Literature review: There is a need for new disease modifying therapies for Alzheimer disease. In order to develop these, animal models with better Alzheimer disease pathology are required. Old rat models like giving scopolamine or MK-801 or using aged rats don't have many of the characteristics of Alzheimer disease although they diminish cognitive functions in different models. Newer models like transgenic and Aβ-injected or -infused rats have much more analogy to the pathology of Alzheimer disease - at least when Aβ-pathophysiology is concerned. Taupathophysiology however doesn't occur in either of the models. On the other hand Aβ has a bigger role in the pathophysiology of Alzheimer disease so it's more important to have that in both models. These two models seem to be quite similar in modelling the disease. Injecting or infusing Aβ to the brain of the rat may be easier to conduct in practice than to create a transgenic rat line. However in transgenic rats Aβ-pathophysiology is developed intracellularly like in Alzheimer disease instead of giving aggregated Aβ outside of the brain. Still both of the models can be used as well to study new therapies especially affecting Aβ-pathophysiology. Experimental part: The purpose of the study was to validate elevated plus-maze (EPM) as a cognition model with a Trial1/Trial2-protocol (T1/T2) in mice. In this experiment a-five-minute-trial was used and thus different parameters related to cognition were measured. The memory of the mice was tried to be disrupted with time delay (1-18 d) between trials or with muscarinic receptor antagonist scopolamine (0.1-0.8 mg/kg i.p.) 30 minutes pre-T1. These experiments were conducted in C57BL/6J- and ICR:(CD-1)-mice. The only group in the time interval experiment that had a trend of forgetting was the 18 d group of ICR:(CD-1)-mice. Thus 21 d interval was also studied, but clear signs of forgetting couldn't be seen. Scopolamine didn't disrupt memory in ICR:(CD-1)-mice but in C57BL/6J-mice it did significantly with doses 0.2-0.8 mg/kg. Based on this 0.2 mg/kg was selected to be used in further studies in C57BL/6J-mice. In this model the nootropic effects of donepezile (0.3, 0.8 and 1.5 mg/kg s.c.), memantine (5.0 and 10.0 mg/kg s.c.) and an experimental 5-HT6-antagonist SB742457 (1.5 and 6.0 mg/kg s.c.) were studied. These compounds were allocated 40 minutes pre-T1 and scopolamine 30 minutes pre-T1. Memantine (5.0 mg/kg) clearly and donepezile (1.5 mg/kg) with a strong trend enhanced cognition disrupted by scopolamine. These results suggest that EPM can be used when testing nootropic effects.

Objective. Difficulties in naming are common already in the very early stages of Alzheimer's Disease, and the difficulties increase as the disease progresses. There are few studies of naming errors in confrontation naming tests by Finnish persons with Alzheimer's disease to date. The purpose of this study was to examine the naming errors and correction attempts produced in the Boston Naming Test (BNT) by Finnish speaking persons with mild and moderate Alzheimer's disease, and how those naming errors and correction attempts change both quantitatively and qualitatively as the disease progresses. Methods. Participants in this study were Finnish speaking persons with mild (n=20) and moderate (n=20) Alzheimer's disease, and healthy age-matched controls (n=30). Participants were given the Boston Naming Test in 1994–1997. Patients with probable Alzheimer's disease came from the Memory Research Unit of the Department of Neurology, Helsinki University Hospital. Control subjects were volunteers from the Helsinki Aging Brain Study which started in 1989, and the controls were chosen from various age groups (55, 60, 65, 70, 75, and 80 years) by random sampling. All the participants underwent complete neurological and neuropsychological examinations. Naming errors and correction attempts produced in the BNT were classified, and the scores were analyzed with the non-parametric Kruskal-Wallis one-way analysis of variance, as well as with chi-square test and Mann-Whitney U test for post hoc pairwise comparisons between groups. Results and conclusions. Compared to healthy age-matched controls, patients with Alzheimer's disease made more naming errors and naming attempts, the number of which increased distinctly as the severity of the disease progressed. Several kinds of semantic naming errors were the most common errors in all three study groups. Patients with Alzheimer's disease gave a particularly large number of descriptions of the target word, as well as unrelated answers. The results show that naming errors change both quantitatively and qualitatively in the course of Alzheimer's disease, and the changes continue as the disease progresses. These results are congruent with earlier studies. A new observation in this study was that during confrontation naming the quantity of empty speech which was included in the correction attempts was almost twice as high in the group with mild Alzheimer's disease compared to healthy controls. Future research is needed to detect at which point of the trajectory of Alzheimer's disease the aforementioned changes are observable.

Tutkimuksessa tarkastellaan dementiakuolleisuutta sekä siihen vaikuttavia sosiaalisia tekijöitä. Dementia on oireyhtymä, jota pääasiassa sairastavat yli 65-vuotiaat henkilöt. Väestön ikääntyessä sekä elinajanodotteen kasvaessa on odotettavissa, että dementiaa sairastavien määrä tulee kasvamaan merkittävästi lähivuosina. On viitteitä siitä, että dementiaan sairastumisen riskiin vaikuttavat erilaiset sosiaaliset tekijät kuten koulutus, mutta varsinkin dementiakuolleisuudesta tiedetään vähän. Tutkielman aineistona käytettiin Tilastokeskuksen muodostamaa Elinolot ja kuolinsyyt -rekisteriaineistoa, joka koostuu väestölaskentatiedoista sekä työssäkäyntitilaston pitkittäisaineistosta, johon on liitetty kuolinsyytietoja. Peruskuolinsyyn lisäksi aineistossa oli tieto korkeintaan kolmesta myötävaikuttavasta syystä. Dementiakuolleisuuden on esitetty aliarvioituvan peruskuolinsyynä, joten dementiakuolleisuuden määrittelyssä käytettiin myös tietoa myötävaikuttavista syistä. Rajausten jälkeen aineistossa on 317 944 henkilöä, joista 128 562 on miehiä ja 189 382 naisia. Pääanalyysimenetelmänä on käytetty elinaikamalleihin kuuluvaa Coxin regressiota. Dementiakuolleisuudessa oli vaihtelua kaikkien tutkimuksessa käytettyjen muuttujien, eli koulutuksen, sosiaaliluokan, tulojen, siviilisäädyn sekä perhemuodon mukaan. Koulutuksen vaikutus välittyi osin ammattiasemaan perustuvan sosiaaliluokan kautta. Suurimpia ryhmien väliset suhteelliset erot olivat nuoremmissa ikäryhmissä sekä sosiaaliluokan ja siviilisäädyn kohdalla. Eronneilla ja naimattomilla oli selvästi kohonnut riski suhteessa naimisissa oleviin. Myös työntekijöillä havaittiin kohonnut riski suhteessa ylempiin toimihenkilöihin. Siviilisääty vaikutti olevan merkittävä tekijä siinä mielessä, että koulutuksen, sosiaaliluokan ja tulojen tuominen malliin ei juuri vaikuttanut siviilisäätyryhmien välillä havaittuun vaihteluun. Dementiakuolleisuudessa havaitut ryhmien väliset suhteelliset erot olivat hieman pienempiä kuin muissa syissä, mutta kuitenkin hyvin samaa suuruusluokkaa. Tulosten perusteella on identifioitavissa tekijöitä, jotka suojaavat dementialta. Erityisesti avioliitto, korkea koulutus sekä ylemmät toimihenkilöammatit vaikuttavat olevan dementialta suojaavia tekijöitä. Avioliiton suojaavan vaikutuksen voidaan tulkita liittyvän sosiaaliseen kanssakäymiseen sekä puolison tukeen ja läsnäoloon. Korkea koulutus sekä toimihenkilöammatit indikoivat virikkeellisempää työympäristöä, mutta niiden vaikutus voi myös kulkea ylipäänsä aktiivisemman ja kognitiivisesti virikkeellisemmän elämäntavan kautta. Aktiivisen ja kognitiivisesti haastavan elämäntavan on esitetty suojaavan dementiaan sairastumiselta. Tuloksia voidaan tulkita elämänkaarinäkökulman kautta. Jo nuoruudessa vaikuttavilla tekijöillä, kuten koulutuksella, on vaikutusta. Tämän lisäksi elämänkaaren aikana myöhemmin vaikuttavat tekijät ovat merkityksellisiä. Näiden tekijöiden on esitetty vaikuttavan aivojen hermoverkostoon ja -yhteyksiin ja luovan kognitiivista reserviä, minkä on esitetty ehkäisevän tai lykkäävän dementiaan sairastumista.

Background: Development of cognitive abilities involves both environmental and genetic factors. Childhood socioeconomic status (SES) associates with cognitive abilities later in life; however there is only little research on the interaction of SES and genes on cognitive ability. Specific genomic loci associating with cognitive abilities are scarce and potential candidates might be genetic variants linked with Alzheimer's disease such as APOE ε4 isomorph and rs405509 located in the APOE promoter region. I studied how childhood SES and APOE ε4 and rs405509 and their interactions associate with cognitive abilities in late adulthood in the Helsinki Birth Cohort Study (HBCS) sample. Methods: The participants of this study consisted of 607 men belonging to the HBCS who were born in Helsinki, Finland between 1934 and 1944. They participated in the test for general cognitive abilities at the average age of 68, and who were successfully genotyped. Associations and interactions of childhood SES, APOE and rs405509 on cognitive ability were studied. Results and conclusions: Lower childhood SES associated with lower verbal subscale score and total score. APOE ε4 was not independently associated with cognitive abilities. The number of G-alleles in rs405509 associated with lower verbal subscale score and total score when adjusted for age, but no longer after adjusting for adulthood SES. Interactions of rs405509 and childhood SES were not associated with cognitive ability. Socioeconomically less advantaged childhood environment has long-term consequences on cognitive abilities, and the effects last until late adulthood. The study suggests that rs405509 G-allele might have an independent effect on cognitive ability before the outset of Alzheimer's disease, but the results require further replication with larger sample size.

Alzheimer’s disease is the most common type of dementia in Finland. Very early on, it can impair the linguistic and cognitive abilities. Dysgraphia, the disorder in writing, is a common symptom in Alzheimer’s disease. There has been little research on dysgraphia and texts written by people suffering from dementia in Finland, and presumably no research has been done previously regarding the cohesion of written texts. The aim of this study is to examine, if the number of cohesive devices, the linguistic devices creating cohesion, changes in the diary entries written by a person with Alzheimer’s disease as the disease progresses, and if it is possible to see the outset of the possible changes. The data of this study were the diaries written by a person with Alzheimer’s disease during the years 1967–2012. The diary entries written in June 1986, 1991, 1996, 2001, 2006, 2008, 2010 and 2012 were selected for the analysis. The number of grammatical and lexical cohesive devices as well as the number of exophoric pronouns or the pronouns referring to the extralinguistic situation in the diary entries was counted. The IBM SPSS Statistics 24 program was used for the quantitative analysis of the data. A scatter diagram of the number of the cohesive devices was created, and a line of best fit was added to the diagram in order to demonstrate the temporal changes. The correlation between the number of cohesive devices and years was measured with Spearman’s rho or Spearman’s rank correlation coefficient. The study showed that the number of all grammatical cohesive devices, exophora, anaphora or the expression that depends upon an antecedent expression and reiteration seemed to have increased as time passed by. The number of all lexical cohesive devices, collocation or the semantically related words and ellipsis or the omission of words seemed to have decreased. The results were not statistically significant. The changes seemed to have begun year 2001, but the result was inaccurate, because the data varied considerably. The writing style of the person with Alzheimer’s disease resembled note taking, which influenced the occurrence of cohesive devices. Examining the spontaneously written texts by people with dementia provides more knowledge of the effects of dementia on the linguistic abilities and the possibility to develop diagnostic tools for the speech-language pathologists.

Objectives. The semantic fluency task is a widely used clinical tool for diagnosing Alzheimer’s disease (AD). Performance differences between semantic categories such as animals versus tools have been widely studied, but in the present study, we examine finer-grained performance within the animal-category. We compare amnestic Mild Cognitive Impairment (aMCI) and very early AD patients with healthy controls to investigate whether the groups move in semantic space differently and examine whether the patient groups exhibit decline in discrimination of semantically similar objects, which is putatively a very early sign of AD. Methods. In the semantic fluency task, participants (42 healthy, 24 aMCI, 18 AD) named as many animals as they could within a minute. We condensed the semantic space using a dimensionality reduction algorithm (t-SNE) on the word2vec vector-model. Sub-categories were formed of the t-SNE result based on visual inspection. Moving in semantic space was estimated with the number of words, sub-categories, and switches and returns to sub-categories. Multinomial logistic regression models were used to predict the diagnostic group with these independent variables. Results and conclusions. We discovered eight meaningful sub-categories inside the animal-category and found differences between groups in how they utilised the semantic space. Our results did not provide direct support for decline in processing semantically similar objects in prodromal AD. In classifying the groups, only returning to sub-category provided additional information on top of the number of words produced. Our findings provide new perspectives on navigation in sub-category level fine-grained semantic space in the context of prodromal AD.

Neuronal nicotinic receptors are widely expressed throughout the brain and they facilitate fast synaptic neurotransmission. They are also involved in regulation of the release of other neurotransmitters like GABA, dopamine and glutamate. The most common subtypes are alfa4beta2 and alfa7 subunits containing receptors. Neuronal nicotinic receptors are involved in nicotine addiction but also in many neurological diseases like Alzheimer's disease, schizophrenia, depression and attention deficit/hyperactivity disorder. The cholinergic stimulation enhances cognition in vivo and in human. There is not many drugs on the market that act via nicotinic receptors but many drug companies have new nicotinic agonists and antagonist under clinical research. When using nicotinic receptor agonists the problem is desensitization, which occurs in alfa7 nicotinic receptor rapidly after agonist exposure. When desensitized the receptor no longer responds to agonist even if it is there available to bind to receptor. The desensitization may lead to tachyphylaxis and losing of the clinical effect. Conventional agonists, like acetylcholine, bind to the binding site located in the extracellular part on nicotinic receptor subunit. There is also some other binding sites, which are called allosteric binding sites. It has been found out, that allosterically binding ligands, for example PNU-120596, can cause potentiation of agonist induced responses and/or prevent desensitization of receptor. These kinds of agents are called positive allosteric modulators and they are considered to be a new therapeutic option for CNS diseases containing cholinergic deficits. The mechanism of action of positive allosteric modulators is so far unclear. The purpose of my study was to characterize positive allosteric modulators on alfa7 nicotinic receptor. It had been found out earlier in the Millar laboratory that mutation L247T in the transmembrane domain converts positive allosteric modulators to agonists. The aim was to use site-directed mutagenesis to generate mutation in the agonist-binding site of alfa7 and alfa7L247T receptors and see how it effects on the ability of PNU-120596 to act as an agonist on the receptor. Second aim was to generate a mutation in the transmembrane part of the receptor to an assumed binding site of allosteric potentiators' and test how it effects on allosteric potentiator's ability to act as an agonist on the alfa7L247T. Mutated receptors were expressed on oocytes by microinjeting the mRNA into oocyte. The function of receptors was studied with electrophysiology using two-electrode voltageclamp technique. All the mutations were successfully inserted in nicotinic receptor alfa7 and alfa7L247T. Mutation in orthosteric agonist binding site had a very profound effect on wild type alfa7 receptor; it had an effect on either acetylcholine binding or receptor gating. It was not possible to record any proper responses neither with acetylcholine nor with PNU-120596. In the double-mutated receptor alfa7W149M/L247T the W149M mutation had a much greater effect on dose-response curves than it had on PNU-120596 curves compared with alfa7L247T. The transmembrane domain mutation M253L did not have much effect on PNU-120596's ability to act as an agonist to alfa7L247T and either it did not effect on acetylcholine dose-response curves. The results from this study support the previous results that the binding site of positive allosteric modulators is located in the transmembrane domain of the alfa7 receptor. The results are little controversial with the M253L mutation but because the L247T mutation has so profound effect on the function on alfa7 receptor it might be that it masks the other mutation which is located quite close to it. On the other hand it might be so that the amino acid M253 has only effect on the receptor's ability to be potentiated not the allosteric binding.

Objectives. Studies have shown that word finding difficulties form a significant trouble source in speech of individuals with moderate Alzheimer's disease (AD). However systematic research has focused typically in naming tests even though managing in test situations does not reveal how word finding difficulties really affect in conversational interaction. Analysis of conversation have shown that continuing word finding difficulties complicates person's possibilities to participate in an interaction. The aim of this study is to report what kind of word searches appear in a conversational interaction of individuals with moderate AD. Using conversation analytic approach this study focuses on what kind of traits typically appear in word searches and how speakers deal with word searches. Methods. Participants of this study were four individuals with moderate AD who participated in a conversation group. Database was formed from two filmed appointments and the total duration was 70 minutes 16 seconds. Conversation group appointments were held by two speech and language therapist students and their instructor. Appointments were transcribed and word searches were identified by using verbal and nonverbal traits that indicates word search. Using conversation analytic approach word searches were analyzed and each indicating trait was classified. Results and conclusions. Nearly three thirds of all word searches found in this data were solved successfully. Approximately half of them were solved by the speaker with AD himself and a bit less than fifth of word searches were solved in co-operation with the communication partner. However solution was not always completing target word but reformulating the trouble source or elaboration made by the communication partner. Around fourth of word searches were left unsolved and persons with AD had great difficulties to handle the trouble source. This study has given knowledge about conversational interaction of individuals with moderate AD and results highlights the significance of conversation partner in maintaining a conversation.

Alzheimer's disease is a neurodegenerative brain disease and it is the leading cause of dementia worldwide. However, there are not any medical treatments available to slow down or cure the disease. The typical microscopic changes in Alzheimer patients' brain are extracellular amyloid deposits and intracellular neurofibrillary tangles. Serine/threonine kinases are protein kinases that take part in the regulation of cellular functions. At least protein kinase C (PKC), glycogen synthase kinase 3 (GSK-3), cyclin-dependent kinase 5 (CDK5) and Ca2+/calmodulin-dependent protein kinase II (CaMKII) are involved in the pathogenesis of Alzheimer's disease. There are currently molecules in development that either activate or inhibit these protein kinases in order to stop the progression of the disease. PKC is an interesting kinase considering this project. It has been shown that PKC activation prevents the formation of amyloid deposits and protects neurons from premature death. This could slow down or prevent the progression of the disease. The purpose of this study was to investigate the effects of dialkyl 5-(hydroxy-methyl)isophthalates (HMI-1a3 and HMI-1b11) on SH-SY5Y-neuroblastoma cell proliferation and morphology with live cell imaging and to Alzheimer's disease-related Wnt, ERK1/2 and PKC signaling pathways with Western blotting. The main purpose was to evaluate the potential of the compounds for further in vitro and in vivo experiments. According to the results of this study both isophthalates, HMI-1a3 and HMI-1b11, had good binding affinities to PKCα and PKCδ. Both of them caused a dramatic increase in ERK1/2 phosphorylation which may be due to PKC activation and may thus suggest a PKC-dependent mechanism of action. However, the possible PKC activation did not cause downregulation of the PKC-isoforms α, β and δ. In addition, both HMI-1a3 and HMI-1b11 inhibited SH-SY5Y cell proliferation. HMI-1a3 was cytotoxic at 20 µM, while HMI-1b11 did not cause any cell death. Both compounds also induced neurite outgrowth. In addition, HMI-1a3 increased the amount of β-catenin. That could indicate the activation of Wnt-signaling, which is inhibited in Alzheimer's disease. Both of the compounds have potential for further studies because of the good binding to PKC and the beneficial effects on neurite outgrowth and Wnt signaling.

Goals. Event schema or a script is a knowledge structure that describes appropriate sequences of events in a particular context. Script contains components which are vertically and horizontally connected to each other. A person may learn about scripts by personal experience, reading about them, hearing about them and seeing them done. Therefore, scripts contain information from episodic and semantic memory. Script research provides information about memory functions and the representation and the damage of the systems in different diseases affecting the neural systems, such as in Alzheimer's disease (AD). With increasing theoretical knowledge it is possible to develop differential diagnostic and rehabilitation methods for the patients in clinical work. The purpose of the study is to examine the script production of two different scripts in the mild and moderate stage of AD. Methods. The material of AD patients was gathered in 1994-1997 at the Department of Neurology (Memory Clinic) of the Helsinki University Central Hospital. The normal control subjects were from the pool of participants of the Helsinki Aging Brain Study which started in 1989. Ten people with mild AD (LiAT), ten with moderate AD (KoAT) and ten matched normal controls (NoI) were asked to produce as many script events as possible for two scripts: What do you do between waking up and having lunch? (The Morning script) representing episodic memory and What happens at a doctor's appointment? (The Doctor script) representing semantic memory. Sixty seconds were allotted for each script. The scripts were scored for the total number of events, the number of event repetitions, the informativeness of the contents and the plausibility and the centrality of the events. Statistical methods used were the Kruskal-Wallis one way variance analysis and the Mann-Whitney U –test post hoc –test. Results and conclusions. The results showed that the number of events for the both script types was statistically significantly lower for the people with AD compared to the control group. In addition, the ratio of informativeness was statistically significantly poorer for the people with AD. Depending on the script type, people with AD produced less plausible and central events than the control group. The results of the study are consistent in many aspects with the literature and the studies of AD suggesting that episodic memory is first impaired in AD, followed by the impairment of semantic memory.