Abstract The Northern Finland 1966 Birth Cohort (NFBC 1966) is a general population study started in the 1960’s including 12,058 people born in the provinces of Oulu and Lapland. We studied magnetic resonance imaging (MRI) changes of the brain in subjects with schizophrenia at age 33–35 years. Another sub-group consisted of non-psychotic members of the NFBC 1966 who were born premature. In subjects with schizophrenia (n = 54) the volumes of whole brain, grey and white matter were reduced 2–3% and the volume of CSF was increased 7% compared to the general population control subjects (n = 100) without a psychotic episode. Regional grey matter density was reduced in several regions including frontal, temporal, parietal and occipital cortices, deep grey matter and cerebellum. Grey matter density was increased in the basal ganglia, anterior cingulate and medial orbitofrontal cortex. There were white matter deficits in inter- and intrahemispheric tracts bilaterally in the frontal, temporal, parietal and occipital lobes, subcortical structures, cerebellum and brainstem. CSF excesses were found in the lateral and third ventricles. Grey and white matter deficits were associated with duration of illness, so that the longer the duration, the smaller the density in the deficit regions. The hippocampal volume was reduced 2-3%, but the change was explained by the total brain volume reduction. We also investigated the effect of preterm birth or low birth weight on education, occupation (n = 715; controls 10,132), cognitive capacity and brain structure (n = 9; controls 95) in adulthood in the non-psychotic group of the NFBC 1966. The premature subjects had slightly lower educational and occupational performance in adulthood and they performed more poorly in verbal learning. There were no differences in the tissue segmentation analysis of the brain; however, we could not determine whether the negative finding was due to small sample size. In conclusion, we have confirmed previous findings of brain abnormalities in schizophrenia in an epidemiological population-based sample. The grey and white matter deficits were widespread and the abnormalities were associated with duration of illness, suggesting progressive changes. In the premature group of the NFBC, minor adult cognitive deviances were found in the absence of major imaging findings. / Tiivistelmä Pohjois-Suomen vuoden 1966 syntymäkohortti on epidemiologinen seurantatutkimus, joka on käynnistetty 1960-luvulla ja johon kuuluu 12,058 Oulun ja Lapin läänissä 1966 syntynyttä lasta. Tutkimme aivojen magneettikuvausmuutoksia 33–35v. ikäisillä skitsofreniaan sairastuneilla kohortin jäsenillä. Toinen tutkimusjoukkomme koostui kohortin keskosena syntyneistä ei-psykoottisista aikuisista. Aivotilavuus, harmaan ja valkean aineen tilavuus olivat 2–3 % pienempiä ja aivoselkäydinnesteen tilavuus 7 % suurempi skitsofreniapotilailla (n = 54) verrattuna syntymäkohortin kontrollihenkilöihin (n = 100), joilla ei ollut sairaushistoriassaan psykoosiepisodia. Skitsofreniapotilailla harmaan aineen tiheys oli alentunut otsa-, ohimo-, päälaen- ja takaraivon lohkon kuorikerroksessa, syvällä harmaan aineen alueella sekä pikkuaivoissa. Harmaan aineen tiheys oli lisääntynyt tyvitumakealueilla sekä paikallisesti otsalohkon kuorikerroksessa. Valkean aineen tiheys oli vähentynyt laaja-alaisesti aivojen eri lohkoissa. Aivoselkäydinnesteen määrä oli lisääntynyt aivokammioissa. Harmaan ja valkean aineen tiheyden muutos edellä mainituilla alueilla oli suhteessa sairauden kestoon siten, että pitempään sairastaneilla tiheys oli vähentynyt enemmän. Hippokampustilavuus oli pienentynyt 2–3 %, mutta tämä selittyi aivojen kokonaistilavuuden pienenemisellä. Selvitimme kohortin ei-psykoottisten ryhmässä ennenaikaisen syntymän ja pienen syntymäpainon vaikutusta aikuisiän koulutustasoon, työllistymiseen (n = 715; kontrolleja 10,132), sekä kognitiivisissa testeissä suoriutumiseen ja aivorakenteisiin (n = 9; kontrolleja 95). Keskosena syntyneillä oli hieman keskimääräistä alhaisempi koulutustaso ja työllistyminen aikuisiässä. Lisäksi he suoriutuivat huonommin kielellisen oppimisen testissä. Aivorakennemuutoksia heillä ei kuitenkaan löytynyt, mutta tämä negatiivinen löydös jää epävarmaksi pienen otoskoon vuoksi. Varmistimme aiempia tutkimuslöydöksiä rakenteellisista aivomuutoksista skitsofreniassa epidemiologisessa otoksessa väestötasolla. Muutokset olivat laaja-alaisia, ja tulokset viittaavat etenevään prosessiin. Kohortin keskosena syntyneillä todettiin aikuisiässä lieviä muutoksia kognitiivisessa suoritumisessa ilman selkeitä magneettikuvauslöydöksiä.

Abstract Schizophrenia is a complex mental health disorder and its etiology can be investigated based on different theoretical prerequisites. The present thesis examines schizophrenia from the neurodevelopmental and psychosis continuum perspectives. Neurodevelopmental theories of schizophrenia see abnormalities in the developing nervous system as early predictors of vulnerability to the disease. Schizophrenia can be seen also as a progressive disorder and a continuum of symptomatology from personality traits (schizotypy) to full-blown schizophrenia. The aim of the present thesis is to study incidence of schizophrenia; prevalence of schizotypy; and associations between schizophrenia and schizotypy with early motor developmental milestones. The research design includes prospective cohort studies and systematic review, and meta-analysis. In two successive Northern Finland Birth Cohorts (NFBC) studies, 20 years apart (1966 and 1986), the incidence of schizophrenia remained the same, but the incidence of other psychoses and therefore all psychoses was higher in NFBC 1986. In NFBC 1966, mean schizotypy scores were among the lowest and the highest scores among 24 general population studies. When early motor developmental milestones were investigated in the meta-analyses (3 to 5 studies), a significant small effect size for walking, sitting, and standing unsupported was found with respect to adult schizophrenia. When schizotypy outcome was studied in the NFBC 1966, later achievement of turning from back to tummy, touching thumb with index finger, standing up, sitting unsupported, and walking with support were found to be associated with an increase in schizotypy scales and varied somewhat by gender. To conclude, there have been changes in the incidence of all psychoses but not in schizophrenia between the two NFBCs. This is in line with other studies on the trends of incidence of psychoses, which highlights the role of changes in diagnostic systems and practices that can influence rates. In this project, mean schizotypy scores were both among the highest and the lowest estimates in the studies on schizotypy in the general population. Early motor developmental milestones were both predictors of schizophrenia and schizotypy, and thus this finding supports both the neurodevelopmental and psychosis continuum approaches to the aetiology of schizophrenia. / Tiivistelmä Skitsofrenia on monimuotoinen mielenterveyden häiriö, jonka etiologiaa voidaan tutkia erilaisissa teoreettisissa viitekehyksissä. Tämä väitöskirja tutkii skitsofreniaa neurologisen kehityksen ja psykoosin jatkumon näkökulmista. Skitsofrenian neurokehitykselliset teoriat pitävät kehittyvän keskushermoston poikkeavuuksia varhaisina skitsofrenian alttiuden ennustajina. Skitsofreniaa voidaan pitää myös progressiivisena sairautena ja oireiden jatkumona persoonallisuuden piirteistä (skitsotypaalisuudesta) täysimittaiseen skitsofreniaan. Tämän väitöskirjatutkimuksen tavoitteena on tutkia skitsofrenian ilmaantuvuutta, skitsotypaalisten piirteiden yleisyyttä ja skitsofrenian ja skitsotypaalisten piirteiden yhteyttä varhaiseen motoriseen kehitykseen. Tutkimusasetelmina ovat prospektiiviset syntymäkohortit, systemaattinen katsaus ja meta-analyysi. Kahdessa peräkkäisessä 20 vuoden välein kerätyssä Pohjois-Suomen syntymäkohortissa (1966 ja 1986) skitsofrenian ilmaantuvuus pysyi samana, mutta muiden psykoosien ja siten kaikkien psykoosien ilmaantuvuudet olivat korkeampia vuoden 1986 syntymäkohortissa. Vuoden 1966 syntymäkohortissa negatiivisen skitsotypaalisuuden piirteet olivat korkeita ja positiivisen skitsotypaalisuuden piirteet alhaisia verrattuna 24 muuhun väestöaineistoon. Varhaisen motorisen kehityksen ja aikuisiän skitsofrenian välistä yhteyttä tutkittiin meta-analyysin (3–5 tutkimusta) avulla. Tilastollisesti merkitsevä pieni negatiivinen yhteys löytyi aikuisiän skitsofrenian ja kävelemään, istumaan ja seisomaan oppimisen välillä. Pohjois-Suomen vuoden 1966 syntymäkohortissa skitsotypaaliset piirteet liittyivät hitaampaan vatsalleen kääntymisen, peukalo-etusormi otteen, seisomisen, tuetta istumisen ja tuen kanssa kävelemisen oppimiseen. Näissä yhteyksissä oli vaihtelua tutkittavan sukupuolen mukaan. Yhteenvetona voidaan todeta, että psykoosien ilmaantuvuus on kasvanut Pohjois-Suomen syntymäkohorteissa, mutta skitsofrenian ei. Tämä on linjassa aikaisempien tutkimusten kanssa. On kuitenkin huomioitava myös diagnostisten järjestelmien ja käytäntöjen merkitys näiden muutosten arvioimisessa. Varhainen motorinen kehitys ennusti sekä skitsofreniaa että skitsotypaalisia piirteitä. Havainto tukee sekä neurokehityksellistä että psykoosin jatkumoon liittyvää lähestymistapaa skitsofrenian etiologiassa.

Contexte : La structure du sommeil évolue grandement dans les premières années de vie. Les réveils nocturnes occasionnels chez les enfants d'âge préscolaire font partie d’un processus normal de développement et de maturation du sommeil. Ils sont cependant considérés comme anormalement fréquents lorsqu’ils surviennent une nuit sur deux ou plus. La littérature suggère que les réveils nocturnes fréquents sont associés de manière transversale à des difficultés comportementales du jeune enfant. Or, l’évolution des réveils nocturnes dans la petite enfance, les facteurs associés à leurs trajectoires et les liens longitudinaux avec le comportement sont peu connus. Objectifs : Modéliser l’évolution des réveils nocturnes entre l’âge de 2 et 5-6 ans et explorer leurs liens avec des facteurs précoces familiaux et de l’enfant. Analyser les associations entre les trajectoires de réveils nocturnes et le comportement de l’enfant avant l’entrée à l’école. Population et méthode : Nos analyses ont porté sur les données de l’étude EDEN. Il s’agit d’une cohorte mère enfant, qui a recruté 2 002 femmes enceintes entre 2003 et 2006 dans les maternités de Nancy et Poitiers. Les réveils nocturnes et le comportement ont été mesurés par des questionnaires parentaux à l’âge de 2, 3 et 5-6 ans. La méthode du « group-based trajectory modeling » nous a permis de modéliser l’évolution des réveils nocturnes et de difficultés d’attention, et ainsi d’identifier des trajectoires, décrivant différentes histoires développementales entre l’âge de 2 et 5-6 ans. Les analyses statistiques pour mesurer les associations entre les trajectoires de réveils nocturnes, les facteurs précoces et le comportement de l’enfant, ont été faites par régressions logistiques, ajustées sur les facteurs de confusion potentiels. Résultats : Deux trajectoires distinctes de réveils nocturnes ont été identifiées chez les enfants entre 2 et 5-6 ans. L’une, nommée “réveils nocturnes rares”, représentait 77% des enfants. Ce groupe suivait une trajectoire linéaire proche de zéro et légèrement décroissante avec le temps. La seconde trajectoire, nommée « réveils nocturnes communs », représentait 23% des enfants. Elle était plus haute que la première trajectoire à chaque point de suivi, et présentait un pic à l’âge de 3 ans. Les facteurs de risque d’appartenir à la trajectoire de « réveils nocturnes communs » étaient essentiellement environnementaux : l’exposition au tabagisme passif, un mode de garde collectif et le temps passé devant la télévision. Les enfants appartenant à la trajectoire de réveils nocturnes communs présentent un risque accru de présenter des symptômes émotionnels, des problèmes de conduite et des problèmes d'hyperactivité/inattention à l’âge de 5-6 ans. Aucune association n'a été trouvée avec le comportement pro-social ou avec les problèmes de relations avec les pairs. Trois trajectoires d’inattention/hyperactivité ont été identifiées, une trajectoire basse, intermédiaire et une haute, toutes trois stables au cours du temps. Le risque d’appartenir à une trajectoire haute d’inattention/hyperactivité, par rapport à une trajectoire basse, était quatre fois plus important pour les enfants avec une trajectoire de « réveils nocturnes communs » comparativement à ceux avec trajectoire de « réveils nocturnes rares ». Conclusion : Les réveils nocturnes et les troubles d’inattention/hyperactivité persistent dans la petite enfance. Une trajectoire de réveils nocturnes communs durant cette période est un facteur de risque de plusieurs troubles du comportement : symptôme émotionnel, troubles de conduites et inattention/hyperactivité. Ces derniers co-évoluent avec les troubles du sommeil. Nos résultats soulignent l’importance d’identifier et de prendre en charge les difficultés de sommeil dès le plus jeune âge, surtout en présence de difficultés de comportement. / Context: The structure of sleep evolves greatly in the first years of life. Occasional nightwaking is thus normal in young children, but waking-up every other night or more is considered adversely frequent. The scientific literature suggests that frequent night-waking is associated with concomitant behavioral difficulties in children. Yet, little is known about the evolution of night-waking in preschool years and its longitudinal association with behavior. Objectives: To model the evolution of night-waking between the age of 2 and 5-6 years and explore the association with family and child related factors. To analyze the associations between night-waking trajectories and behavior before school entry. Population and methods: Analyses were based on the French birth-cohort study EDEN, which recruited 2 002 pregnant women between 2003 and 2006 in the maternity of Poitiers and Nancy. Information regarding night-waking and behavior were assessed using parental questionnaires at the ages of 2, 3 and 5-6 years. The « group based trajectory modeling » method allowed us to model the evolution of night-waking and of inattention/hyperactivity, describing different developmental trends between the age of 2 and 5-6 years. The associations between night-waking trajectories, family and child related factors and behavior, were analyzed using logistic regressions, adjusted on potential confounding factors. Results: Two distinct night-waking trajectories were identified in children between the age of 2 and 5-6 years. One, named « rare night-waking », represented 77% of the children. This group followed a linear trajectory, which was close to zero and slightly declining with time. The second trajectory, named « common night-waking », represented 23% of the children. It was higher than the first trajectory at each time-point, and a peak was observed at age 3. Risk factors for belonging to the « common night-waking » trajectory were life-style related factors: exposures to second hand smoking, collective care arrangement, and time spent in front of the television. Children belonging to the common night-waking trajectory had higher risk of having emotional symptoms, conduct problems and inattention/hyperactivity at age 5-6. No associations were found with prosocial behavior nor peer-relationship problems. Three trajectories of inattention/hyperactivity were identified, a low, an intermediate and a high one, all stable in time. The risk of belonging to a high inattention/hyperactivity trajectory, compared to a low one, were four time more important for children with a « common night-waking » trajectory. Conclusion: Night-waking and inattention/hyperactivity persist in preschool years. A common night-waking trajectory during this period is a risk factor of diverse behavioral difficulties: emotional symptoms, conduct problems and inattention/hyperactivity. The latter co-evolves with night-waking. Our results highlight the importance of identifying sleep problems in early years, especially in the presence of behavioral difficulties.

No description available.

Introdução: A fisiologia normal da gravidez inclui vários componentes da Síndrome Metabólica (SM), como um certo grau de resistência à insulina, acumulação de tecido adiposo, hiperlipidemia e ativação da cascata inflamatória. Apesar disso, poucos estudos têm se dedicado a avaliar o perfil metabólico de gestantes. Objetivos: Identificar e comparar as alterações metabólicas que ocorrem durante a gestação em duas coortes de nascimento no ano de 2010 nas cidades de Ribeirão Preto (RP) e São Luís (SL). Métodos: Foram estudadas, em dois momentos, gestantes (1400 em RP e 1447 em SL) e binômios mãe-RN (1370 em RP e 1382 em SL) participantes das coortes de nascimentos dos dois municípios. As informações foram obtidas por meio de questionários aplicados a estas mulheres, além de avaliação antropométrica e bioquímica e medida de pressão arterial. SM foi definida por uma adaptação dos critérios do NCEPIII. Para comparação dos dois municípios foram utilizados testes de qui-quadrado e t de Student, com nível de significância de 5%. Para avaliar a associação entre parto pré-termo e perfil metabólico alterado foram calculados RR não-ajustados e seus IC a 95%. Resultados: Comparado com SL, RP mostrou maiores taxas de sobrepeso e obesidade pré-gestacionais (40,1% vs 25,8%) e de nascimento pré-termo (9,7% vs 7,4%). A frequência de SM foi quase duas vezes maior em RP (5,7% vs 3,3%), assim como pressão arterial alterada (4% vs 2%) e glicemia alterada (16,5% vs 9,9%). HDL Colesterol alterado foi mais frequente nas gestantes de SL (13,9% vs 7,5%). Com respeito as médias do perfil bioquímico, RP apresentou maiores valores que SL, exceto para triglicerídeos, que não foi diferente entre as cidades. Gestantes com SM não tiveram risco de parto pré-termo (RR1,40; IC95% 0,80-2,54), apenas as hipertensas (RR 3,27; IC95% 1,92-5,55). Conclusões: As gestantes de RP apresentaram mais alterações metabólicas que as de SL. / Background: The regular physiology of pregnancy includes several components of metabolic syndrome (MS), such as some degree of resistance to insulin, accumulation of adipose tissue, hyperlipidemia and activation of the inflammatory cascade. Despite this, few studies have been dedicated to evaluating the metabolic profile of pregnant women. Objectives: To identify and compare the metabolic changes that occur during pregnancy in two birth cohorts in 2010 in the cities of Ribeirão Preto (RP) and São Luís (SL). Methods: Pregnant women (1400 in PR and 1447 in SL) and mother-RN pairs (1370 in RP and 1382 in SL) were studied in two moments of the birth cohorts of the two municipalities. The information was obtained through questionnaires applied to these women, in addition to anthropometric and biochemical evaluation and blood pressure measurement. Metabolic syndrome (MS) was defined by an adaptation of the NCEPIII criteria. For the comparison of the two municipalities, chi-square and Student\'s t-tests were used, with a significance level of 5%. To evaluate the association between preterm delivery and altered metabolic profile, unadjusted RRs and their 95% CI were calculated. Results: Compared with SL, RP showed higher rates of pre-gestational overweight and obesity (40.1% vs 25.8%) and preterm birth (9.7% vs 7.4%). The frequency of MS was almost twice as high in PR (5.7% vs 3.3%), as well as altered blood pressure (4% vs 2%) and altered blood glucose (16.5% vs. 9.9%). HDL Cholesterol alteration was more frequent in pregnant women with SL (13.9% vs 7.5%). Regarding the means of the biochemical profile, RP presented higher values than SL, except for triglycerides, which was not different between cities. Pregnant women with MS had no risk of preterm delivery (RR 1.40, 95% CI 0.80-2.54), only those with hypertension (RR 3.27, 95% CI, 1.92-5.55). Conclusion: PR women presented more metabolic alterations than SL women due, in part, to the more advanced state in nutritional transition for women in RP.

Introdução: A fisiologia normal da gravidez inclui vários componentes da Síndrome Metabólica (SM), como um certo grau de resistência à insulina, acumulação de tecido adiposo, hiperlipidemia e ativação da cascata inflamatória. Apesar disso, poucos estudos têm se dedicado a avaliar o perfil metabólico de gestantes. Objetivos: Identificar e comparar as alterações metabólicas que ocorrem durante a gestação em duas coortes de nascimento no ano de 2010 nas cidades de Ribeirão Preto (RP) e São Luís (SL). Métodos: Foram estudadas, em dois momentos, gestantes (1400 em RP e 1447 em SL) e binômios mãe-RN (1370 em RP e 1382 em SL) participantes das coortes de nascimentos dos dois municípios. As informações foram obtidas por meio de questionários aplicados a estas mulheres, além de avaliação antropométrica e bioquímica e medida de pressão arterial. SM foi definida por uma adaptação dos critérios do NCEPIII. Para comparação dos dois municípios foram utilizados testes de qui-quadrado e t de Student, com nível de significância de 5%. Para avaliar a associação entre parto pré-termo e perfil metabólico alterado foram calculados RR não-ajustados e seus IC a 95%. Resultados: Comparado com SL, RP mostrou maiores taxas de sobrepeso e obesidade pré-gestacionais (40,1% vs 25,8%) e de nascimento pré-termo (9,7% vs 7,4%). A frequência de SM foi quase duas vezes maior em RP (5,7% vs 3,3%), assim como pressão arterial alterada (4% vs 2%) e glicemia alterada (16,5% vs 9,9%). HDL Colesterol alterado foi mais frequente nas gestantes de SL (13,9% vs 7,5%). Com respeito as médias do perfil bioquímico, RP apresentou maiores valores que SL, exceto para triglicerídeos, que não foi diferente entre as cidades. Gestantes com SM não tiveram risco de parto pré-termo (RR1,40; IC95% 0,80-2,54), apenas as hipertensas (RR 3,27; IC95% 1,92-5,55). Conclusões: As gestantes de RP apresentaram mais alterações metabólicas que as de SL. / Background: The regular physiology of pregnancy includes several components of metabolic syndrome (MS), such as some degree of resistance to insulin, accumulation of adipose tissue, hyperlipidemia and activation of the inflammatory cascade. Despite this, few studies have been dedicated to evaluating the metabolic profile of pregnant women. Objectives: To identify and compare the metabolic changes that occur during pregnancy in two birth cohorts in 2010 in the cities of Ribeirão Preto (RP) and São Luís (SL). Methods: Pregnant women (1400 in PR and 1447 in SL) and mother-RN pairs (1370 in RP and 1382 in SL) were studied in two moments of the birth cohorts of the two municipalities. The information was obtained through questionnaires applied to these women, in addition to anthropometric and biochemical evaluation and blood pressure measurement. Metabolic syndrome (MS) was defined by an adaptation of the NCEPIII criteria. For the comparison of the two municipalities, chi-square and Student\'s t-tests were used, with a significance level of 5%. To evaluate the association between preterm delivery and altered metabolic profile, unadjusted RRs and their 95% CI were calculated. Results: Compared with SL, RP showed higher rates of pre-gestational overweight and obesity (40.1% vs 25.8%) and preterm birth (9.7% vs 7.4%). The frequency of MS was almost twice as high in PR (5.7% vs 3.3%), as well as altered blood pressure (4% vs 2%) and altered blood glucose (16.5% vs. 9.9%). HDL Cholesterol alteration was more frequent in pregnant women with SL (13.9% vs 7.5%). Regarding the means of the biochemical profile, RP presented higher values than SL, except for triglycerides, which was not different between cities. Pregnant women with MS had no risk of preterm delivery (RR 1.40, 95% CI 0.80-2.54), only those with hypertension (RR 3.27, 95% CI, 1.92-5.55). Conclusion: PR women presented more metabolic alterations than SL women due, in part, to the more advanced state in nutritional transition for women in RP.

Abstract The aim of this study was to investigate whether risk factors for psychosis are different among those with and without parental psychosis, and to study the interaction between parental psychosis and risk factors. Protective factors for psychosis were also examined. Data from the Northern Finland Birth Cohort 1966 (N = 10,458) was used. Biological risk factors in particular increased the risk for schizophrenia and other psychosis among those with parental psychosis. In the same group, the risk for schizophrenia was increased if the achievement of holding the head up and touching the thumb with the index finger was delayed. A new born’s large size, advanced maternal age and mother’s antenatal depressed mood had interactions with parental psychosis regarding risk for schizophrenia and the mother’s smoking during pregnancy regarding risk for other psychosis. Parental psychosis and delayed touching the thumb with the index finger had an interaction regarding risk for schizophrenia and other psychosis. Several variables were associated with the decreased risk for psychosis in the total sample. In the parental psychosis group, only a mother’s non-depressed mood and a mother’s working outside the home or studying associated to remaining unaffected. This study is one of the few studies to investigate risk factors for psychosis among those with and without parental psychosis and to examine interactions between parental psychosis and risk factors. This study showed that many risk factors increased the risk for schizophrenia and other psychosis only among those with parental psychosis. Hence, parental psychosis might even explain part of the association between some risk factors. Surprisingly few protective factors were found among those with parental psychosis. Further studies on the protective factors for psychosis are important in order to prevent psychosis in individuals at high risk. / Tiivistelmä Tämän tutkimuksen tavoitteena oli selvittää, eroavatko psykoosien riskitekijät henkilöillä, joiden vanhemmalla oli psykoosi verrattuna niihin joiden vanhemmalla ei ollut psykoosia sekä tutkia vanhemman psykoosin ja riskitekijöiden yhdysvaikutusta. Myös psykoosilta suojaavia tekijöitä tutkittiin. Tutkimusaineistona oli Pohjois-Suomen vuoden 1966 syntymäkohortti (N = 10458). Erityisesti biologiset tekijät lisäsivät skitsofrenian ja muiden psykoosien riskiä henkilöillä, joiden vanhemmalla oli psykoosi. Viivästynyt pään kannattelun ja pinsettiotteen oppiminen lisäsivät skitsofreniariskiä henkilöillä joiden vanhemmalla oli psykoosi. Vastasyntyneen suurella koolla, äidin korkealla iällä ja raskaudenaikaisella masentuneella mielialalla oli yhdysvaikutus vanhemman psykoosin kanssa skitsofreniariskin osalta ja äidin raskaudenaikaisella tupakoinnilla muiden psykoosien riskin osalta. Vanhemman psykoosilla ja viivästyneellä pinsettiotteen oppimisella oli yhdysvaikutus sekä skitsofrenian että muiden psykoosien riskin osalta. Koko aineistossa useat tekijät liittyivät alentuneeseen psykoosiriskiin. Vain äidin ei-masentunut mieliala ja työskentely kodin ulkopuolella tai opiskelu suojasivat psykoosilta henkilöitä, joiden vanhemmalla oli psykoosi. Tämä on yksi harvoista tutkimuksista, jossa on tutkittu psykoosien riskitekijöitä erikseen henkilöillä, joiden vanhemmalla oli tai ei ollut psykoosia sekä vanhempien psykoosin ja riskitekijöiden yhdysvaikutusta. Useat riskitekijät lisäsivät skitsofreniariskiä ainoastaan henkilöillä, joiden vanhemmalla oli psykoosi, joten vanhemman psykoosi voisi selittää osan psykoosien riskitekijöistä. Psykoosilta suojaavia tekijöitä löydettiin yllättävän vähän niillä, joiden vanhemmalla oli psykoosi. Suojaavien tekijöiden tutkiminen on tärkeää, jotta suuressa psykoosiriskissä olevien sairastumista voidaan ennaltaehkäistä.

Abstract There is an extensive literature on advanced paternal age (APA) as a risk factor for a wide variety of adverse health outcomes in the offspring that occur throughout the lifespan. APA is also a well-replicated and relatively robust risk factor for schizophrenia in the offspring. The aim of this study was to investigate advanced paternal age (APA) as a risk factor for schizophrenia and mortality in the offspring in four perspectives and original publications. The Northern Finland 1966 Birth Cohort (NFBC 1966) consists of 12,068 pregnant women with expected dates of delivery in 1966, and their 12,058 live-born children. The data used here were collected prospectively for 11,058 singleton-birth cohort members who were living in Finland at age one. The Helsinki 1951–1960 Schizophrenia Cohort consists of 529 persons born in Helsinki, Finland, between January 1, 1951 and December 31, 1960, who developed nonaffective psychosis before 1999. The Finnish Nonaffective Psychosis Cohort (Finnish NAP Cohort) consists of all 13,712 persons born in Finland between 1950 and 1969, who developed nonaffective psychosis before 1992. Both APA (≥30) and younger paternal age (<25) increased the risk of schizophrenia; younger paternal age may be associated with an increased risk in males but not females. In the general population, APA was associated with increased all-causes mortality and suicide in females but not males. Within NAP, in females but not males, there was a significant increase in all-causes mortality and natural deaths in offspring of fathers age ≥40. In both the general population and within NAP, APA was associated with having a mother with schizophrenia. An understanding of APA has substantial public health potential, as average paternal ages are increasing, and APA is common, has widespread effects, and is potentially preventable. We have provided important information for future epidemiological and clinical studies of all conditions associated with APA. Accounting for the APA effect as a potential confounding factor may also increase the signal-to-noise ratio in other epidemiological and genetic analyses. Our results have generated new and more refined hypotheses regarding psychosocial and/or biological mechanisms of the APA effect, and lay the foundation for animal models for its mechanism of action. Subsequent studies will be important to clarifying the pathophysiology of a potentially preventable determinant of schizophrenia and mortality. / Tiivistelmä Isän korkean iän (advanced paternal age, APA) on havaittu olevan yhteydessä laajaan kirjoon eri terveysongelmia. Aiemmassa tutkimuksessa havaittiin APA:n liittyvän tyttärien ylikuolleisuuteen, mutta pojilla vastaavaa yhteyttä ei havaittu. Tätä yhteyttä ei ole aiemmin tutkittu väestöpohjaisessa otoksessa. APA:n on myös havaittu olevan yksi skitsofrenian riskitekijöistä, mutta vaikutuksen suuruutta sairastumisriskiin, mahdollisia sukupuolieroja, kliinisiä piirteitä tai yhteyttä kuvantamislöydöksiin ei tunneta. Tämän tutkimuksen tarkoitus oli selvittää APA:n vaikutusta lasten skitsofreniariskiin ja kuolleisuuteen. Pohjois-Suomen vuoden 1966 syntymäkohortti (Northern Finland 1966 Birth Cohort, NFBC 1966) käsittää 12 068 raskaana olevaa naista ja heidän 12 058 elävänä syntynyttä lastaan. Tässä tutkimuksessa käytetty tieto on kerätty prospektiivisesti 11 058 kohortin jäsenestä, jotka asuivat Suomessa yhden vuoden ikäisinä eivätkä olleet kaksosia. Helsingin vuosien 1951–1960 skitsofreniakohortin 529 Helsingissä 1951–1960 syntynyttä jäsentä seurattiin tätä tutkimusta varten prospektiivisesti kesäkuuhun 2006 asti. Suomalaiseen psykoosikohorttiin (The Finnish Nonaffective Psychosis Cohort, Finnish NAP Cohort) kuuluu 13 712 psykoosia sairastavaa henkilöä, jotka ovat syntyneet 1950–1969. Sekä isän korkea (≥30) että nuori ikä (<25) lisäsivät riskiä sairastua skitsofreniaan. Isän nuori ikä näytti lisäävän riskiä ainoastaan pojilla. Yleisväestössä isän korkea ikä oli yhteydessä lisääntyneeseen kokonaiskuolleisuuteen ja itsemurhiin naisilla, mutta vastaavaa yhteyttä ei havaittu miehillä. Psykoosia sairastavilla naisilla isän ikä ≥40 oli yhteydessä lisääntyneeseen kokonaiskuolleisuuteen ja luonnollisiin kuolemiin. Yleisväestössä ja psykoosia sairastavilla korkea isän ikä oli yhteydessä äidin skitsofreniaan. Skitsofreniaa sairastavilla korkea isän ikä liittyi pitempään hoitamattoman psykoosin kestoon, huonompaan sosiaaliseen ja ammatilliseen toimintakykyyn sekä lisääntyneeseen päihteiden käyttöön. Tämä tutkimus vahvisti aiempaa käsitystä isän korkean iän yhteydestä kuolleisuuteen ja skitsofreniaan. Löydöksellä on mahdollisia kansanterveydellisiä vaikutuksia, koska keskimääräinen isän ikä on noussut ja on yleistä väestössä. Isän ikään on mahdollista vaikuttaa. Isän ikä on myös mahdollinen sekoittava tekijä tutkittaessa skitsofrenian kausaalisia tekijöitä ja kehityskulkuja.

Abstract The aim of this study was to investigate risk factors, developmental pathways and the rate of attempted or accomplished suicide in a longitudinal population-based prospective birth cohort. The Northern Finland 1966 Birth Cohort (NFBC 1966) consists of 12,068 pregnant women with expected dates of delivery in 1966, and their 12,058 live-born children. The data used here was collected prospectively for 10,934 individuals who were alive and resident in Finland at the age of 16. This study utilized an extensive data set collected in antenatal clinics at mid-pregnancy, by postal questionnaire at the age of 14 years and through national registers. A total of 121 suicide attempts (57 males) and 69 suicides (56 males) had occurred by the end of 2005. A single-parent family was a risk factor for attempted suicides and grand multiparity for suicides in male offspring. Adolescent regular smoking was associated with an increased risk of suicide attempts in both genders and for suicide among males. Good school performance at age 16 years was associated with an increased risk of suicide in psychosis cases, whereas in persons who did not develop psychosis it was associated with a lower suicide risk. The suicide rate in new-onset schizophrenia followed until the age of 39 was 7%. Over two thirds of the suicides took place during the first 3 years of the illness. This was the first study of suicide rates in a prospectively followed population-based birth cohort of individuals with schizophrenia. This study replicated association between some early family-related risk factors for attempted and accomplished suicide, and also presented data for previously unstudied early factors, namely maternal antenatal depression, smoking and unwanted pregnancy This study has clarified the association between adolescent smoking and later suicide risk. It also revealed the association between good school performance and elevated risk of suicide in psychotic people, in contrast to its protective effect in the non-psychotic population. However, even though there were significant antenatal and developmental risk factors, a later psychiatric disorder seems to be the major risk factor for both attempted and accomplished suicide. Nevertheless, suicide usually seems to be a long multifactorial process that begins in early life and has complex trajectories in adolescence or early midlife. / Tiivistelmä Tämän tutkimuksen tarkoitus oli tutkia itsemurhien esiintyvyyttä, riskitekijöitä, siihen johtavia kehityspolkuja yleisväestöön perustuvassa prospektiivisessa pitkittäistutkimuksessa. Pohjois-Suomen vuoden 1966 syntymäkohorttiin kuului alun perin 12,068 raskaana olevaa naista joiden laskettu aika oli vuonna 1966, ja heidän 12,058 elävänä syntynyttä lastaan, kohortin jäsenet. Tässä tutkimuksessa käytetty aineisto on kerätty 11,017 kohortin jäsenestä, jotka olivat elossa ja asuivat Suomessa 16-vuotiaana. Käytetty aineisto on kerätty äitiysneuvoloissa, 14-vuotiaana tehdyssä postikyselyssä ja kansallisista rekistereistä. Kaikkiaan 121 itsemurhayritystä (joista 57 miehillä) ja 69 itsemurhaa (56 miehillä) tapahtui vuoden 2005 loppuun mennessä. Yhden vanhemman perhe syntymän aikaan oli riski myöhemmälle itsemurhayritykselle ja syntyminen monilapsiseen perheeseen (yli viisi lasta) oli riski itsemurhalle. Tupakointi 14-vuotiaana ennusti itsemurhayrityksiä kummallakin sukupuolella sekä itsemurhia miehillä. Hyvä koulumenestys 16-vuotiaana liittyi kohonneeseen itsemurhavaaraan niillä jotka myöhemmin sairastuivat psykoosiin, kun muilla se liittyi alentuneeseen vaaraan. Skitsofreniaan sairastuneista 7 % teki itsemurhan ja yli kaksi kolmannesta skitsofreniaan sairastuneiden itsemurhista tapahtui kolmen vuoden kuluessa sairastumisesta. Tämä tutkimus vahvisti aikaisempia havaintoja varhaisista riskitekijöistä itsemurhayrityksiin ja itsemurhiin. Tässä tutkimuksessa tutkittiin myös kokonaan uusia varhaisia riskitekijöitä, joita ei ole ennen tutkittu suhteessa itsemurhaan tai itsemurhayrityksiin, kuten äidin raskaudenaikainen masennus ja tupakointi sekä ei-toivottu raskaus. Tämän tutkimuksen avulla saatiin myös uutta tietoa teini-iässä aloitetun tupakoinnin suhteesta itsemurhiin ja -yrityksiin. Tutkimus paljasti hyvän koulumenestyksen lisäävän riskiä itsemurhaan henkilöillä jotka sairastuvat myöhemmin psykoosiin. Tämä oli ensimmäinen tutkimus, jossa skitsofreniaa sairastavien henkilöiden itsemurhakuolleisuutta selvitettiin yleisväestöön pohjautuvassa syntymäkohortissa. Vaikka tutkimuksessa tuli ilmi sekä syntymän, että nuoruuden aikaisia varhaisia riskitekijöitä, myöhempi psykiatrinen sairaus on merkittävin itsemurhan ja -yritysten riskitekijä. Siitä huolimatta itsemurha on aina monitekijäinen prosessi, joka voi alkaa jo ennen syntymää ja johon myöhemmät elämänvaiheet vaikuttavat.

Understanding the ageing process is of increasing importance to an ageing society and one aspect of this is investigating what role the brain has in this process. Cognitive ability declines as we age and it is one of the most distressing aspects of getting older. Brain tissue deterioration is a significant contributor to lower cognitive ability in late life but the underlying biological mechanisms in the brain are not yet fully understood. One reason for this is the difficulty in obtaining accurate measures of potential ageing-related brain biomarkers. The chapters in this thesis explore the difficulties of quantifying brain changes in the ageing brain from Magnetic Resonance Imaging (MRI), and how the changes identified are related to cognition in later life. The data was acquired as part of the second wave of the longitudinal Lothian Birth Cohort 1936 study in which 866 people aged 73 years, returned for cognitive and medical assessment. At this stage of the study 702 underwent MR imaging resulting in 627 complete datasets across all testing. The entire data, a randomly chosen subset of 150 and 416 freely available data were used to investigate global and regional measurement methods in older brains and how the resultant measurements related to cognitive performance. Furthermore the presence of early life cognitive data in the form of a general intelligence test sat at age 11, served as an indicator of cognitive ability prior to the potential influence of the ageing process. The chapters concerning global measures at first establish, that a measure of intracranial volume (ICV) serves as both a way of correcting for individual differences in brain size between participants and as a proxy premorbid measure of brain size. The analysis, utilising freely available cross-sectional MRI data (http://www.oasis-brains.org) revealed that ICV differed very little between 18-28 year olds and 84-96 year olds where as total brain tissue volume (TBV) differed by 14.1% between the two groups, which was more than twice the standard deviation across the entire age range (18-96 years). Second a validated, reliable method for measuring ICV was investigated using 150 people randomly chosen from the LBC1936 study. Automated and semi-automated methods were validated against reference measurements the results of which showed that common ageing features make automated and semi-automated methods that do not have an additional manual editing step, ineffective at producing accurate ICV measurements. This analysis also highlighted the need to employ additional spatial overlap assessment to volumetric comparison of measurement methods to reduce the effect of false-positives and false-negatives skewing apparent discrepancies between methods. Using the information gained here ICV and TBV from the entire LBC1936 cohort were analysed in a structural equation model, alongside cognitive ability measures at both age 11 and age 73. We found that TBV was a stronger predictor of later life cognitive ability, after accounting for early life ability, but that a modest association remained between ICV and late life cognition. This suggests that early life factors pay a role in how well we age, though the relationship is complex. The regional measures chapters look at two brain regions commonly associated with ageing, the hippocampus and the frontal lobes. Measuring either of these brain regions in large samples of healthy older adults is challenging for many reasons. The hippocampus is small and as with all brain regions shows greater variation in older age, this makes employing automated methods that have the advantage of being fast and reproducible difficult. Following the results of our systematic review of automated methods for measuring the hippocampus, the two most commonly used and available automated methods were validated against reference standard measurements. The results indicated that although automated methods present an attractive alternative to laborious manual measurements they still require manual editing to produce accurate measurements in older adults. The modified strategy employed across the LBC1936 was to use an automated method and then manually edit the output; these segmentations were used to investigate the potential of multimodal image analysis in clarifying associations between the hippocampus and cognitive ability in old age. The analysis focused on associations between longitudinal relaxation time (T1), magnetization transfer ratio (MTR), fractional anisotropy (FA) and mean diffusivity (MD) in the hippocampus and general factors of fluid intelligence, cognitive processing speed and memory. The findings show that multi-modal MRI assessments were more sensitive than volumetric measurements at detecting associations with cognitive measures. The difficulty with producing a relevant frontal lobe measure was made apparent when the result of a large systematic review looking at the manual protocols used revealed 19 methods and 15 different landmarks had been employed. This resulted in an analysis that took the 5 most common boundaries reported and applied them to 10 randomly selected participants from the LBC1936. The results showed significant differences between the resultant volumes, with the smallest measurement when using the genu as the posterior marker representing only 35% of the measurement acquired using the central sulcus. The results from the studies presented in this thesis strongly highlight the need to develop age specific methods when using brain MRI to study ageing. Furthermore the implications of using unstandardised protocols, making assumptions about a methods performance based on validation in younger samples and the need to account for early life factors in this area of research have been made clearer. Studies building on these findings will be beneficial in elucidating the role of the brain in ageing.