Genetically Determined Hypometabolism in Alzheimer’s Disease and Midlife Risk Factors for Cognitive Impairment

The role of genetic factors in the pathogenesis of Alzheimer’s disease (AD) is not completely understood. In order to improve this understanding, the cerebral glucose metabolism of seven monozygotic and nine dizygotic twin pairs discordant for AD was compared to that of 13 unrelated controls using positron emission tomography (PET). Traditional region of interest analysis revealed no differences between the non-demented dizygotic co-twins and controls. In contrast, in voxel-level and automated region of interest analyses, the non-demented monozygotic co-twins displayed a lower metabolic rate in temporal and parietal cortices as well as in subcortical grey matter structures when compared to controls. Again, no reductions were seen in the non-demented dizygotic co-twins. The reductions seen in the non-demented monozygotic co-twins may indicate a higher genetically mediated risk of AD or genetically mediated hypometabolism possibly rendering them more vulnerable to AD pathogenesis. With no disease modifying treatment available for AD, prevention of dementia is of the utmost importance. A total of 2 165 at least 65 years old twins of the Finnish Twin Cohort with questionnaire data from 1981 participated in a validated telephone interview assessing cognitive function between 1999 and 2007. Those subjects reporting heavy alcohol drinking in 1981 had an elevated cognitive impairment risk over 20 years later compared to light drinkers. In addition, binge drinking was associated with an increased risk even when total alcohol consumption was controlled for, suggesting that binge drinking is an independent risk factor for cognitive impairment. When compared to light drinkers, also non-drinkers had an increased risk of cognitive impairment. Midlife hypertension, obesity and low leisure time physical activity but not hypercholesterolemia were significant risk factors for cognitive impairment. The accumulation of risk factors increased cognitive impairment risk in an additive manner. A previously postulated dementia risk score based on midlife demographic and cardiovascular factors was validated. The risk score was found to well predict cognitive impairment risk, and cognitive impairment risk increased significantly as the score became higher. However, the risk score is not accurate enough for use in the clinic without further testing.

New [18F]Tracers for Alzheimer's Disease Imaging. Labeling Synthesis And Biological Testing

Alzheimer’s disease (AD) is the most common form of dementia. Characteristic changes in an AD brain are the formation of β-amyloid protein (Aβ) plaques and neurofibrillary tangles, though other alterations in the brain have also been connected to AD. No cure is available for AD and it is one of the leading causes of death among the elderly in developed countries. Liposomes are biocompatible and biodegradable spherical phospholipid bilayer vesicles that can enclose various compounds. Several functional groups can be attached on the surface of liposomes in order to achieve long-circulating target-specific liposomes. Liposomes can be utilized as drug carriers and vehicles for imaging agents. Positron emission tomography (PET) is a non-invasive imaging method to study biological processes in living organisms. In this study using nucleophilic 18F-labeling synthesis, various synthesis approaches and leaving groups for novel PET imaging tracers have been developed to target AD pathology in the brain. The tracers were the thioflavin derivative [18F]flutemetamol, curcumin derivative [18F]treg-curcumin, and functionalized [18F]nanoliposomes, which all target Aβ in the AD brain. These tracers were evaluated using transgenic AD mouse models. In addition, 18F-labeling synthesis was developed for a tracer targeting the S1P3 receptor. The chosen 18F-fluorination strategy had an effect on the radiochemical yield and specific activity of the tracers. [18F]Treg-curcumin and functionalized [18F]nanoliposomes had low uptake in AD mouse brain, whereas [18F]flutemetamol exhibited the appropriate properties for preclinical Aβ-imaging. All of these tracers can be utilized in studies of the pathology and treatment of AD and related diseases.

Kotona asuvan muistipotilaan läheisen sosiaali- ja terveyspalvelujen käyttö

Tutkimuksen tarkoituksena oli kuvata kotona asuvan muistipotilaan läheisen sosiaali- ja terveyspalvelujen käyttöä. Tavoitteena oli selvittää, miten muistipotilaaseen ja hänen läheiseensä itseensä liittyvät tekijät ovat yhteydessä muistipotilaan läheisen sosiaali- ja terveyspalvelujen käyttöön. Tutkimus oli osa Euroopan Unionin rahoittamaa RightTi-mePlaceCare -tutkimusprojektia (FP7-Health-F3-2010–242153). Tutkimuksen kohderyhmän muodostivat säännöllisen kotihoidon piirissä olevat yli 65-vuotiaat muistipotilaat sekä heidän läheiset (N=182). Tutkimus toteutettiin Varsinais-Suomessa kolmen kaupungin alueelta tarkoituksenmukaista otantaa käyttäen. Aineisto kerättiin 19.11.2010–29.2.2012 välisenä aikana muistipotilaiden kotona haastattelemalla muistipotilaan nimeämää yhtä läheistä strukturoidun haastattelulomakkeen avulla, joka sisälsi neljä mittaria. Resource Utilization in Dementia (RUD)-mittarilla kerättiin tietoa läheisten taustasta, ajankäytöstä ja sosiaali- ja terveyspalvelujen käytöstä. Läheisten elämälaatuun liittyvää terveydentilaa tutkittiin EQ-5D-mittarilla. Muistipotilaan päivittäisistä toiminnoista selviytymistä kuvattiin KATZ (The KATZ Index of Independence in Activities of Daily Living)-mittarin avulla ja kognitiivista toimintakykyä S-MMSE (Standardized Mini-Mental State Examination)-mittarilla. Aineisto analysoitiin tilastollisin menetelmien SPSS -tilasto-ohjelmalla. Läheisten keski-ikä oli 65 vuotta ja heistä yli puolet oli muistipotilaiden lapsia (54 %) ja naisia (60 %). Vajaa puolet (45 %) läheisistä asui muistipotilaan kanssa samassa taloudessa. Muistipotilaiden keski-ikä oli 83 vuotta ja heistä yli puolet (63 %) oli naisia. Läheisten sosiaali- ja terveyspalvelujen käyttö oli vähäistä. Eniten he käyttivät yleislääkärin, fysioterapeutin palveluita ja maksettuja kuljetuspalveluita. Muistipotilaiden puolisot ja heidän kanssaan asuvat sekä naispuoliset läheiset käyttivät eniten palveluita. Kyseiset tekijät olivat yhteydessä palvelujen käyttöön. Muistipotilaat tarvitsivat jonkin verran apua päivittäisissä toiminnoissa. Läheiset, jotka käyttivät eniten aikaa muistipotilaan päivittäisissä toiminnoissa auttamiseen, käyttivät enemmän palveluita. Läheisten palvelujen käyttö oli yhteydessä muistipotilaan valvontaan käytetyn ajan kanssa. Muistipotilaan ja hänen läheisensä taustaan liittyvillä tekijöillä on merkittävä rooli läheisten sosiaali- ja terveyspalvelujen käyttöön. Läheisten palvelujen käyttöön liittyvät tekijät tulee ottaa huomioon kun tuloksia hyödynnetään käytäntöön ja kun muistipotilaan läheisiä tukevia sosiaali- ja terveyspalveluita suunnitellaan ja kohdennetaan läheisille.

Genetics of inherited small vessel diseases – in search of a novel small vessel disease and modifiers of the clinical course of CADASIL

The genetic and environmental risk factors of vascular cognitive impairment are still largely unknown. This thesis aimed to assess the genetic background of two clinically similar familial small vessel diseases (SVD), CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) and Swedish hMID (hereditary multi-infarct dementia of Swedish type). In the first study, selected genetic modifiers of CADASIL were studied in a homogenous Finnish CADASIL population of 134 patients, all carrying the p.Arg133Cys mutation in NOTCH3. Apolipoprotein E (APOE) genotypes, angiotensinogen (AGT) p.Met268Thr polymorphism and eight NOTCH3 polymorphisms were studied, but no associations between any particular genetic variant and first-ever stroke or migraine were seen. In the second study, smoking, statin medication and physical activity were suggested to be the most profound environmental differences among the monozygotic twins with CADASIL. Swedish hMID was for long misdiagnosed as CADASIL. In the third study, the CADASIL diagnosis in the Swedish hMID family was ruled out on the basis of genetic, radiological and pathological findings, and Swedish hMID was suggested to represent a novel SVD. In the fourth study, the gene defect of Swedish hMID was then sought using whole exome sequencing paired with a linkage analysis. The strongest candidate for the pathogenic mutation was a 3’UTR variant in the COL4A1 gene, but further studies are needed to confirm its functionality. This study provided new information about the genetic background of two inherited SVDs. Profound knowledge about the pathogenic mutations causing familial SVD is also important for correct diagnosis and treatment options.

The alpha2C-adrenoceptor as a neuropsychiatric drug tar-get - PET studies in human subjects

Positron emission tomography imaging has both academic and applied uses in revealing the distribution and density of different molecular targets in the central nervous system. Following the significant progress made with the dopamine D2 receptor, advances have been made in developing PET tracers to allow analysis of receptor occupancy of many other receptor types as well as evaluating changes in endogenous synaptic transmitter concentrations of transmitters e.g. serotonin and noradrenaline. Noradrenergic receptors are divided into α1-, α2- and β-adrenoceptor subfamilies, in humans each of which is composed of three receptor subtypes. The α2-adrenoceptors have an important presynaptic auto-inhibitory function on noradrenaline release but they also have postsynaptic roles in modulating the release of other neurotransmitters, such as serotonin and dopamine. One of the subtypes, the α2C-adrenoceptor, has been detected at distinct locations in the central nervous system, most notably the dorsal striatum. Several serious neurological conditions causing dementia, Alzheimer’s disease and Parkinson’s disease have been linked to disturbed noradrenergic signaling. Furthermore, altered noradrenergic signaling has also been implicated in conditions like ADHD, depression, anxiety and schizophrenia. In order to benefit future research into these central nervous system disorders as well as being useful in the clinical development of drugs affecting brain noradrenergic neurotransmission, validation work of a novel tracer for positron emission tomography studies in humans was performed. Altogether 85 PET imaging experiments were performed during four separate clinical trials. The repeatability of [11C]ORM-13070 binding was tested in healthy individuals, followed by a study to evaluate the dose-dependent displacement of [11C]ORM-13070 from α2C-adrenoceptors by a competing ligand, and the final two studies examined the sensitivity of [11C]ORM-13070 binding to reflect changes in endogenous noradrenaline levels. The repeatability of [11C]ORM-13070 binding was very high. The binding properties of the tracer allowed for a reliable estimation of α2C-AR occupancy by using the reference tissue ratio method with low test-retest variability. [11C]ORM-13070 was dose-dependently displaced from its specific binding sites by the subtype-nonselective α2-adrenoceptor antagonist atipamezole, and thus it proved suitable for use in clinical drug development of novel α2C-adrenoceptor ligands e.g. to determine the best doses and dosing intervals for clinical trials. Convincing experimental evidence was gained to support the suitability of [11C]ORM-13070 for detecting an increase in endogenous synaptic noradrenaline in the human brain. Tracer binding in the thalamus tended to increase in accordance with reduced activity of noradrenergic projections from the locus coeruleus, although statistical significance was not reached. Thus, the investigation was unable to fully validate [11C]ORM-13070 for the detection of pharmacologically evoked reductions in noradrenaline levels.