| 1. |
- Agholme, Lotta
(författare)
-
The involvement of degradation pathways and neuron-to-neuron transmission in Alzheimer’s disease
- 2012
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Although the vast majority of Alzheimer’s disease (AD) cases are of the sporadic type, mutations causing the familial form have been the focus of AD research for decades. The disease is pathologically characterised by β-amyloid (Aβ) and tau protein aggregates in neuritic plaques and neurofibrillary tangles. Furthermore, it is known that AD pathology spreads throughout the brain, most often along the same anatomical pattern. However, so far no cause for the sporadic form of the disease has been found. Accumulation of protein aggregates as well as decreased activity of the protein degradation systems, lysosomes and proteasomes, is found in diseased brains. This indicates that defective degradation contributes to sporadic AD.The aim of this thesis was to develop an improved neuronal model, and study the effects of decreased proteasome function on tau phosphorylation and axonal transport. In addition, the effects on Aβ accumulation and generation upon proteasome inhibition were investigated. Finally, the possibility that intracellularly accumulated Aβ oligomers could be transferred from one neuron to another was tested.Differentiation of human SH-SY5Y neuroblastoma cells in an extracellular matrix gel, using a set of neurotrophic factors, resulted in cells with neuronal phenotype, expressing neuron specific markers and all six adult isoforms of tau. Within this neuronal model, we found that reduced proteasome activity inhibited neuritic transport, and caused tau phosphorylation in a c-Jun and ERK 1/2 dependent manner. Using proteasome inhibition in APP overexpressing cells, we found an autophagy dependent intralysosomal Aβ accumulation, together with elevation of intra- and extracellular concentrations of Aβ. Autophagy inhibition protected the cells from the toxicity induced by decreased proteasome activity. Finally, we could, as the first group, show that Aβ can be directly transferred from one neuron to another through connected neurites. Furthermore, accumulation of Aβ in the endo-lysosomal compartment of receiving cells caused toxicity and neurodegeneration.We believe that cells not able to degrade accumulated Aβ, due to increased generation or reduced degradative capacity, instead tries to clear its content through transfer to connected neurons. If not properly degraded in the receiving cell, this can accelerate AD pathology and cause neuritic and neuronal degeneration spreading throughout the brain. Increasing the activity of the degradative systems, or inhibiting transmission of Aβ between neurons could therefore be novel treatments for AD.
|
|
| 2. |
- Bagheri, Maryam
(författare)
-
Neuroprotective Effect of Genistein : Studies in Rat Models of Parkinson’s and Alzheimer’s Disease
- 2012
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Parkinson’s disease (PD) and Alzheimer’s disease (AD) are neurodegenerative disorders that mainly affect the elderly population. It is believed that oxidative stress is involved in development of both these diseases and that estrogen deficiency is a risk factor for development of AD. Genistein is a plant-derived compound that is similar in structure to estrogen and has anti-oxidative properties. The general objective of the present research was to evaluate the effects of genistein on neurodegeneration in rat models of PD and AD.Using a rat model of PD, we found that a single intraperitoneal dose of genistein 1 h before intrastriatal injection of 6-hydroxydopamine (6-OHDA) attenuated apomorphine-induced rotational behavior and protected the neurons of substantia nigra pars compacta against 6-OHDA toxicity.To produce an animal model of AD, we injected Aβ1–40 into the hippocampus of rats. Using groups of these Aβ1–40-lesioned animals, the involvement of estrogen receptors (ERs) was evaluated by intracerebroventricular injection of the estrogen receptor antagonist fulvestrant, and the role of oxidative stress was studied by measuring levels of malondialdehyde (MDA), nitrite, and superoxide dismutase (SOD) activity. The results showed that intrahippocampal injection of Aβ1–40 caused the following: lower spontaneous alternation score in Y-maze tasks, impaired retention and recall capability in the passive avoidance test, and fewer correct choices and more errors in a radial arm maze (RAM task), elevated levels of MDA and nitrite, and a signiHcant reduction in SOD activity in the brain tissue. Furthermore, hippocampus in theses rats exhibited Aβ1–40 immunoreactive aggregates close to the lateral blade of the dentate gyrus (DGlb), extensive neuronal degeneration in the DGlb, high intracellular iNOS+ and nNOS+ immunoreactivity, and extensive astrogliosis.Genistein pretreatment ameliorated the Aβ-induced impairment of short-term spatial memory, and this effect occurred via an estrogenic pathway and through attenuation of oxidative stress. Genistein also ameliorated the degeneration of neurons, inhibited the formation of Aβ1–40-positive aggregates, and alleviated Aβ1–40-induced astrogliosis in the hippocampus.
|
|
| 3. |
- Bjartmar, Lisa, 1966-
(författare)
-
Pharmacological and Developmental Aspects on Neuronal Plasticity
- 2009
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Neuronal plasticity means the ability of the brain, its cells and networks to adapt and adjust to new challenges, a process which is ongoing throughout life. The goal of this thesis was to gain better understanding of the molecular events that follow different types of stimulations of brain structures such as the hippocampus, a key region for cognitive functions with overriding control on the corticosteroid system. A better knowledge of the mechanisms involved in neuronal plasticity is fundamental in the development of strategies for improving health in patients suffering from major depression or cognitive disorders such as Alzheimer’s disease.Antidepressant drugs induce the expression of several genes involved in neuronal plasticity, a mechanism which may explain the several weeks time lag between treatment initiation and clinical effect commonly observed in patients. Besides, there are indications that disturbances in the corticosteroid system are involved in the pathogenesis of major depression. Therefore, the mRNA expression of the glucocorticoid receptors (GR) and mineralocorticoid receptors (MR) as well as of the immediate-early genes NGFI-A and NGFI-B was analyzed using in situ hybridization in the hippocampus and cortex after 21 days treatment with various antidepressant drugs having different monoaminergic profiles. The mRNA expression of the transcription factors was selectively increased depending on region and also on the monoaminergic profile of the drug given. Generally, drugs with less specificity for monoamines had an overall more anatomically wide-spread inducible effect.In a follow-up study the message expression of the synaptic protein NP2 was investigated in a similar setting where long-term (21 days) was compared with short-term (3 days) antidepressant treatment. In addition to the hippocampus, the medial habenula, a relay station within the limbic system was analyzed. Overall there was an upregulation of NP2 mRNA expression following long-term treatment irrespective of the monoaminergic profile of the drug. Simultaneously, NP2 mRNA was analyzed in rats exposed to enriched, normal or deprived environments respectively, an experimental setting known to affect neuronal plasticity. However, in contrast to the pharmacological treatment, this environmental stimulation did not lead to alterations in NP2 mRNA expression in any of the regions studied.Finally, the function of NP2 as well as the closely related proteins NP1 and NPR was investigated. The “knock-out mouse” technique was used to eliminate these neuronal pentraxins (NPs), both individually and in various combinations. Since previous data had suggested that the NPs are involved in synaptic development, axonal refinement in the visual system during development was analyzed in these animals. In the NP1/NP2 knock-out mice, synaptic formation, axonal development and refinement occurred at a significantly slower rate than in wild-type mice, indicating that the NPs may be necessary for activity-dependent synaptogenesis.In conclusion, the results of the studies constituting this thesis demonstrate that long-term treatment with antidepressant drugs, possessing different monoaminergic profiles, has selective effects on the expression of NGFI-A, NGFI-B, GR and MR in the mammalian brain. In general, the least selective drugs exhibit the most profound effect suggesting that induction of neuronal plasticity is more effective with multiple neuronal inputs. The results also show that NP2 expression is induced by antidepressant drugs, in contrast to environmental stimulation, supporting the presence of different pathways for inducing neuronal plasticity depending on type of stimuli. Finally, this thesis indicates that the neuronal pentraxins play an important part in synaptic development.
|
|
| 4. |
- Domert, Jakob, 1986-
(författare)
-
Neuron-to-neuron propagation of neurodegenerative proteins; relation to degradative systems
- 2017
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Alzheimer’s disease (AD) and Parkinson’s disease (PD) are defined by neurodegeneration and accumulations of misfolded proteins that spread through the brain in a well characterized manner. In AD these accumulations consist mainly of β-amyloid (Aβ) and tau, while in PD, α-synuclein (α-syn) make up the characteristic lewy pathology. The general aim of this thesis was to investigate mechanisms associated with neurotoxic peptide activity by Aβ, tau and α-syn in relation to cellular degradation and transfer with a cell-to-cell transfer model system. We found that intercellular transfer of oligomeric Aβ occurs independently of isoform. However, the amount of transfer correlates with each isoforms ability to resist degradation or cellular clearance. The Aβ1-42 isoform showed particular resistance to clearance, which resulted in higher levels of cell-to-cell transfer of the isoform and lysosomal stress caused by accumulation. As Aβ accumulations can inhibit the proteasomal degradation we investigated how reduced proteasomal degradation affected neuron-like cells. We found increased levels of phosphorylated tau protein, disturbed microtubule stability and impaired neuritic transport after reduced proteasomal activity. These changes was partly linked to c-Jun and ERK 1/2 kinase activity. We could also show that α-syn transferred from cell-to-cell in our model system, with a higher degree of transfer for the larger oligomer and fibrillar species. Similar to Aβ, α-syn mainly colocalized with lysosomes, before and after transfer. Lastly, we have developed our cell-to-cell transfer system into a model suitable for high throughput screening (HTS). The type of cells have been upgraded from SH-SY5Y cells to induced pluripotent stem cells (iPSCs), with a differentiation profile more similar to mature neurons. The next step will be screening a small molecular library for substances with inhibitory effect on cell-to-cell transfer of Aβ peptides. The importance of the degradative systems in maintaining protein homeostasis and prevent toxic accumulations in general is well known. Our findings shows the importance of these systems for neurodegenerative diseases and also highlight the link between degradation and cell-to-cell transfer. To restore or enhance the degradative systems would be an interesting avenue to treat neurodegenerative diseases. Another way would be to inhibit the transfer of misfolded protein aggregates. By using the HTS model we developed, a candidate substance with good inhibitory effect on transfer can hopefully be found.
|
|
| 5. |
- Johansson, Maria, 1967-
(författare)
-
Cognitive impairment and its consequences in everyday life
- 2015
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The overall aim was to improve knowledge of the consequences of cognitive dysfunction in everyday life and of instruments to make these assessments. The thesis contains four studies each of different design using different populations.In study I, the relationship between cognitive function, ability to perform activities of daily living and perceived health-related quality of life were investigated in a population of 85-year-old individuals in the community of Linköping (n = 373). The study was part of the Elderly in Linköping Screening Assessment 85 (ELSA 85). Even mild cognitive dysfunction correlated with impaired ability to perform activities of daily living and lower health-related quality of life.In study II, the diagnostic accuracy and clinical utility of Cognistat, a cognitive screening instrument, were evaluated for identifying individuals with cognitive impairment in a primary care population. Cognistat has relatively good diagnostic accuracy with a sensitivity of 0.85, a specificity of 0.79 and a Clinical Utility Index (CUI) of 0.72. The corresponding values were 0.59, 0.91 and 0.53 for the Mini Mental State Examination (MMSE), and 0.26, 0.88 and 0.20 for the Clock Drawing Test (CDT).In study III, the aim was to develop an instrument measuring self-perceived or caregiver reported ability to perform everyday life activities in persons with suspected cognitive impairment or dementia and to perform psychometric testing of this instrument, named the Cognitive Impairment in Daily Life (CID). The CID was found to have good content validity.In study IV, experiences of cognitive impairment, its consequences in everyday life and the need for support in persons with mild cognitive impairment (MCI) or mild dementia and their relatives were explored. Interviews were performed with five people with MCI, eight people with mild dementia and their relatives (n = 13). The main finding was that persons with MCI and dementia experienced cognitive changes that could be burdensome and result in changed activity patterns.In conclusion, the findings support earlier research and show that cognitive dysfunction even at mild stages has an impact on everyday life and reduces perceived quality of life. To improve interventions for persons with cognitive impairment, it is important to assess not only cognitive function but also its consequences in everyday life activities.
|
|
| 6. |
- Nord, Magnus, 1967-
(författare)
-
Proactive Primary Care for Older Adults at High Risk of Hospital Admission
- 2022
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Demographic change is leading to a higher proportion of older adults in most parts of the world. A minority of older adults have poor health, but this group has high care needs due to frailty and/or multimorbidity. Guidelines for the management of frailty emphasise early detection of frailty and recommend comprehensive care approaches in primary care, but the evidence for these interventions is low. To provide effective and individualised care, the health system needs to identify these patients and develop proactive interventions to improve quality of life and avoid treatments that are of no benefit to the individual. The aim of this thesis was to study the effects of a proactive primary care working model in which vulnerable older adults were identified and received individually tailored care, using an adaptation of comprehensive geriatric assessment (CGA). Methods: A pragmatic controlled trial was conducted in 19 primary care practices in Sweden from 2017 to 2020. A predictive model, using electronic medical records to assess the risk of hospital admission, selected participants at high risk. Participants in the intervention practices were offered a comprehensive geriatric assessment in their primary care practice and subsequent follow-up by a team consisting of a nurse and the patient's doctor. A new CGA tool - PASTEL (Primary care ASsessment Tool for Elders) was used for assessment and care planning. The primary outcome for the intervention was hospital care days and secondary outcomes were hospital care episodes, mortality, outpatient visits, healthcare costs and cost-effectiveness. The outcomes were adjusted for age, sex and risk score and ana-lysed according to intention-to-treat. The predictive model was validated, and performance was assessed using the C-statistic. Focus group interviews were conducted to explore primary care nurses' and doctors' experiences with the new tool PASTEL. Results: 1304 older adults were included in the trial. The mean age was 82.2 years, 51% were female. During the follow-up period of 24 months, the relative risk reduction of hospital care days in the intervention group was - 22% (CI 95% = -35% to - 4%, p = 0.02) compared with usual care. There was no significant difference in mortality and outpatient visits. The reduction in healthcare costs was - € 4324 (- € 7962 to - € 686, p = 0.02). The intervention was cost-effective compared with usual care, mainly due to lower costs.The predictive model had an AUC of 0.69 (CI 0.68- 0.70). Primary care staff considered PASTEL valuable and feasible in the primary care context.In conclusion, the results of this thesis indicate that vulnerable older adults at risk of hospitalisation can be identified by a predictive model. Proactive intervention with a comprehensive geriatric assessment adapted to pri-mary care can reduce the need for hospital care. Future studies in similar contexts are needed to determine whether these results are generalisable.
|
|
| 7. |
- Rådholm, Karin, 1976-
(författare)
-
Cardiovascular risk factors in elderly : With special emphasis on atrial fibrillation, hypertension and diabetes
- 2015
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- BackgroundThe part of the population that belongs to the oldest-old (ages 80 years or older) increases rapidly, worldwide. Cardiovascular disease (CVD) is the leading cause of death and disease burden globally. Multimorbidity is common in old age and stroke, diabetes mellitus (DM) and atrial fibrillation (AF) are strongly associated with age. Cardiovascular risk factors are well studied and documented in younger and middle ages, but not as well in old and frail individuals. Therefore, preventive treatment choices are mostly based on evidence for younger patients. The aim of this thesis was to explore age and other aspects of cardiovascular risk factors; AF, hypertension and DM, in relation to comorbidity, cardiovascular outcome and mortality.MethodsThis thesis was based on four different studies:The ELSA85 study of 85 years old in Linköping, SwedenThe international, multicentre, randomised controlled INTERACT2 trial of spontaneous intracranial haemorrhage (ICH), mean age 64 years.The prospective SHADES study of nursing home residents, mean age 85 years.The prospective, national SWE-diadep study of dispensed antidiabetics, antidepressantsand prevalent myocardial infarction (MI) in 45-84 years old.Data was obtained from questionnaires (ELSA85, INTERACT2), medical records and medical examination (ELSA85, INTERACT2, SHADES), and national registers (SWE-Diadep).ResultsThe ELSA85 study showed that 16% (n=53) had an ECG showing AF. There was an increased hazard ratio (HR) for all-cause mortality in participants with AF at baseline, at 90 years of age (HR 1.59, 95% [Confidence Interval] CI 1.04-2.44) adjusted for sex. This increase in HR did not persist when adjusted for congestive heart failure (CHF). In the INTERACT2 study, increasing age was associated with increasing frequency of death or dependency (odds ratio [OR] 4.36, 95% [CI] 3.12-6.08 for >75 years vs <52 years, p value for trend <0.001). The SHADES study showed that participants with Systolic blood pressure (SBP) <120 mmHg had an increased HR for mortality (1.56, 95% CI, 1.08–2.27; p=0.019) but there were no differences between SBP groups 140–159 mmHg and ≥160 mmHg compared with the reference group SBP 120–139 mmHg. SBP decreased during the prospective study period. In the SWE-diadep study, individuals with antidiabetics and antidepressants combined had a greater HR for MI compared to the reference of no antidiabetics or antidepressants, mostly so in women aged 45-64 years (HR 7.4, 95% CI: 6.3-8.6).ConclusionRisk factors for CVDs in elderly differ from cardiovascular risk factors in middle aged individuals an
|
|
| 8. |
- Segernäs Kvitting, Anna, 1977-
(författare)
-
Dementia diagnostics in primary care : with a focus on cognitive testing
- 2019
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- BackgroundAge is the greatest risk factor for developing dementia and the total number of people aged 60 years and above is expected to more than double globally from 2013 to 2050 (1). Primary health care (PHC) is important for basic diagnostic evaluations. Objective test measurements have been shown to be more reliable than a patient's subjective memory complaints in dementia assessments (2). However, several studies indicate the low use of objective cognitive screening tools in dementia diagnostics in PHC (3). Some general practitioners (GPs) do not perceive today’s cognitive instruments as helpful in the diagnostic process and administration problems have been reported in PHC (4, 5).The overall aim of this thesis was to investigate the accuracy of several cognitive tests used in dementia assessments in PHC, especially among older patients: A Quick Test of Cognitive Speed (AQT), Cognistat and Cognitive Assessment Battery (CAB). The normative values of the Mini Mental Status Examination (MMSE) in the oldest old was also studied.MethodsThe studies included in this thesis are from two different study populations.Studies I, II and IV. Patients with and without cognitive symptoms were recruited from four primary health care centres in Sweden between 2007 and 2009.Study III. The Elderly in Linköping Screening Assessment (ELSA 85) cohort-population examined people born in 1922 in the municipality of Linköping, Sweden.ResultsStudy I. Results showed that AQT is a usable test for dementia diagnosis in PHC. Sensitivity for AQT is superior to the Clock Drawing Test (CDT), equivalent to MMSE and the combination MMSE and CDT. The AUC for AQT was 0.773, valued good enough.Study II. Overall, the results for Cognistat in this study are superior to MMSE and CDT, also in combination. Cognistat is promising for improved dementia diagnosis in PHC with a quick and easily administered multi-domain test for dementia assessments.Study III. This study presents valuable information about normative MMSE data for the oldest patients. Results, suggest using the 25th percentile in MMSE of 25 to 26 points, and indicate that MMSE 26 is as a reasonable cut-off for cognitive decline and further medical evaluation in older persons aged from 85 to 93 years.Study IV. In summary, the additive value of the CAB test in dementia investigations in PHC is not obvious. In addition to questionable accuracy, the test is quite time consuming and normative values are scarce. By introducing the numerical sum (CABsum) the accuracy was increased.ConclusionIn conclusion, objective cognitive tests are an important part of dementia diagnosis in PHC and there is a need for improved instruments and norm-values. From our results, several cognitive quick tests are usable in PHC - MMSE, AQT and Cognistat - but they have some disadvantages. MMSE 26 is a reasonable cut-off for cognitive decline in the oldest patients 85 to 93 years from a well-educated population with quite good socioeconomic. There is a great interest in finding short and better multi-domain instruments but the additive value of CAB in dementia investigations in PHC is questionable.
|
|
| 9. |
- Zheng, Lin
(författare)
-
Lysosomal Involvement in the Pathogenesis of Alzheimer's Disease
- 2012
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Alzheimer’s disease (AD), the major cause of senile dementia, is associated with progressive formation of neurofibrillary tangles and extraneuronal plaques composed of amyloid beta peptide (Aβ). Aβ has been also found within Alzheimer neurons in association with the lysosomal system, an acidic vacuolar compartment possessing numerous hydrolytic enzymes. Lysosomes have been shown to be involved in both the formation of Aβ and its toxicity to neurons. Another line of evidence implicates oxidative stress as an important factor in the development of AD. It is reported that oxidative damage is one of the earliest changes in AD and plays an important role in the development of the disease. Although both the lysosomal system and reactive oxygen species are involved in AD, the mechanisms of this involvement are not well understood.To gain insight into the relationship between oxidative stress and the lysosomal system in AD pathogenesis, we focused our study on: 1) The effect of oxidative stress on intracellular distribution of Aβ; 2) the role of endogenous Aβ in oxidant-induced apoptosis; 3) the role of autophagy and APP processing in oxidant induced damage; and, 4) the intraneuronal localization of Aβ and its relationship to the lysosomal system.In our study, hyperoxia (40% versus 8% ambient oxygen) was used as a model of mild oxidative stress in vitro, while transfected cells producing different amounts of Aβ were used to assess toxicity due to endogenous Aβ. It was found that: 1) oxidative stress induces autophagic uptake of Aβ, resulting in its partial accumulation within lysosomes; 2) oxidative stress can induce neuronal death through macroautophagy of Aβ and consequent lysosomal membrane permeabilization; 3) increased cellular Aβ production is associated with enhanced oxidative stress and enhanced macroautophagy, resulting in increased intralysosomal Aβ accumulation and consequent apoptosis; and, 4) in normal conditions, intracellular Aβ shows primarily cytosolic distribution, not related to lysosomes and other acidic vacuoles, endoplasmic reticulum, Golgi complexes, synaptic vesicles or mitochondria. Only a minor portion of Aβ shows partial colocalization with cellular organelles. Inhibition of secretion significantly increased Aβ colocalization with endoplasmic reticulum, Golgi complexes, synaptic vesicles and lysosomes, as well as the amount of mitochondrial and cytosolic Aβ.Oxidative stress induces intralysosomal autophagy-generated Aβ accumulation, consequently causing lysosomal membrane permeabilization and apoptosis. Our findings provide a possible explanation of the interactive role of oxidative stress and lysosomal system in AD pathogenesis, and may be helpful for a future therapeutic strategy against AD.
|
|
