| 1. |
- 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. |
- Burman, Maria, 1983-
(författare)
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Malnutrition and obesity among older adults, assessed by Mini Nutritional Assessment and the body mass index, respectively : prevalence and associations with mortality and urinary tract infection
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- INTRODUCTION: Malnutrition and obesity are health concerns among older (aged ≥ 65 years) adults, but the combination of them have not been studied thoroughly nor have they been thoroughly investigated in very old (aged ≥ 85 years) adults. The aims of this thesis were to investigate the prevalence, trends in prevalence and associations with mortality of malnutrition and obesity, assessed by Mini Nutritional Assessment (MNA) and the body mass index (BMI), respectively, and to examine the combined effects of these conditions on mortality. Malnutrition as a risk factor for urinary tract infection (UTI) was also investigated. MATERIAL AND METHODS: The studies reported on in papers I and II were conducted with data from the Umeå85+/Gerontological Regional Database study, a population-based study of cohorts of very old adults. Data from all four Swedish cohorts (2000–2002, 2005–2007, 2010–2012 and 2015–2017), and from the 2000–2002 and 2005–2007 Swedish cohorts and a 2005–2006 Finnish cohort, respectively, were used. In the paper I study, trends in the prevalence of malnutrition (by MNA score) and obesity (by BMI) were investigated across cohorts. In the paper II study, the associations of MNA scores and BMI with 5-year mortality were investigated. The study reported on in paper III was conducted with data from the Senior Alert national quality registry; associations of Mini Nutritional Assessment–Short Form (MNA-SF) scores, BMI and 2-year mortality in older adults living in residential care facilities in Sweden were investigated. The study reported on in paper IV was conducted with data from the Frail Older People–Activity and Nutrition and Umeå Dementia and Exercise studies; risk factors for UTI among older adults in residential care facilities were investigated. RESULTS: In the paper I study, mean BMI increased between 2000–2002 and 2015–2017 and the prevalence of obesity were 13.4% and 18.3%, respectively; the prevalences of underweight were 7.6% and 3.0%, respectively. Mean MNA scores increased between 2000–2002 and 2010–2012 and were slightly lower in 2015–2017. The prevalence of malnutrition according to MNA scores in the four cohorts were 12.2%, 6.4%, 5.1% and 8.7%, respectively, and the prevalence of at risk thereof were 31.8%–37.2%. In the paper II study, 13.3% of participants were malnourished, and 40.3% at risk thereof according to MNA scores, and malnutrition was more common among women than men. Twenty-five percent of the population had BMIs ≥28.0 kg/m2. Of those with malnutrition according to MNA scores, 17.4% had BMIs ≥ 24.7 kg/m2; of those with good nutritional status according to MNA scores, 13.8% had BMIs < 22.2 kg/m2. Compared to malnutrition according to MNA, lesser mortality was found in individuals with good nutritional status. Compared to individuals with BMI <22.2 kg/m2, lesser mortality was found in those with BMI ≥28.0 kg/m2. In the paper III study, 14.6% of the population was malnourished, and 45.0% at risk of malnutrition according to MNA-SF scores and 16.0% were obese. Compared to individuals with good nutritional status, greater mortality was found in those with malnutrition according to MNA-SF. Mortality was greater among underweight than among normal-weight participants and lesser among participants with obesity, including severe obesity. Higher BMIs were also associated with reduced mortality in subgroups defined by MNA-SF scores. In the paper IV study, malnutrition according to MNA scores was not a risk factor for UTI in the whole sample or in women. In men, the MNA score was associated with UTI in univariate analysis. CONCLUSIONS: The results of this thesis highlight the importance of nutritional screening in older adults in residential care facilities and in very old adults, since malnutrition risk was common and associated with greater mortality among these populations. Malnutrition according to MNA was not a clear risk factor for UTI in older adults living in residential care facilities. Time trends indicated an increasing prevalence of obesity whereas no change in nutritional status according to MNA was observed among very old adults, although these trends need further investigation. The results also confirmed that higher BMIs were beneficial for survival in these populations, and in the residential care population this seems to apply also for BMIs reflecting severe obesity. Finally, in the residential care population, regardless of nutritional status according to MNA-SF, higher BMIs were associated with better survival.
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| 3. |
- Forsgren, Elin, 1987-
(författare)
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Using patient-derived cell models to investigate the role of misfolded SOD1 in ALS
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Protein misfolding and aggregation underlie several neurodegenerative proteinopathies including amyotrophic lateral sclerosis (ALS). Superoxide dismutase 1 (SOD1) was the first gene found to be associated with familial ALS. Overexpression of human mutant or wild type SOD1 in transgenic mouse models induces motor neuron (MN) degeneration and an ALS-like phenotype. SOD1 mutations, leading to the destabilization of the SOD1 protein is associated with ALS pathogenesis. However, how misfolded SOD1 toxicity specifically affects human MNs is not clear. The aim of this thesis was to develop patient-derived, cellular models of ALS to help understand the pathogenic mechanisms underlying SOD1.To understand which cellular pathways impact on the level of misfolded SOD1 in human cells, we established a model using patient-derived fibroblasts and quantified misfolded SOD1 in relation to disturbances in several ALS-related cellular pathways. Misfolded SOD1 levels did not change following reduction in autophagy, inhibition of the mitochondrial respiratory chain, or induction of endoplasmic reticulum (ER)-stress. However, inhibition of the ubiquitin-proteasome system (UPS) lead to a dramatic increase in misfolded SOD1 levels. Hence, an age-related decline in proteasome activity might underlie the late-life onset that is typically seen in SOD1 ALS.To address whether or not SOD1 misfolding is enhanced in human MNs, we used mixed MN/astrocyte cultures (MNCs) generated in vitro from patient-specific induced pluripotent stem cells (iPSCs). Levels of soluble misfolded SOD1 were increased in MNCs as well as in pure iPSC-derived astrocytes compared to other cell types, including sensory neuron cultures. Interestingly, this was the case for both mutant and wild type human SOD1, although the increase was enhanced in SOD1 FALS MNCs. Misfolded SOD1 was also found to exist in the same form as in mouse SOD1 overexpression models and was identified as a substrate for 20S proteasome degradation. Hence, the vulnerability of motor areas to ALS could be explained by increased SOD1 misfolding, specifically in MNs and astrocytes.To investigate factors that might promote SOD1 misfolding, we focussed on the stability of SOD1 mediated by a crucial, stabilizing C57-C146 disulphide bond and its redox status. Formation of disulphide bond is dependent on oxidation by O2 and catalysed by CCS. To investigate whether low O2 tension affects the stability of SOD1 in vitro we cultured fibroblasts and iPSC-derived MNCs under different oxygen tensions. Low oxygen tension promoted disulphide-reduction, SOD1 misfolding and aggregation. This response was much greater in MNCs compared to fibroblasts, suggesting that MNs may be especially sensitive to low oxygen tension and areas with low oxygen supply could serve as foci for ALS initiation.SOD1 truncation mutations often lack C146, and cannot adopt a native fold and are rapidly degraded. We characterized soluble misfolded and aggregated SOD1 in patient-derived cells carrying a novel SOD1 D96Mfs*8 mutation as well as in cells fom an unaffected mutation carrier. The truncated protein has a C-terminal fusion of seven non-native amino acids and was found to be extremely prone to aggregation in vitro. Since not all mutation carriers develop ALS, our results suggested this novel mutation is associated with reduced penetrance.In summary, patient derived cells are useful models to study factors affecting SOD1 misfolded and aggregation. We show for the first time that misfolding of a disordered and disease associated protein is enhanced in disease-related cell types. Showing that misfolded SOD1 exists in human cells in the same form as in transgenic mouse models strengthens the translatability of results obtained in the two species. Our results demonstrate disulphide-reduction and misfolding/aggregation of SOD1 and suggest that 20S proteasome could be an important therapeutic target for early stages of disease. This model provides a great opportunity to study pathogenic mechanisms of both familial and sporadic ALS in patient-derived models of ALS.
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| 4. |
- 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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| 5. |
- Johansson, Jonas, 1984-
(författare)
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The Healthy Ageing Initiative : Prevention of falls and fractures
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The world is currently experiencing a dramatic increase in the number of older individuals, an amount that is expected to double between 2015 and 2050. This increase will likely affect the prevalence of age-related functional impairments, such as those caused by fractures. Fractures are often immobilizing events leading to increased individual suffering and vast healthcare costs. Prevention of these events and detection of underlying risk factors are hence of utmost importance. Fracture prevention strategies have traditionally focused on strengthening the skeleton by improving bone mineral density, partly through the mechanical load of increased physical activity. However, research has shown that nine out of ten hip fractures are attributed to falls. While several risk factors behind falls have been identified, there is less knowledge about how aspects such as gait patterns and postural stability predict future falls. The aim of this thesis was to expand upon the current knowledge by investigating objective measures of physical activity in relation to bone parameters, and measures of gait patterns and postural stability in relation to incident falls, in a large population-based sample of 70-year-olds.The samples investigated in the four included studies were drawn from the Healthy Ageing Initiative (HAI) cohort. Study I examined associations between physical activity, objectively measured using accelerometers, and bone parameters, measured by Dual-energy X-ray Absorptiometry and Peripheral Quantitative Computed Tomography. Study II examined how gait variability, measured using the GAITRite electronic walkway system, predicted incident falls in men and women. Studies III and IV examined how center of pressure (COP) sway and limits of stability (LOS), measured using a force platform, predicted incident falls. Independent prediction of bone parameters and incident falls were investigated using multiple linear and logistic regression models.Study I revealed that moderate-to-vigorous physical activity and vertical peak acceleration independently predicted parameters of bone in the weight-bearing skeleton. Study II showed that women’s increased risk of falling could be explained by increased gait variability during dual-task assignments. Study III revealed that the risk of falling was increased by 75-90% for individuals in the highest quintile of COP sway. Study IV integrated COP and LOS data, showing that fall risk was increased by 9-16% per 1-unit increase in COP-LOS ratio. In conclusion, this thesis highlighted several objective predictors of incident falls among older adults. Future studies and recommendations should emphasize strategies to improve balance, muscle strength and physical activity in order to prevent falls and fractures.
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| 6. |
- Ballin, Marcel, 1993-
(författare)
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Physical activity, visceral adipose tissue, and cardiovascular disease in older adults : associations and effects
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- BACKGROUND: Cardiovascular disease (CVD) poses a substantial public health burden and is the leading cause of mortality in older adults. With the population aging rapidly, interventions aimed at improving modifiable risk factors for CVD, such as physical inactivity and visceral obesity, could play an important role in reducing its burden, provided they are proven effective.PURPOSE AND AIMS: The overall purpose of this thesis was to create a deeper understanding of the links between physical activity, visceral adipose tissue (VAT), and CVD in older adults, by studying it from both an observational and an interventional perspective. The specific aims were to investigate the associations of objectively measured physical activity and VAT with the risk of CVD and all-cause mortality, to investigate the effect of structured physical activity (exercise) on VAT, and to review the effects of exercise on CVD and all-cause mortality based on evidence from randomized controlled trials (RCTs).METHODS: This thesis comprised two prospective cohort studies, one RCT, and one narrative review of evidence from RCTs. The cohort studies included about 3,300 men and women aged 70 years with baseline data on physical activity and VAT mass, as obtained using accelerometry and dual-energy X-ray absorptiometry, respectively. Cases of stroke, myocardial infarction, and all-cause mortality during follow-up were collected from Swedish nationwide registers. The RCT included 77 men and women aged 70 years with visceral obesity who were randomly allocated to either 10 weeks of supervised vigorous-intensity exercise or to no exercise, with VAT mass measured before and after the intervention. In the review, evidence from published RCTs and meta-analyses of RCTs reporting on the effects of exercise on CVD (N=19,162) and all-cause mortality (N=37,443) in general older adults and in individuals with chronic conditions (such as obesity, type 2 diabetes, and preexisting CVD) were reviewed.MAIN FINDINGS: In the cohort studies, greater amounts of physical activity of any intensity, but especially that of moderate to vigorous intensity, were associated with lower risk of stroke, myocardial infarction, and all-cause mortality. Conversely, greater VAT mass was associated with higher risk of stroke or myocardial infarction. In the RCT, short-term vigorous-intensity exercise seemed to decrease VAT mass slightly, but the effect was not statistically significant. Finally, the review showed that there is currently no convincing evidence from RCTs that exercise effectively reduces the risk of CVD or all-cause mortality, which stands in sharp contrast to the strong associations typically reported in observational studies. The reasons for the conflicting findings are likely complex and multifactorial. In the RCTs, a lack of statistical power could partly explain why no effects have been detected in the general population of older adults, but it is unlikely to explain the null findings in clinical populations, as some of these trials, including meta-analyses of such trials, have been large. Other potential explanations could be a ceiling effect due to the inclusion of participants who were healthier and more physically active than the general population, or that an effect of exercise was masked by the use of effective medications such as antihypertensives and lipid-lowering agents. On the other hand, observational studies have likely overestimated the benefits of physical activity, because these studies are vulnerable to selection bias, reverse causation, and unmeasured confounding, such as from heritable influences.CONCLUSIONS AND IMPLICATIONS: Despite strong associations, the protective effect of physical activity as a single intervention against CVD and all-cause mortality in older adults is probably not as substantial as is commonly presumed. To uncover the true role of physical activity in preventing CVD, further high-quality trials would be valuable. However, because these trials are very difficult and resource demanding, they should be complemented by innovative observational studies that seek to strengthen causal inference through addressing sources of bias and confounding that are often incompletely accounted for in conventional observational studies. This could include a variety of methodologies, such as utilizing negative control outcomes, instrumental variables, sibling comparisons, and other genetically informed designs. As the aging population continues to grow, it becomes increasingly important to take these scientific steps in order to provide a more definitive answer to the question of the extent to which physical activity alone can reduce the risk of CVD.
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| 7. |
- Bergman, Jonathan, 1993-
(författare)
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Benefits and harms of Bisphosphonates : an observational study
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Bisphosphonates are first-line treatment for osteoporosis, but osteoporosis is considered an undertreated disease. The general aim of this dissertation was to further study the benefits and harms of bisphosphonates. There were four specific research questions: (1) Do bisphosphonates reduce the risk of new fractures in older adults who have a history of fracture? (2) Do bisphosphonates reduce the risk of fracture in people taking glucocorticoids? (3) Does confounding explain why bisphosphonates are associated with lower mortality in observational studies? (4) Do bisphosphonates increase the risk of non-jaw osteonecrosis?Methods: To answer these questions, we used Swedish register data on deaths, diagnoses, and prescription medications to conduct four matched cohort studies of bisphosphonate users and nonusers. The cohorts were selected from patients registered in the Hip Fracture Register and from all residents of Sweden who were aged 50 years or older on December 31, 2005.Results: (1) Bisphosphonate users had an initially increased risk of sustaining new fractures, which appeared to be due to an underlying high risk of fracture. This increased risk diminished over time, which is consistent with a gradual treatment effect, but it is also consistent with a bias known as depletion of susceptibles. (2) Bisphosphonate users had a lower risk of fracture during glucocorticoid therapy. (3) Bisphosphonate users had a lower mortality rate from day 2 of treatment. Although such an early treatment effect cannot be ruled out, this finding is consistent with confounding. (4) Bisphosphonate users had an increased risk of developing non-jaw osteonecrosis. Conclusion: Most of the results were difficult to interpret as true benefits or harms of bisphosphonates because alternative explanations, arising from bias or confounding, were likely. The exception was the results of Study 2, where alternative explanations are more difficult to find. Therefore, Study 2 suggests that bisphosphonates reduce the risk of fractures in glucocorticoid-treated patients. Further research is needed to clarify the potential effects of bisphosphonates on mortality, non-jaw osteonecrosis, and new fractures after a previous fracture.
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| 8. |
- 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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| 9. |
- Brännström, Jon, 1977-
(författare)
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Adverse effects of psychotropic drugs in old age
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: With increasing age, the body and mind transform. Many of our organs gradually lose capacity, making them more sensitive to the effects of several drugs. In parallel, many of us accumulate an increasing burden of disease and other conditions warranting the use of medications. Hence, the use of most classes of drugs increases with age, especially so in elderly women.At the same time, medical science is lagging behind due to the fact that the oldest people in society often are excluded from pharmacological studies, where young males are the most coveted subjects.In the absence of strong evidence, much of the knowledge about the clinical and adverse effects of several drugs in the elderly is derived from observational studies, prone to bias and confounding. The use of psychotropic drugs in elderly people is particularly controversial, and even more so in people suffering from major neurocognitive disorders (NCD). Psychotropics have been associated with several adverse effects as well as limited clinical effect. Still, they are frequently prescribed to elderly patients.Aims: This thesis aims to explore the associations between several types of psychotropic drugs and two of the most severe adversities attributed to their use, increased mortality and the risk of hip fracture. It aims to explore mortality in data from well-controlled studies. It also aims to employ novel statistical methods to investigate the associations between drug exposure and hip fracture, in an attempt to gain information on possible causality from observational data.Methods: This thesis uses quantitative, comparative and epidemiological methods, prospective as well as retrospective. Two of the four papers are based on data collections conducted by the Department of Community Medicine and Rehabilitation, Umeå University, and include 992 and 1,037 individuals, respectively. The other two papers are based on Swedish nationwide registers and include 408,144 and 255,274 subjects, respectively. In all four papers multivariable regression models were used to investigate the associations between the exposures and outcomes, adjusted for possible confounding variables.Results: In a population-based sample of very old people, and in old people with major NCD, ongoing use of psychotropic drugs was not independently associated with increased mortality. Analyses did show, however, a significant impact of sex on the mortality risk, with tendencies for antidepressant drug use to be protective in men, but not in women, and for benzodiazepines to increase the mortality risk in men, but not in women. In two cohorts of old people, based on several nationwide registers, investigating the associations between psychotropic drug use and hip fracture revealed that users of antidepressants, as well as users of antipsychotics, had significantly increased risks of hip fracture, independent of a wide range of covariates. However, when studying how the risk changed over time, the strongest associations were found before the initiation of treatment with the respective drug, and no dose-response relationships were found.Discussion: The finding that psychotropic drug use was not independently associated with an elevated mortality risk was not in line with previous research, most of which have been based on data from large registers, and shown an increased risk of mortality. One reason for this difference is that the cohorts studied in this thesis were thoroughly investigated and characterised, making it possible to perform extensive adjusting for confounding variables. Hence, we expect a lesser amount of residual confounding, than in most other studies. Another explanation is that we studied ongoing drug use at baseline, rather than associations following initiation of treatment. This might have introduced a selection bias in our studies, where the individuals most sensitive to adverse effects would have discontinued treatment or passed away. The finding of a significant impact of sex on the risk of mortality adds to the unexplored field of sex differences in drug responses in old age, and warrants further investigation.In our register studies of psychotropic drug use and the risk of hip fracture, novel methods were applied. We have tried to overcome the hurdles of several types of confounding through the investigation of associations before and after the initiation of antidepressants, and antipsychotics, respectively. Our finding that the associations between psychotropic drug use and hip fracture were not only present, but indeed strongest, before the initiation of treatment indicates a strong presence of residual confounding and confounding by indication, and points toward the absence of a causal relationship between psychotropic drug use and hip fracture.Conclusion: The evidence supporting causal relationships between psychotropic drug use and serious adverse events in old age is insufficient. Our results point towards bias and confounding having strong influences on the observed associations between psychotropic drug use and mortality, and hip fracture, respectively.
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| 10. |
- Karlsson, Åsa, 1972-
(författare)
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Team-based home rehabilitation after hip fracture in older adults : effects, experiences and impact of dementia
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- BACKGROUND: For an older adult a hip fracture may be a traumatic and life-changing event and has shown to be associated with reduced health-related quality of life, disability and increased mortality. Previous rehabilitation studies have often excluded older adults with cognitive impairment and those living in residential care facilities, groups with an additional risk of poor outcome. Moreover, there are few randomized controlled trials that have evaluated interdisciplinary home rehabilitation after hip fracture. These studies did not include older adults with severe cognitive impairment or dementia, those with serious medical conditions, or those living in residential care.OBJECTIVE: The aim of the thesis was to investigate the effects of early discharge followed by geriatric interdisciplinary home rehabilitation (GIHR) for older adults with hip fracture, and specifically among those with dementia, compared to in-hospital geriatric care according to a multifactorial rehabilitation program. An additional aim was to explore how older adults experienced their rehabilitation and recovery during the year following the fracture.METHODS: The thesis evaluated a randomized controlled trial that included 205 participants with hip fracture, 70 years or older, living in ordinary housing or residential care facilities. In hospital, both the GIHR and control groups received care and rehabilitation according to a multifactorial rehabilitation program, but with the aim of early discharge for the GIHR group. The individually designed GIHR intervention focused on walking ability indoors and outdoors, independence in activities of daily living (ADL), and multifactorial fall prevention during a maximum period of 10 weeks. Participants were assessed in-hospital and at 3- and 12-month follow-up visits. Independence in walking and use of walking aids was assessed via an interview along with gait speed tests. Independence in ADL was measured using the Barthel ADL Index, and the ADL Staircase including the Katz ADL Index, and hospital length of stay (LOS) was recorded from medical charts. The effects of GIHR intervention among participants with dementia were investigated in a post hoc subgroup analysis where additional outcomes were falls, mortality and readmissions between discharge and 12 months. Individual interviews were conducted with 20 selected participants just after the 12-month follow-up. Data were analysed using qualitative content analysis.RESULTS: The postoperative hospital LOS was significantly reduced by a median of six days in the GIHR group compared to the control group, although not significantly reduced in the GIHR group for participants with dementia. Binary logistic regression analyses revealed no significant differences between the GIHR and control groups regarding independent walking ability, the ability to walk without a walking device, or independence in ADL at 3 and 12 months. Gait speed was comparable between the two groups at 3 and 12 months. At 12 months, 56% in the GIHR group and 58% in the control group had recovered their prefracture walking ability, and 41% vs. 42% in GIHR and control groups, respectively, had regained their prefracture Barthel ADL Index score. Interaction analyses showed that the GIHR group vs. the control group had comparable effects on walking ability and ADL at 3 and 12 months, and on falls and mortality between discharge and 12 months, regardless of whether the participants had dementia or not (P≥0.05 for all). The number of readmissions and hospital days after discharge was comparable between GIHR and control groups for participants with dementia. Overall, dementia was associated with significantly impaired walking ability and greater dependence in ADL at 3 and 12 months and with increased risk of falling and increased mortality between discharge and 12 months compared to participants without dementia. The interviews revealed that access to rehabilitation, provided by skilled staff, and support from others were important for participants’ well-being and recovery. Participants experienced a fundamental change in their self-image after the fracture, and faced a number of difficulties, but strove for independence and used adaptive strategies to find contentment in their lives.CONCLUSIONS: In older adults with hip fracture, early discharge followed by interdisciplinary home rehabilitation significantly reduced postoperative hospital LOS. Functional recovery during the year following the fracture was nevertheless comparable to in-hospital geriatric care according to a multifactorial rehabilitation program. The GIHR intervention seems to be appropriate also for older adults with dementia since the effects were not different in this subgroup, except for postoperative hospital LOS, which was not significantly reduced in the GIHR group for participants with dementia. Further studies with larger samples are needed to validate these results. Overall, dementia was associated with a substantial negative impact on the outcomes. According to participants’ experiences, receiving rehabilitation and support after the hip fracture seems crucial for successful recovery. Negative psychological reactions were common, suggesting that future interventions should consider both physical and psychological aspects. Different rehabilitation alternatives were appreciated by the participants. Rehabilitation should thus be customised to suit wishes and needs of older adults and may accordingly be carried out in different settings, where rehabilitation in the home can be one suitable alternative. The findings of this thesis indicate that geriatric interdisciplinary home rehabilitation after hip fracture can be an alternative and a complement to in-hospital care and rehabilitation for older adults with and without dementia.
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