipsychotics and benzodiazepines did not increase the risk of mortality in older people with dementia. Neither did antidepressant drugs in very old people. In both samples, gender differences were found in the mortality risk due to antidepressant use. In those with dementia, the mortality risk due to benzodiazepine use also differed by gender. The potential risk from initial treatment and gender differences regarding mortality risk require further investigation in randomized controlled trials or in large cohort studies properly controlled for confounding factors. In older people, living in community and residential care facilities, functional capacity seems to be independently associated with depressive symptoms whereas overall ADL performance may not be associated. Dependency in the individual ADL tasks of transfer and dressing appear to be independently associated with depressive symptoms and may be an important focus for future interdisciplinary multifactorial intervention studies. Among older people with dementia living in residential care facilities, a 4-month high-intensity functional exercise program has no superior effect on depressive symptoms than a control activity. Both exercise and non-exercise group activities may reduce high levels of depressive symptoms. However, this finding must be confirmed in three-armed randomized controlled trials including control groups receiving standard care.
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| 3. |
- Högström, Gabriel, 1991-
(författare)
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Cardiovascular disease and all-cause mortality : influence of fitness, fatness and genetic factors
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- BackgroundLow aerobic fitness and obesity are associated with atherosclerosis, and thereforegreatly increase the risk of cardiovascular disease (CVD) and early death. It has long been known that atherosclerosis my begin early in life. Despite this fact, it remains unknown how obesity and aerobic fitness early in life influence the risks of atherosclerosis, CVD and death. Furthermore, it is unknown whether high aerobic fitness can compensate for the risks associated with obesity, and how genetic confounding affects the relationshipsof aerobic fitness with CVD and all-cause mortality. Thus, the main aims of this thesis were to investigate the associations of aerobic fitness in late adolescence with myocardial infarction (Study I), stroke (Study II) and all-cause mortality (Study III), and how genetic confounding influences the relationshipsof aerobic fitness with CVD, diabetes and death (Study IV).MethodsThe study population comprised up to1.3 million men who participated in mandatory Swedish military conscription. During conscription, all conscripts underwent highly standardized tests to assess aerobic fitness, body mass index, blood pressure and cognitive function. A physician also examined all conscripts. Data on subjects’ diagnoses, death and socioeconomic status during follow-up were retrieved using record linkage. Subjects were subsequently followed until the study endpoint, date of death or date of any outcome of interest. Associations between baseline variables and the risks of adverse outcomes were assessed using Cox’s proportional hazard models. Genetic confounding of the relationships between aerobic fitness and diabetes, CVD and death was assessed using a twin population and a paired logistic regression model. ResultsIn Study I, low aerobic fitness at conscription was associated with an increased risk of myocardial infarction (MI) during follow-up (hazard ratio [HR] 0.82 per standard deviation increase). Similarly, in Study II, high aerobic fitness reduced the risk of stroke (HR 0.84 for ischemic stroke, HR 0.82 for hemorrhagic stroke; P < 0.001 for all), and obesity was associated with an increased risk of stroke (HR 1.15 for ischemic stroke, HR 1.18 for hemorrhagic stroke; P < 0.001 for all). In Study III, high aerobic fitness was also associated with reduced all-cause mortality later in life (HR 0.49, P < 0.001). High aerobic fitness exerted the strongest protection against death from substance and alcohol abuse, suicide and trauma (HRs 0.20, 0.41 and 0.52, respectively; P < 0.001 for all). Obese individuals with aerobic fitness were at higher risk of MI and all-cause mortality than were normal-weight individuals with low fitness (Studies I and III). In Study IV, fit twins had no reduced risk of CVD or death during follow-up compared with their unfit twin siblings (odds ratio 1.11, 95% confidence interval 0.88–1.40), regardless of how large the difference in fitness was. However, the fitter twins were protected against diabetes during follow-up.ConclusionsAlready early in life, aerobic fitness is a strong predictor of CVD and all-cause mortality later in life. In contrast to the “fat but fit” hypothesis, it seems that high aerobic fitness cannot fully compensate for the risks associated with obesity. The associationsof aerobic fitness with CVD and all-cause mortality appear to be mediated by genetic factors. Together, these findings have implications for the view of aerobic fitness as a causal risk factor for CVD and early death.
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| 4. |
- Nyström, Helena, 1985-
(författare)
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Parkinson’s disease : the prodromal phase and consequences with respect to working life
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Parkinson’s disease (PD) is a common, progressive neurodegenerative disorder, recognized by the motor symptoms of bradykinesia, tremor, rigidity, and postural impairment. At clinical onset, extensive amounts of dopaminergic neurons have already been lost. The duration of this prodromal phase is uncertain, and it is thought to include predominantly non-motor symptoms. The progressive nature and the symptoms of PD are disabling and reduces the quality of life. Among patients affected in working age, early cessation of employment is common, and such socioeconomic consequences of PD may contribute to an impaired quality of life. The aims of this thesis were to investigate the life situation for people affected by PD in working age, with attention to factors of importance for quality of life and working situation, and to evaluate long-term associations between potential prodromal signs and the later development of PD.Methods: We used a postal survey to investigate the self-perceived life situation among working-aged individuals with PD compared to matched controls, with a specific attention to socioeconomic consequences of disease (paper I). To investigate risk markers preceding the diagnosis of PD (paper II-IV), we used data from nationwide registers. Study II was performed as a cohort study, based on the Swedish Military Service Conscription Register, and study III-IV were performed as nested case-control studies based on a cohort comprising all Swedish citizens aged ≥50 years in 2005.Results: In the survey study (paper I), 38% of the PD participants and 9% of the controls were dissatisfied with life as a whole, and the working situation was an independent risk factor for dissatisfaction with life. In total, 59% of the PD participants had reduced working hours or stopped working due to PD, and many PD participants struggled to cope with their work demands. Support from employer was associated with a higher likelihood to remain employed.We found that low muscle strength in young adulthood, (paper II) and depression (paper III) were associated with an increased risk of PD over follow-up times of more than 2 decades, and that patients with PD were at increased risk of fall-related injuries, hip fractures in particular, a decade or more before the PD diagnosis (paper IV). For depression and fall-related injuries, the association with PD was clearly time-dependent, strongest in the last years before the diagnosis of PD.Conclusions: The results suggest that the prodromal phase of PD may last for more than 2 decades and include also motor symptoms. The consequences of PD include a reduced quality of life associated with the working situation. Employer’s support appear to be particularly important for a successful vocational rehabilitation.
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| 5. |
- Weidung, Bodil, 1988-
(författare)
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Blood pressure in very old age : determinants, adverse outcomes, and heterogeneity
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: High blood pressure (BP) is the leading risk factor for disease and mortality worldwide. However, risks associated with high BP in very old age (≥ 80 or ≥ 85 years) are not entirely understood, as the majority of scientific studies have been performed with younger populations and existing scientific knowledge about very old individuals is sometimes contradictory. Results of previous studies of very old individuals suggest that the associations of BP with mortality and stroke differ with levels of physical and cognitive function. More studies that are representative of very old individuals, including individuals with multimorbidity, that are of adequate size, involve proper adjustment, and investigate non-linear associations, are needed to investigate these issues.Systolic blood pressure (SBP) decline is common among very old individuals and has been shown to precede adverse events. Previous studies have shown that SBP change is associated with baseline SBP, age, and health-related factors, but determinants of SBP change have not been investigated using comprehensive, multivariate models.The three main aims of this thesis were to investigate, in a sample of individuals aged ≥ 85 years, 1) determinants of SBP change, 2) the association of BP with mortality risk and whether this association differs with respect to gait speed and/or Mini-Mental State Examination (MMSE) score, and 3) the association of BP with stroke risk and whether this association differs with respect to the Barthel Activities of Daily Living (ADL) index and/or MMSE score.Methods: The studies conducted for this thesis were based on data from the population-based Umeå 85+/Gerontological regional database study, which provided cross-sectional and longitudinal data on socioeconomic factors, medical conditions, drug prescriptions, and health-related assessments from 2000 to 2015. Participants were aged 85, 90, and ≥ 95 years, and lived in Västerbotten, Sweden, and Österbotten/Pohjanmaa, Finland. Follow-up assessments were conducted after 5 years. Mortality data were collected after 2 and 5 years, and stroke data were collected after 5 years, from death certificates, medical records, population registers, and the inpatient diagnosis register. Comprehensive multivariate models were developed to investigate determinants of SBP change using multiple linear regression, and to investigate associations of mortality and stroke risks with BP using Cox proportional-hazard regression models.Results: Average (± standard deviation) baseline SBP was 146 ± 23 mm Hg, and average diastolic blood pressure (DBP) was 74 ± 11 mm Hg. Within 5 years, 61% of participants had died and 10% had had incident strokes. Among participants followed for 5 years, the average annual SBP decline was 2.6 ± 5.4 mm Hg.In a multivariate model, SBP decline was associated with later investigation year (p = .009), higher baseline SBP (p < .001), baseline antidepressant drug use (p = .011), incident acute myocardial infarction during follow-up (p = .003), use of a new diuretic drug during follow-up (p = .044), and declining Barthel ADL index scores during follow-up (p < .001).In an age- and sex-adjusted analysis of the total sample, mortality risk was decreased in higher (vs. lower) BP categories (SBP ≥ 165 vs. ≤ 125 mm Hg: hazard ratio [HR] .50, p < .001; DBP 70–74 vs. 75–80 mm Hg: HR 1.32, p = .031). In a comprehensively adjusted analysis of the total sample, SBP was not associated significantly with mortality risk. The associations of SBP with mortality in the gait speed < .5 m/s subcohort corresponded with those found in the total sample. In comprehensively adjusted analyses in the gait speed ≥ .5 m/s subcohort, mortality risk increased independently with higher (vs. lower) BP (SBP ≥ 165 vs. 126–139 mm Hg: HR 2.13, p = .048; DBP > 80 vs. 75–80 mm Hg: HR 1.76, p = .026). In comprehensively adjusted analyses in the MMSE score subcohorts, SBP was associated significantly with mortality risk only in the 0–10 MMSE score subcohort; high and low SBP categories were associated independently with increased mortality risk, compared with an intermediary SBP category (SBP ≥ 165 vs. 126–139 mm Hg; HR 4.54, p = .007; SBP ≤ 125 vs. 126–139 mm Hg: HR 2.23, p = .023). Higher BP was associated significantly with increased stroke risk in multivariate models (SBP per 10 mm Hg increment: HR 1.19, p < .001; DBP per 10 mm Hg increment: HR 1.26, p = .013). SBP was not associated with stroke risk in participants with SBP < 140 mm Hg.Interaction effects on the association with mortality were significant between SBP and gait speed (age- and sex-adjusted model: p = .031) but not between SBP and MMSE score. No interaction in the association with stroke was found between any BP measure and Barthel ADL index or MMSE score.Conclusion: The decline in BP in very old age may be explained by health-related factors. Low BP may be a risk marker for short life expectancy, due to morbidity, in the general very old population and among very old individuals with low gait speeds. High BP seems to be an independent risk factor for mortality only in certain groups, which may be distinguished by high gait speed or very severe cognitive impairment. High SBP and DBP seem to increase stroke risk in very old age. These findings may contribute to a better understanding of the risks of adverse outcomes in very old individuals with different BP levels, the importance of comorbidity for these risks, and the etiology of SBP change.
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