The association between steroid hormones and cognitive performance in adulthood

ENGLISH The aim of this thesis was to investigate whether endogenous estrogen and testosterone were associated with cognitive performance in adulthood and whether hand preference affected the pattern of sex differences in cognitive performance. The analyses in Studies I-IV were based on data from the Betula project in Umea, Sweden; a population-based longitudinal study on aging and memory. At the second follow-up, there were 3011 participants between 35 and 90 years of age, some entering the project for the first time and others visiting the second or third time. In Study I, the association between endogenous testosterone and cognitive performance was investigated in men and women. We used (a) a reliable hormone assay, (b) a wide range of cognitive measures to discern regular trends in the data, and (c) participants of a wide age range to explore the hypothesized age-testosterone interaction. The results showed a positive association between testosterone and performance on episodic and spatial tasks for men that increased with age. In contrast, there was a negative trend between testosterone and cognitive performance in women. The results show that testosterone has a sex specific effect on cognition, with opposite directional effects observed for men and women. The aim of Study II was to investigate whether there were sex differences in cognitive performance in non-right-handed individuals. Given that the bulk of individuals are righthanded, reports of sex differences are based on the majori studies have found an interaction between sex and hand preference in cognitive performance. Results from Study II revealed that there were sex differences in episodic memory, verbal fluency, and spatial ability among right-handed, but not among non-right-handed individuals. Non-right-handed men tended to perform better on verbal tasks and lower on the spatial task in contrast to right-handed men. Furthermore, non-right-handed women showed the reverse pattern, with lower verbal and higher spatial performance as compared to right-handed women. Tentatively, these data suggest atypical lateralization pattern for right-handed and non-right-handed individuals. In Studies III and IV, the aim was to investigate whether the diminishing levels of estrogen in menopause were associated with cognitive decline. When cross-sectional data was investigated in Study III, no association between menopause phase and cognitive performance was found. In Study IV, longitudinal data was explored to investigate whether cognitive performance changed systematically for women passing through menopause, independent of age-related change in cognition. Results indicate that post-menopausal women show accelerated decline, or less gain, on tasks that measure spatial ability, verbal fluency, and episodic memory. The association between estrogen and accelerated rate of change was most pronounced in normal weight women. This association may reflect the fact that estrogen is largely produced in fat tissue post menopause, with women with higher body mass index (BMI) values having higher levels of estrogen. This thesis shows that (a) there is a positive association between testosterone and cognitive performance in men, a relationship that increases with increasing age, (b) there are no sex differences in cognition in groups of non-right-handed individuals, (c) cognitive performance does not differ between groups of pre-, peri-, and postmenopausal women, but (d) following menopause, women reveal a higher rate of change for some cognitive measures independent of age-related cognitive change, an effect that is chiefly observed for women with normal BMI. ABSTRAKT SVENSKA Syftet med denna avhandling var att undersoka huruvida endogent ostrogen och testosteron ar kopplade till kognitiv prestation i vuxen alder och om handpreferens har en effekt pa monstret i kognitiva konsskillnader. Analyserna i Studie I-IV ar baserade pa data fran Betulaprojektet i Umea, Sverige; en populationsbaserad longitudinell studie rorande aldrande och minne. Vid den andra uppfoljningen inbegrep studien 3011 individer mellan 35 och 90 ar, nagra deltog for forsta gangen och andra hade varit med vid tidigare testtillfallen. I Studie I, undersoktes associationen mellan endogent testosteron och kognitiv prestation hos man och kvinnor. I Studie I anvandes (a) en palitlig hormonanalys, (b) ett brett urval av kognitiva matt for att kunna skonja regelbundna trender i data, och (c) och ett brett aldersspann sa att eventuell interaktion mellan alder och testosteron kunde undersokas. Resultaten visade ett positivt samband som tilltar med alder mellan testosteron och prestation i episodiskt minne och spatial formaga hos man. Hos kvinnor, daremot, fanns en negativ trend mellan testosteron och kognitiv prestation. Resultaten indikerar att testosteron har en konsspecifik effekt pa kognition, med motsatt riktning for man och kvinnor. Syftet med Studie II var att undersoka huruvida det finns konsskillnader i kognitiv prestation for icke-hogerhanta personer. Eftersom att flertalet individer ar hogerhanta sa utgar rapporter kring konsskillnader fran majoritetens kognitiva profil. Tidigare studier har funnit en interaktion mellan kon och handpreferens i kognitiv prestation. Resultaten fran Studie II visade konsskillnader i episodiskt minne, verbalt flode och spatial formaga for hogerhanta, men inte for icke-hogerhanta individer. Icke-hogerhanta man tenderar att prestera pa en hogre niva pa verbala test och lagre pa spatiala uppgifter an hogerhanta man. Vidare visar ickehogerhanta kvinnor ett omvant resultat, med lagre verbal och hogre spatial formaga, jamfort med hogerhanta kvinnor. Dessa resultat indikerar ett eventuellt atypiskt lateraliseringsmonster for hogerhanta och icke-hogerhanta individer. I Studie III och IV var syftet att undersoka huruvida minskningen i ostrogen i klimakteriet ar associerad med kognitiv nedgang. Nar tvarsnittsdata undersoktes i Studie III kunde inget samband mellan klimakteriefas och kognitiv prestation skonjas. I Studie IV undersokte vi longitudinellt huruvida kognitiv prestation forandras hos kvinnor som genomgar klimakteriet med hansyn tagen till den aldersrelaterade forandringen i kognition. Resultaten visade att kvinnor efter klimakteriet forsamras i hogre takt, eller visar mindre forbattring, i uppgifter som mater spatial formaga, verbalt flode och episodiskt minne. Sambandet mellan ostrogen och snabbare forandringstakt finns framfor allt hos normalviktiga kvinnor. Associationen speglar mojligen faktumet att ostrogen huvudsakligen produceras i fettvavnad efter klimakteriet, dar kvinnor med hogre body mass index (BMI) ocksa har hogre nivaer av ostrogen. Avhandling visar att (a) det finns ett positivt samband mellan testosteron och kognitiv prestation hos man, ett samband som okar med tilltagande alder, (b) konsskillnader i kognition inte kan pavisas for icke-hogerhanta individer, (c) den kognitiva prestationen inte skiljer sig at mellan grupper av kvinnor fore, i och efter klimakteriet, men (d) att kvinnor efter klimakteriet visar en okad nedgang i vissa kognitiva uppgifter utover aldersrelaterade kognitiva forandringar, en effekt som framfor allt kan ses hos kvinnor med normalt BMI. LIST OF PUBLICATIONS I Thilers P.P., MacDonald S.W. , Herlitz A. 2006. The association between endogenous free testosterone and cognitive performance: A population-based study in 35 to 90-year-old men and women. Psychoneuroendocrinology, 31, 565-576. II Thilers P.P., MacDonald S.W. , Herlitz A. 2007. Sex differences in cognition: The role of handedness. Physiol Behav, 92, 105-109. III Herlitz A. , Habib R. , Thilers P.P. 2007. Endogenous estrogen is not associated with cognitive performance before, during, or after menopause. Menopause, 14, 425-431. IV Thilers P.P., MacDonald S.W. , Nilsson L-G. , Herlitz A. Accelerated postmenopausal cognitive decline is restricted to women with normal BMI: Longitudinal evidence from the Betula Project. Submitted CONTENTS