Verbal learning in mild cognitive impairment and alzheimer's disease : behavioural and neural approaches

The main focus of the present thesis was at verbal episodic memory processes that are particularly vulnerable to preclinical and clinical Alzheimer’s disease (AD). Here these processes were studied by a word learning paradigm, cutting across the domains of memory and language learning studies. Moreover, the differentiation between normal aging, mild cognitive impairment (MCI) and AD was studied by the cognitive screening test CERAD. In study I, the aim was to examine how patients with amnestic MCI differ from healthy controls in the different CERAD subtests. Also, the sensitivity and specificity of the CERAD screening test to MCI and AD was examined, as previous studies on the sensitivity and specificity of the CERAD have not included MCI patients. The results indicated that MCI is characterized by an encoding deficit, as shown by the overall worse performance on the CERAD Wordlist learning test compared with controls. As a screening test, CERAD was not very sensitive to MCI. In study II, verbal learning and forgetting in amnestic MCI, AD and healthy elderly controls was investigated with an experimental word learning paradigm, where names of 40 unfamiliar objects (mainly archaic tools) were trained with or without semantic support. The object names were trained during a 4-day long period and a follow-up was conducted one week, 4 weeks and 8 weeks after the training period. Manipulation of semantic support was included in the paradigm because it was hypothesized that semantic support might have some beneficial effects in the present learning task especially for the MCI group, as semantic memory is quite well preserved in MCI in contrast to episodic memory. We found that word learning was significantly impaired in MCI and AD patients, whereas forgetting patterns were similar across groups. Semantic support showed a beneficial effect on object name retrieval in the MCI group 8 weeks after training, indicating that the MCI patients’ preserved semantic memory abilities compensated for their impaired episodic memory. The MCI group performed equally well as the controls in the tasks tapping incidental learning and recognition memory, whereas the AD group showed impairment. Both the MCI and the AD group benefited less from phonological cueing than the controls. Our findings indicate that acquisition is compromised in both MCI and AD, whereas long13 term retention is not affected to the same extent. Incidental learning and recognition memory seem to be well preserved in MCI. In studies III and IV, the neural correlates of naming newly learned objects were examined in healthy elderly subjects and in amnestic MCI patients by means of positron emission tomography (PET) right after the training period. The naming of newly learned objects by healthy elderly subjects recruited a left-lateralized network, including frontotemporal regions and the cerebellum, which was more extensive than the one related to the naming of familiar objects (study III). Semantic support showed no effects on the PET results for the healthy subjects. The observed activation increases may reflect lexicalsemantic and lexical-phonological retrieval, as well as more general associative memory mechanisms. In study IV, compared to the controls, the MCI patients showed increased anterior cingulate activation when naming newly learned objects that had been learned without semantic support. This suggests a recruitment of additional executive and attentional resources in the MCI group.

Mild Cognitive Impairment and Early Detection of Alzheimer`s Disease. A Positron Emission Tomography Study

Alzheimer`s disease (AD) is characterised neuropathologically by the presence of extracellular amyloid plaques, intraneuronal neurofibrillary tangles, and cerebral neuronal loss. The pathological changes in AD are believed to start even decades before clinical symptoms are detectable. AD gradually affects episodic memory, cognition, behaviour and the ability to perform everyday activities. Mild cognitive impairment (MCI) represents a transitional state between normal aging and dementia disorders, especially AD. The predictive accuracy of the current and commonly used MCI criteria devide this disorder into amnestic (aMCI) and non-amnestic (naMCI) MCI. It seems that many individuals with aMCI tend to convert to AD. However many MCI individuals will remain stable and some may even recover. At present, the principal drugs for the treatment of AD provide only symptomatic and palliative benefits. Safe and effective mechanism-based therapies are needed for this devastating neurodegenerative disease of later life. In conjunction with the development of new therapeutic drugs, tools for early detection of AD would be important. In future one of the challenges will be to detect at an early stage these MCI individuals who will convert to AD. Methods which can predict which MCI subjects will convert to AD will be much more important if the new drug candidates prove to have disease-arresting or even disease–slowing effects. These types of drugs are likely to have the best efficacy if administered in the early or even in the presymptomatic phase of the disease when the synaptic and neuronal loss has not become too widespread. There is no clinical method to determine with certainly which MCI individuals will progress to AD. However there are several methods which have been suggested as predictors of conversion to AD, e.g. increased [11C] PIB uptake, hippocampal atrophy in MRI, low CSF A beta 42 level, high CSF tau-protein level, apolipoprotein E (APOE) ε4 allele and impairment in episodic memory and executive functions. In the present study subjects with MCI appear to have significantly higher [¹¹C] PIB uptake vs healthy elderly in several brain areas including frontal cortex, the posterior cingulate, the parietal and lateral temporal cortices, putamen and caudate. Also results from this PET study indicate that over time, MCI subjects who display increased [¹¹C] PIB uptake appear to be significantly more likely to convert to AD than MCI subjects with negative [¹¹C] PIB retention. Also hippocampal atrophy seems to increase in MCI individuals clearly during the conversion to AD. In this study [¹¹C] PIB uptake increases early and changes relatively little during the AD process whereas there is progressive hippocampal atrophy during the disease. In addition to increased [¹¹C] PIB retention and hippocampal atrophy, the status of APOE ε4 allele might contribute to the conversion from MCI to AD.

Geneettisten ja ympäristötekijöiden merkitys toiminnanvajausten kehittymisessä - The Finnish Twin Study on Aging (FITSA)

Summary: Genetic and environmental factors in the disablement process. The Finnish Twin Study on Aging (FITSA)

Paperin hydrofobiliimauksen purkautumiseen vaikuttavat mekanismit

Työssä tutkittiin liimauksen reversiota ja häviämistä erilaisilla hydrofobiliimoilla alkaalisessa paperinvalmistuksessa käytettävien täyteaineiden kanssa. Liimauksen reversiota ja häviämistä arvioitiin arkkimuotilla valmistetuista koearkeista mittaamalla hydrofobiliimautuneisuutta kuvaavia ominaisuuksia kuten raakareunan absorptio ja kontaktikulma. Liimauksen reversiota kiihdytettiin lämpökäsittelyllä ja UV-säteilytyksellä. Liimauksen häviämistä tutkittiin muuttamalla viiraveden alkaalisuutta ja käyttämällä kalsiumkarbonaattia täyteaineena. Verrattaessa käytettyjä hydrofobiliimoja ASA1+AKD -liimayhdistelmällä ja AKD -liimauksella saavutettiin paperille paras liimautuneisuus. ASA2 -liimauksella saavutettiin paperille parempi liimautuneisuus kuin ASA1 -liimalla. Kalsiumkarbonaatilla täytetyillä arkeilla mitattiin korkeampi liimautuneisuus kuin kaoliinilla täytetyillä arkeilla. Kokeellisessa osassa tutkittiin myös 4 tuntia kestävän 105°C lämpökäsittelyn ja UV-säteilytyksen sekä viiraveden alkaalisuuden vaikutusta hydrofobiliimauksen reversioon ja häviämiseen. Liimauksen reversiota aikaansai UV-säteily ja lämpökäsittely. UV-säteily ja lämpökäsittely näyttävät aikaansaavan kovalenttisen esterisidoksen katkeamisen tai hydrolysoitumisen liimamolekyylin ja selluloosan karboksyyliryhmän välillä. Liimauksen reversiota havaittiin jokaisella hydrofobiliimalla. Liimauksen häviämistä aikaansai korkea viiraveden alkaalisuus (520 ppm CaCO3). Liimauksen häviämisen aiheuttamaa alhaisempaa liimautuneisuutta havaittiin myös viiraveden alkaalisuuden ollessa normaalia tasoa (250 ppm CaCO3), kun täyteaineena käytettiin saostettua kalsiumkarbonaattia.

Sleep and Menopause. Hormone Therapy and Sleep Deprivation

This study evaluated the effect of menopause, hormone therapy (HT) and aging on sleep. Further, the mechanisms behind these effects were examined by studying the associations between sleep and the nocturnal profiles of sleep-related hormones. Crosssectional study protocols were used to evaluate sleep in normal conditions and during recovery from sleep deprivation. The effect of initiation of HT on sleep and sleeprelated hormones was studied in a prospective controlled trial. Young, premenopausal and postmenopausal women were studied, and the methods included polysomnography, 24-h blood sampling, questionnaires and cognitive tests of attention. Postmenopausal women were less satisfied with their sleep quality than premenopausal women, but this was not reflected in sleepiness or attention. The objective sleep quality was mainly similar in pre- and postmenopausal women, but differed from young women. The recovery mechanisms from sleep deprivation were relatively well-preserved after menopause. HT offered no advantage to sleep after sleep deprivation or under normal conditions. The decreased growth hormone (GH) and prolactin (PRL) levels after menopause were reversible with HT. Neither menopause nor HT had any effect on cortisol levels. In premenopausal women, HT had only minor effects on PRL and cortisol levels. The temporal link between GH and slow wave sleep (SWS) was weaker after menopause. PRL levels were temporally associated with sleep stages, and higher levels were seen during SWS and lower during rapid-eye-movement (REM) sleep. Sleep quality after menopause is better determined by age than by menopausal state. Although HT restores the decreased levels of GH and PRL after menopause, it offers no advantage to sleep quality under normal conditions or after sleep deprivation.

Study of mesoscopic tunnel junctions between two normal metals

The main purpose of this work was to study different kinds of metal-based tunnel junctions at low temperatures. The problem which had to be solved was creating a junction with appropriate properties at these temperatures. The materials for junctions were found experimentally. The goal was to find an alloy material that can provide a high quality tunnel junction, which remains in the normal conductive state at low temperatures without applying magnetic field. The fabrication technology of such a device, based on an alloy of aluminium and manganese, is described in detail. In this thesis theoretical properties of tunnel junctions are considered and results of experiments with tunnel junctions are described and quantitative properties of the junctions are analyzed based on the experimental data.

Aging based maintenance and reinvestment scheduling of electric distribution

The maintenance of electric distribution network is a topical question for distribution system operators because of increasing significance of failure costs. In this dissertation the maintenance practices of the distribution system operators are analyzed and a theory for scheduling maintenance activities and reinvestment of distribution components is created. The scheduling is based on the deterioration of components and the increasing failure rates due to aging. The dynamic programming algorithm is used as a solving method to maintenance problem which is caused by the increasing failure rates of the network. The other impacts of network maintenance like environmental and regulation reasons are not included to the scope of this thesis. Further the tree trimming of the corridors and the major disturbance of the network are not included to the problem optimized in this thesis. For optimizing, four dynamic programming models are presented and the models are tested. Programming is made in VBA-language to the computer. For testing two different kinds of test networks are used. Because electric distribution system operators want to operate with bigger component groups, optimal timing for component groups is also analyzed. A maintenance software package is created to apply the presented theories in practice. An overview of the program is presented.

Normal Mannesmann-Mulag kardanvagn

kuv., 24 x 16 cm

M.A.N. normal 2-2 1/2 tons lastvagn

kuv., 23 x 16 cm

Normal Mannesmann-Mulag kedjevagn

kuv., 23 x 16 cm

Normal Mannesmann-Mulag 5-tons lastvagn

kuv., 23 x 16 cm

Radio-frequency-based measurement methods for bearing current analysis in induction motors

The most common reason for a low-voltage induction motor breakdown is a bearing failure. Along with the increasing popularity of modern frequency converters, bearing failures have become the most important motor fault type. Conditions in which bearing currents are likely to occur are generated as a side effect of fast du/dt switching transients. Once present, different types of bearing currents can accelerate the mechanical wear of bearings by causing deformation of metal parts in the bearing and degradation of the lubricating oil properties.The bearing current phenomena are well known, and several bearing current measurement and mitigation methods have been proposed. Nevertheless, in order to develop more feasible methods to measure and mitigate bearing currents, better knowledge of the phenomena is required. When mechanical wear is caused by bearing currents, the resulting aging impact has to be monitored and dealt with. Moreover, because of the stepwise aging mechanism, periodically executed condition monitoring measurements have been found ineffective. Thus, there is a need for feasible bearing current measurement methods that can be applied in parallel with the normal operation of series production drive systems. In order to reach the objectives of feasibility and applicability, nonintrusive measurement methods are preferred. In this doctoral dissertation, the characteristics and conditions of bearings that are related to the occurrence of different kinds of bearing currents are studied. Further, the study introduces some nonintrusive radio-frequency-signal-based approaches to detect and measure parameters that are associated with the accelerated bearing wear caused by bearing currents.

Spin Polarization and Normal Reflection at Nanoscale Point Contacts

This thesis presents point-contact measurements between superconductors (Nb, Ta, Sn,Al, Zn) and ferromagnets (Co, Fe, Ni) as well as non-magnetic metals (Ag, Au, Cu, Pt).The point contacts were fabricated using the shear method. The differential resistanceof the contacts was measured either in liquid He at 4.2 K or in vacuum in a dilutionrefrigerator at varying temperature down to 0.1 K. The contact properties were investigatedas function of size and temperature. The measured Andreev-reflection spectrawere analysed in the framework of the BTK model – a three parameter model that describescurrent transport across a superconductor - normal conductor interface. Theoriginal BTK model was modified to include the effects of spin polarization or finitelifetime of the Cooper pairs. Our polarization values for the ferromagnets at 4.2 K agree with the literature data, but the analysis was ambiguous because the experimental spectra both with ferromagnets and non-magnets could be described equally well either with spin polarization or finite lifetime effects in the BTK model. With the polarization model the Z parametervaries from almost 0 to 0.8 while the lifetime model produces Z values close to 0.5. Measurements at lower temperatures partly lift this ambiguity because the magnitude of thermal broadening is small enough to separate lifetime broadening from the polarization. The reduced magnitude of the superconducting anomalies for Zn-Fe contacts required an additional modification of the BTK model which was implemented as a scaling factor. Adding this parameter led to reduced polarization values. However, reliable data is difficult to obtain because different parameter sets produce almost identical spectra.

Formin proteins in normal tissues and cancer

The actin cytoskeleton is a dynamic structure that determines cell shape. Actin turnover is mandatory for migration in normal and malignant cells. In epithelial cancers invasion is frequently accompanied by epithelial to mesenchymal transition (EMT). In EMT, cancer cells acquire a migratory phenotype through transcriptional reprogramming. EMT requires substantial re-organization of actin. During the past decade, new actin regulating proteins have been discovered. Among these are members of the formin family. To study formin expression in tissues and cells, antibodies for detection of formin proteins FMNL1 (Formin-like protein 1), FMNL2 (Formin-like protein 2) and FHOD1 (Formin homology 2 domain containing protein 1) were used. The expression of formins was characterized in normal tissues and selected cancers using immunohistochemistry. The functional roles of formins were studied in cancer cell lines. We found that FMNL2 is widely expressed. It is a filopodial component in cultured melanoma cells. In clinical melanoma, FMNL2 expression has prognostic significance. FHOD1 is a formin expressed in mesenchymal cell types. FHOD1 expression is increased in oral squamous cell carcinoma (SCC) EMT. Importantly, FHOD1 participates in invasion of cultured oral SCC cells. FMNL1 expression is low in normal epithelia, but high in leukocytes and smooth muscle cells. Expression of FMNL1 can be found in carcinoma; we detected FMNL1 expressing cells in basal type of breast cancer. Our results indicate that formins are differentially expressed in normal tissues and that their expression may shift in cancer. Functionally FMNL2 and FHOD1 participate in processes related to cancer progression. Studying formins is increasingly important since they are potential drug targets.