PET and MR imaging in Parkinson’s disease patients with cognitive impairment. A study of dopaminergic dysfunction, amyloid deposition, cortical hypometabolism and brain atrophy

Parkinson’s disease (PD) is the second most common neurodegenerative disorder. It is characterized by a severe loss of substantia nigra dopaminergic neurons leading to dopamine depletion in the striatum. PD affects movement, producing motor symptoms such as rigidity, tremor and bradykinesia. Non-motor symptoms include autonomic dysfunction, neurobehavioral problems and cognitive impairment, which may lead to dementia. The pathophysiological basis of cognitive impairment and dementia in PD is unclear. The aim of this thesis was to study the pathophysiological basis of cognitive impairment and dementia in PD. We evaluated the relation between frontostriatal dopaminergic dysfunction and the cognitive symptoms in PD patients with [18F]Fdopa PET. We also combined [C]PIB and [¹⁸F]FDG PET and magnetic resonance imaging in PD patients with and without dementia. In addition, we analysed subregional striatal [¹⁸F]Fdopa PET data to find out whether a simple ratio approach would reliably separate PD patients from healthy controls. The impaired dopaminergic function of the frontostriatal regions was related to the impairment in cognitive functions, such as memory and cognitive processing in PD patients. PD patients with dementia showed an impaired glucose metabolism but not amyloid deposition in the cortical brain regions, and the hypometabolism was associated with the degree of cognitive impairment. PD patients had atrophy, both in the prefrontal cortex and in the hippocampus, and the hippocampal atrophy was related to impaired memory. A single 15-min scan 75 min after a tracer injection seemed to be sufficient for separating patients with PD from healthy controls in a clinical research environment. In conclusion, the occurrence of cognitive impairment and dementia in PD seems to be multifactorial and relates to changes, such as reduced dopaminergic activity, hypometabolism, brain atrophy and rarely to amyloid accumulation.

Kjærlighet i forbundethet : en kraft i gamle menneskers åndelighet og verdighet

The thesis is rooted in caring science and the notion that the human being is an indivisible unity of body, soul and spirit. The purpose is to search for new, or expanded knowledge and understanding of the substance of the human’s spiritual space, as well as aspects that may constitute a foundation for the safeguard of human dignity. The clinical research study concerns the importance of spirituality and dignity in the care for older people. The thesis consists of three substudies with four articles, and the methodology is based on Gadamer’s philosophical hermeneutics. Through a metasynthesis of 17 research articles, sub-study I searched for understanding of the concept of spirituality as it may appear in reality (deduction). 17 older people were interviewed in sub-study II. This sub-study sought understanding for spirituality and dignity in the specific reality (induction). Sub-study III searched for theory development regarding spirituality, through a literature review of 20 research articles and a text by Tillich (abduction). The findings imply that spirituality entails human beings’ connectedness with one’s inner space and connectedness beyond oneself. Love in connectedness appears as a force in both spirituality and dignity. Themes portrayed include understanding of the spiritual space, religiousness, dignity, and spiritual care. The relationship between dignity and spirituality can be seen in the confirmation of human worth and care for the whole human being, including the spiritual dimension, and this is understood as a prerequisite for perceived dignity. It seems to be important that older people feel valued, loved, not abandoned, and alive. The theoretical model portrays love as a reunifying and connecting force that may foster confirmation, serving, longing and holiness. The movement towards connectedness may create room for the human being’s perception of dignity and holiness, and as such, it may be a force in the search for wholeness and becoming in health.

Enhancing the Availability of Electronic Health Records for Secondary Purposes – A Case Study

Due to the sensitive nature of patient data, the secondary use of electronic health records (EHR) is restricted in scientific research and product development. Such restrictions pursue to preserve the privacy of respective patients by limiting the availability and variety of sensitive patient data. Current limitations do not correspond with the actual needs requested by the potential secondary users. In this thesis, the secondary use of Finnish and Swedish EHR data is explored for the purpose of enhancing the availability of such data for clinical research and product development. Involved EHR-related procedures and technologies are analysed to identify the issues limiting the secondary use of patient data. Successful secondary use of patient data increases the data value. To explore the identified circumstances, a case study of potential secondary users and use intentions regarding EHR data was carried out in Finland and Sweden. The data collection for the conducted case study was performed using semi-structured interviews. In total, 14 Finnish and Swedish experts representing scientific research, health management, and business were interviewed. The motivation for the corresponding interviews was to evaluate the protection of EHR data used for secondary purposes. The efficiency of implemented procedures and technologies was analysed in terms of data availability and privacy preserving. The results of the conducted case study show that the factors affecting EHR availability are divided to three categories: management of patient data, preservation of patients' privacy, and potential secondary users. Identified issues regarding data management included laborious and inconsistent data request procedures and the role and effect of external service providers. Based on the study findings, two secondary use approaches enabling the secondary use of EHR data are identified: data alteration and protected processing environment. Data alteration increases the availability of relevant EHR data, further decreasing the value of such data. Protected processing approach restricts the amount of potential users and use intentions while providing more valuable data content.

Clinical Learning Environment and Supervision. Development and Validation of the CLES Evaluation Scale

The purpose of the study is: (1) to describe how nursing students' experienced their clinical learning environment and the supervision given by staff nurses working in hospital settings; and (2) to develop and test an evaluation scale of Clinical Learning Environment and Supervision (CLES). The study has been carried out in different phases. The pilot study (n=163) explored the association between the characteristics of a ward and its evaluation as a learning environment by students. The second version of research instrument (which was developed by the results of this pilot study) were tested by an expert panel (n=9 nurse teachers) and test-retest group formed by student nurses (n=38). After this evaluative phase, the CLES was formed as the basic research instrument for this study and it was tested with the Finnish main sample (n=416). In this phase, a concurrent validity instrument (Dunn & Burnett 1995) was used to confirm the validation process of CLES. The international comparative study was made by comparing the Finnish main sample with a British sample (n=142). The international comparative study was necessary for two reasons. In the instrument developing process, there is a need to test the new instrument in some other nursing culture. Other reason for comparative international study is the reflecting the impact of open employment markets in the European Union (EU) on the need to evaluate and to integrate EU health care educational systems. The results showed that the individualised supervision system is the most used supervision model and the supervisory relationship with personal mentor is the most meaningful single element of supervision evaluated by nursing students. The ward atmosphere and the management style of ward manager are the most important environmental factors of the clinical ward. The study integrates two theoretical elements - learning environment and supervision - in developing a preliminary theoretical model. The comparative international study showed that, Finnish students were more satisfied and evaluated their clinical placements and supervision with higher scores than students in the United Kingdom (UK). The difference between groups was statistical highly significant (p= 0.000). In the UK, clinical placements were longer but students met their nurse teachers less frequently than students in Finland. Arrangements for supervision were similar. This research process has produced the evaluation scale (CLES), which can be used in research and quality assessments of clinical learning environment and supervision in Finland and in the UK. CLES consists of 27 items and it is sub-divided into five sub-dimensions. Cronbach's alpha coefficient varied from high 0.94 to marginal 0.73. CLES is a compact evaluation scale and user-friendliness makes it suitable for continuing evaluation.

Imaging of the Vulnerable Atherosclerotic Plaque. Pre-Clinical Evaluation of PET Tracers for Vascular Inflammation

Atherosclerosis is a vascular inflammatory disease causing coronary artery disease, myocardial infarct and stroke, the leading causes of death in Finland and in many other countries. The development of atherosclerotic plaques starts already in childhood and is an ongoing process throughout life. Rupture of a plaque and the following occlusion of the vessel is the main reason for myocardial infarct and stroke, but despite extensive research, the prediction of rupture remains a major clinical problem. Inflammation is considered a key factor in the vulnerability of plaques to rupture. Measuring the inflammation in plaques non-invasively is one potential approach for identification of vulnerable plaques. The aim of this study was to evaluate tracers for positron emission tomography (PET) imaging of vascular inflammation. The studies were performed with a mouse model of atherosclerosis by using ex vivo biodistribution, autoradiography and in vivo PET and computed tomography (CT). Several tracers for inflammation activity were tested and compared with the morphology of the plaques. Inflammation in the atherosclerotic plaques was evaluated as expression of active macrophages. Systematic analysis revealed that the uptake of 18F-FDG and 11C-choline, tracers for metabolic activity in inflammatory cells, was more prominent in the atherosclerotic plaques than in the surrounding healthy vessel wall. The tracer for αvβ3 integrin, 18Fgalacto- RGD, was also found to have high potential for imaging inflammation in the plaques. While 11C-PK11195, a tracer targeted to receptors in active macrophages, was shown to accumulate in active plaques, the target-to-background ratio was not found to be ideal for in vivo imaging purposes. In conclusion, tracers for the imaging of inflammation in atherosclerotic plaques can be tested in experimental pre-clinical settings to select potential imaging agents for further clinical testing. 18F-FDG, 18F-galacto-RGD and 11C-choline choline have good properties, and further studies to clarify their applicability for atherosclerosis imaging in humans are warranted.

Use of preclinical and early clinical data for dose selection of a selective estrogen receptor modulator toremifene in treatment of breast cancer

In development of human medicines, it is important to predict early and accurately enough the disease and patient population to be treated as well as the effective and safe dose range of the studied medicine. This is pursued by using preclinical research models, clinical pharmacology and early clinical studies with small sample sizes. When successful, this enables effective development of medicines and reduces unnecessary exposure of healthy subjects and patients to ineffectice or harmfull doses of experimental compounds. Toremifene is a selective estrogen receptor modulator (SERM) used for treatment of breast cancer. Its development was initiated in 1980s when selection of treatment indications and doses were based on research in cell and animal models and on noncomparative clinical studies including small number of patients. Since the early development phase, the treatment indication, the patient population and the dose range were confirmed in large comparative clinical studies in patients. Based on the currently available large and long term clinical study data the aim of this study was to investigate how the early phase studies were able to predict the treatment indication, patient population and the dose range of the SERM. As a conclusion and based on the estrogen receptor mediated mechanism of action early studies were able to predict the treatment indication, target patient population and a dose range to be studied in confirmatory clinical studies. However, comparative clinical studies are needed to optimize dose selection of the SERM in treatment of breast cancer.

Bioactive Glass in Lumbar Spondylodesis. A Pre-Clinical and Clinical Study

Bioactive glasses (BGs) form a group of synthetic, surface-active, composition-dependent, silica-based biomaterials with osteoconductive, osteopromotive, and even angiogenic, as well as antibacterial, properties. A national interdisciplinary research group, within the Combio Technology Program (2003–2007), developed a porous load-bearing composite for surgical applications made of BG 1–98 and polymer fibers. The pre-clinical part of this thesis focused on the in vitro and in vivo testing of the composite materials in a rabbit femur and spinal posterolateral fusion model. The femur model failed to demonstrate the previously seen positive effect of BG 1–98 on osteogenesis, probably due to the changed resorption properties of BG in the form of fibers. The spine study was terminated early due to adverse events. In vitro cultures showed the growth inhibition of human mesenchymal stems next to BG 1–98 fibers and radical pH changes. A prospective, long-term, follow-up study was conducted on BG–S53P4 and autogenous bone used as bone graft substitutes for instrumented posterolateral spondylodesis in the treatment of degenerative spondylolisthesis (n=17) and unstable burst fractures (n=10) during 1996–1998. The operative outcome was evaluated from X-rays and CT scans, and a clinical examination was also performed. On the BG side, a solid fusion was observed in the CT scans of 12 patients, and a partial fusion was found in 5 patients, the result being a total fusion rate in all fusion sites (n=41) 88% for levels L4/5 and L5/S1 in the spondylolisthesis group. In the spine fracture group, solid fusion was observed in five patients, and partial fusion was found in five resulting in a total fusion rate of 71% of all fusion sites (n=21). The pre-clinical results suggest that under certain conditions the physical form of BG can be more critical than its chemical composition when a clinical application is designed. The first long-term clinical results concerning the use of BG S53P4 as bone graft material in instrumented posterolateral spondylodesis seems to be a safe procedure, associated with a very low complication rate. BG S53P4 used as a stand-alone bone substitute cannot be regarded as being as efficient as AB in promoting solid fusion.

Intracranial Nimodipine Implant: Feasibility and Implications for the Treatment of Subarachnoid Hemorrhage – A Pre-Clinical Study

Intracranial aneurysmal subarachnoid hemorrhage (aSAH) is a life-threatening condition requiring immediate neurocritical care. A ruptured aneurysm must be isolated from arterial circulation to prevent rebleeding. Open surgical clipping of the neck of the aneurysm or intra-arterial filling of the aneurysm sack with platinum coils are major treatment strategies in an acute phase. About 40% of the patients suffering from aSAH die within a year of the bleeding despite the intensive treatment. After aSAH, the patient may develop a serious complication called vasospasm. Major risk for the vasospasm takes place at days 5–14 after the primary bleeding. In vasospasm, cerebral arteries contract uncontrollably causing brain ischemia that may lead to death. Nimodipine (NDP) is used to treat of vasospasm and it is administrated intravenously or orally every four hours for 21 days. NDP treatment has been scientifically proven to improve patients’ clinical outcome. The therapeutic effect of L-type calcium channel blocker NDP is due to the ability to dilate cerebral arteries. In addition to vasodilatation, recent research has shown the pleiotropic effect of NDP such as inhibition of neuronal apoptosis and inhibition of microthrombi formation. Indeed, NDP inhibits cortical spreading ischemia. Knowledge of the pathophysiology of the vasospasm has evolved in recent years to a complex entity of early brain injury, secondary injuries and cortical spreading ischemia, instead of being pure intracranial vessel spasm. High NDP levels are beneficial since they protect neurons and inhibit the cortical spreading ischemia. One of the drawbacks of the intravenous or oral administration of NPD is systemic hypotension, which is harmful particularly when the brain is injured. Maximizing the beneficial effects and avoiding systemic hypotension of NDP, we developed a sustained release biodegradable NDP implant that was surgically positioned in the basal cistern of animal models (dog and pig). Higher concentrations were achieved locally and lower concentrations systemically. Using this treatment approach in humans, it may be possible to reduce incidence of harmful hypotension and potentiate beneficial effects of NDP on neurons. Intracellular calcium regulation has a pivotal role in brain plasticity. NDP blocks L-type calcium channels in neurons, substantially decreasing intracellular calcium levels. Thus, we were interested in how NDP affects brain plasticity and tested the hypothesis in a mouse model. We found that NDP activates Brain-derived neurotrophic factor (BDNF) receptor TrkB and its downstream signaling in a reminiscent of antidepressant drugs. In contrast to antidepressant drugs, NDP activates Akt, a major survival-promoting factor. Our group’s previous findings demonstrate that long-term antidepressant treatment reactivates developmental-type of plasticity mechanisms in the adult brain, which allows the remodeling of neuronal networks if combined with appropriate rehabilitation. It seems that NDP has antidepressant-like properties and it is able to induce neuronal plasticity. In general, drug induced neuronal plasticity has a huge potential in neurorehabilitation and more studies are warranted.