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- Domert, Jakob, 1986-
(författare)
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Neuron-to-neuron propagation of neurodegenerative proteins; relation to degradative systems
- 2017
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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.
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| 2. |
- Johansson, Maria, 1967-
(författare)
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Cognitive impairment and its consequences in everyday life
- 2015
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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.
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| 3. |
- Rådholm, Karin, 1976-
(författare)
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Cardiovascular risk factors in elderly : With special emphasis on atrial fibrillation, hypertension and diabetes
- 2015
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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
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| 4. |
- Segernäs Kvitting, Anna, 1977-
(författare)
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Dementia diagnostics in primary care : with a focus on cognitive testing
- 2019
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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.
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