Immune system-wide Mendelian randomization and triangulation analyses support autoimmunity as a modifiable component in dementia-causing diseases

Publisher Copyright: © 2022, The Author(s).Immune system and blood–brain barrier dysfunction are implicated in the development of Alzheimer’s and other dementia-causing diseases, but their causal role remains unknown. We performed Mendelian randomization for 1,827 immune system- and blood–brain barrier-related biomarkers and identified 127 potential causal risk factors for dementia-causing diseases. Pathway analyses linked these biomarkers to amyloid-β, tau and α-synuclein pathways and to autoimmunity-related processes. A phenome-wide analysis using Mendelian randomization-based polygenic risk score in the FinnGen study (n = 339,233) for the biomarkers indicated shared genetic background for dementias and autoimmune diseases. This association was further supported by human leukocyte antigen analyses. In inverse-probability-weighted analyses that simulate randomized controlled drug trials in observational data, anti-inflammatory methotrexate treatment reduced the incidence of Alzheimer’s disease in high-risk individuals (hazard ratio compared with no treatment, 0.64, 95% confidence interval 0.49–0.88, P = 0.005). These converging results from different lines of human research suggest that autoimmunity is a modifiable component in dementia-causing diseases.Peer reviewe

Immune system-wide Mendelian randomization and triangulation analyses support autoimmunity as a modifiable component in dementia-causing diseases

Immune system and blood–brain barrier dysfunction are implicated in the development of Alzheimer’s and other dementia-causing diseases, but their causal role remains unknown. We performed Mendelian randomization for 1,827 immune system- and blood–brain barrier-related biomarkers and identified 127 potential causal risk factors for dementia-causing diseases. Pathway analyses linked these biomarkers to amyloid-β, tau and α-synuclein pathways and to autoimmunity-related processes. A phenome-wide analysis using Mendelian randomization-based polygenic risk score in the FinnGen study (n = 339,233) for the biomarkers indicated shared genetic background for dementias and autoimmune diseases. This association was further supported by human leukocyte antigen analyses. In inverse-probability-weighted analyses that simulate randomized controlled drug trials in observational data, anti-inflammatory methotrexate treatment reduced the incidence of Alzheimer’s disease in high-risk individuals (hazard ratio compared with no treatment, 0.64, 95% confidence interval 0.49–0.88, P = 0.005). These converging results from different lines of human research suggest that autoimmunity is a modifiable component in dementia-causing diseases

Genome-wide association study to identify single nucleotide polymorphisms associated with diabetic nephropathy and estimated glomerular filtration rate in FIND study

Diabetes mellitus is characterized by a chronic increase in blood glucose levels due to a dysfunction of carbohydrate, fat and protein metabolism, which in turn are the result of insulin resistance and/or insulin action disturbances. Its cardinal symptoms include polyuria, thirst and weight loss; its long term complications include neuropathy, nephropathy, and retinopathy. It is predicted that this rate will increase to 9.9% of the adult population by 2030. Although the rate of new cases of End Stage Renal Disease (ESRD) in 2011 decreased 4.2% compared to the year 2010, nephropathy due to diabetes continued to be the most common cause of ESRD in the USA. In this study a genome-wide association approach has been performed to identify loci associated with diabetic nephropathy (DN) and variation in estimated Glomerular Filtration Rate (eGFR) value in three distinct ethnic groups, i.e. African American, Mexican American and European American; additionally, the effect of sex has also been studied to reveal potential sex dependency on the loci associated with DN and eGFR value. Dataset provided in "The Family Investigation of Nephropathy and Diabetes” (FIND) Study, contains genotype of 1454 individuals with DN and 1168 individuals without DN .After conducting genome-wide association analyses, in this study, the strongest association with DN and/or eGFR values have been detected on the regions located on the 2p, 2q, 3q, 4q, 5q, 7q, 8q, 9q, 12q, 14q, 15q and Xq chromosomes

Genetic analysis of obstructive sleep apnoea and its associations to cardiometabolic diseases and COVID-19

Obstructive sleep apnoea (OSA) is the most common sleep-related breathing disorder and is characterized by recurrent episodes of complete or partial obstruction of the upper airway leading to reduced or absent breathing during sleep. The prevalence of OSA in adults is approximately 25% in developed countries. The main known risk factors for OSA are increasing age, male sex, menopause, obesity and certain craniofacial structures and anomalies. The role of OSA on the risk of adverse cardiovascular outcomes has been widely studied, and mechanisms linking OSA to its cardiometabolic correlates through intermittent hypoxia, oxidative stress and increasing sympathetic activity are also recognized. Despite the fact that the epidemiology of OSA has been under research for decades, the genetics behind OSA risk have remained mainly unstudied. However, family studies have shown that family members are at a 2–4-fold greater risk of having OSA if there are OSA patients in the family. It is estimated that 40% of the variation in the apnoea-hypopnoea-index (AHI) is genetically regulated. Previous genome-wide-association studies (GWASes) have addressed OSA severity based on AHI or respiratory event duration, but case-control studies have not been previously published. The World Health Organization (WHO) announced COVID-19 as a pandemic in March 2020. Patients with COVID-19 have a wide range of symptoms ranging from mild flu-like symptoms to severe illness. The first studies regarding COVID-19 revealed that male gender, higher age, obesity and diabetes are risk factors for the severe form of the disease, indicating that OSA and COVID-19 share numerous common risk factors and comorbidities. Furthermore, studies have suggested that OSA is a risk factor for the severe form of COVID-19. We estimated the role of OSA in major cardiometabolic disease by utilizing population-based cohorts, including FINRISK, Health 2000 and a subset of the Botnia Study, and registry information to longitudinally assess OSA risk in the Finnish population. Our data consisted of 36,963 individuals with over 500,000 person-years and up to twenty-five years of follow-up data, including 1,568 OSA patients. Using Cox-proportional hazards models, our results revealed that OSA is associated with a 1.36-fold increased risk for coronary heart disease (CHD), including a 2.01-fold increased risk in women independent of other potential confounding factors. Similarly, type 2 diabetes (T2D) correlated with OSA independent of obesity status and revealed a 1.48-fold increased risk. This association was also significant in women, showing a 1.63-fold increased risk. The risk of diabetic kidney disease (DKD) was increased by 1.75-fold in patients with OSA among the T2D study sample. All-cause mortality was increased in individuals with both OSA and T2D by 35%. To study the genetic burden for the risk of OSA we proceeded to identify genetic loci associated with OSA risk and aimed to test if OSA and its comorbidities share a common genetic basis. To elucidate these aims, data from the FinnGen project was used. The FinnGen project combines patient genotype data and nationwide registry information with anthropometric measurements, such as body mass index (BMI) and smoking. Using this information, we conducted the first large-scale case-control GWAS of OSA with 217,955 individuals including 16,761 OSA patients. We identified five genetic loci associated with OSA, highlighting the importance of genetic variation on OSA predisposition. This was further supported by our single nucleotide polymorphism (SNP)-based heritability estimates. We also showed the causal relationship between obesity and OSA by utilizing Mendelian randomization (MR). Although BMI is the major risk factor, we were also able to find a BMI-independent genetic locus for OSA that is associated with antidepressant purchases. However, we could not replicate this locus in independent cohorts. In addition, we found strong genetic correlations between OSA and its comorbidities including BMI, hypertension, T2D, CHD, stroke, depression, hypothyroidism, asthma and inflammatory rheumatic diseases (IRD) in addition to other sleep traits such as sleepiness and sleep efficiency. These findings implicate OSA as a heterogenic disease with several distinct comorbidities, which would be beneficial to consider when treating patients with OSA. When COVID-19 emerged, it became apparent that the risk factors for the severe form of the disease showed similarities with OSA risk factors and comorbidities. Our aim was to study if OSA patients have a higher risk for hospitalisation due to COVID-19 disease in addition to other potential confounding factors, and if OSA associates with an increased risk of contracting COVID-19. We studied 445 individuals with COVID-19 including thirty-eight OSA patients extracted from the FinnGen project data (N=260,405). Of the OSA patients, nineteen required hospital treatment due to COVID-19 infection. OSA was associated with a 2.93-fold increased risk of COVID-19 hospitalisation independent of age, sex, BMI and other comorbidities. The results were further confirmed in a meta-analysis including 15,835 individuals. Importantly, treatment information regarding OSA was also collected and suggested that moderate and severe OSA is a risk factor for severe COVID-19 even if the OSA is well managed. This thesis concentrates on studying OSA as a risk factor for cardiometabolic comorbidities, the genetic variation between OSA and non-OSA individuals and whether OSA creates an elevated risk for severe COVID-19 disease. These studies were conducted by utilizing large and accurate data sets with an epidemiological and longitudinal ascertainment, and by applying modern genetic methods to show that OSA is a relevant topic during the exceptional times of the global COVID-19 pandemic.Obstruktiivisella uniapnealla (uniapnea) tarkoitetaan toistuvia unenaikaisia vähintään kymmenen sekunnin mittaisia hengityskatkoksia (apnea) tai hengityksen vaimentumia (hypopnea), jotka johtuvat ylähengitysteiden ahtautumisesta. Uniapnean prevalenssin on arvioitu olevan jopa 25 % aikuisväestössä. Sen tunnetuimmat riskitekijät ovat korkea ikä, miessukupuoli, vaihdevuosi-ikä, ylipaino ja tietyt kraniofakiaaliset piirteet, kuten pieni tai takana sijaitseva alaleuka. Uniapnean ja sydän- ja verisuonitautien yhteyttä on tutkittu laajasti epidemiologisin tutkimusmenetelmin, ja niitä yhdistävät mekanismit, kuten jaksottainen hapenpuute, oksidatiivinen stressi ja uniapnean vaikutukset sympaattisen hermoston aktiivisuuden lisääntymiseen, tunnetaan. Epidemiologisista tutkimuksista ja tuloksista huolimatta uniapean genetiikan tutkimus on ollut melko vähäistä. Viitteitä on saatu siitä, että uniapneapotilaan perheenjäsenellä on 2–4-kertainen riski sairastua uniapneaan ja lisäksi on arvioitu, että 40 % apnea-hypopnea-indeksin variaatiosta on geneettisesti säädelty. Genominlaajuinen assosiaatioanalyysi on tuonut uuden menetelmän analysoida yleisiä kompleksisia tauteja, kuten uniapneaa. Näissä aiemmissa uniapneaa koskevissa tutkimuksissa on tutkittu taudin vaikeusastetta ja hengitystapahtuman kestoa. Kuitenkaan tapaus-verrokki -tutkimusta koskien uniapneaa ei ole aiemmin julkaistu. Joulukuussa 2019 Kiinan Wuhanista alkoi epidemia, jonka aiheuttajana on ihmiselle uusi koronavirus. Sen aiheuttama tauti on viralliselta nimeltään COVID-19. Virus levisi nopeasti maailmanlaajuisesti ja maaliskuussa 2020 Maailman terveysjärjestö WHO julisti koronavirusepidemian pandemiaksi. COVID-19 aiheuttaa useimmille lieväoireisen hengitystieinfektion, mutta osalle potilaista infektio voi olla jopa henkeä uhkaava. Vakavan COVID-19 infektion riskitekijöihin kuuluvat mm. korkea ikä, ylipaino ja diabetes. Näin ollen COVID-19 ja uniapnea jakavat suuren määrän samoja riskitekijöitä ja liitännäissairauksia. Lisäksi on havaittu, että uniapnea voi lisätä riskiä vakalle COVID-19-infektiolle. Arvioimme uniapnean aiheuttamaa riskiä koronaaritaudille, tyypin 2 diabetekselle, diabeteskomplikaatioille ja kuolleisuudelle hyödyntämällä FINRISKI ja Terveys 2000 kohortteja sekä osajoukkoa Botnia-tutkimuksesta. Tutkimuksemme sisälsi 36 963 henkilöä ja se kattoi yli 500 000 henkilövuotta yltäen jopa yli 25-vuoden seuranta-aikaan. Käyttämällä Cox-elinaikamallia havaitsimme, että uniapnea liittyy koronaaritaudin riskiin 1.36-kertaisesti riippumatta muista riskitekijöistä, kuten verenpainetaudista tai painoindeksistä. Tämä yhteys nähtiin myös naisilla, joilla yhteys riskiin nousi 2.01-kertaiseksi. Vastaavasti uniapnean havaittiin olevan ylipainosta riippumaton riskitekijä tyypin 2 diabetekselle liittyen riskiin 1.48-kertaisesti. Vaikutus havaittiin myös naisilla, joilla uniapnea yhdistyi 1.63-kertaiseen riskiin. Lisäksi uniapnea assosioitui kohonneeseen riskiin diabeetikkojen munuaissairauksille 1.75-kertaisesti ja uniapnean nähtiin lisäävän kuolleisuutta 35 % tyypin 2 diabeetikoilla. Tutkiaksemme uniapnean genetiikkaa hyödynsimme FinnGen-aineistoa, joka yhdistää genomitietoja kansallisiin terveysrekistereihin. Tarkastelimme uniapneaa käyttämällä genominlaajuista assosiaatioanalyysiä sisältäen 217 955 henkilöä, joista 16 761:lla oli uniapneadiagnoosi. Löysimme viisi uniapneariskiin assosioituvaa lokusta. Tämä tutkimus korostaa geneettisen variaation merkitystä uniapnealle altistumisessa, jota heritabiliteettilöydöksemme vahvistaa. Näytimme lisäksi mendeliaanisen randomisaation avulla, että ylipainon ja uniapnean välillä on kausaalinen suhde, joka on ollut nähtävissä epidemiologisissa tutkimuksissa. Huolimatta siitä, että ylipaino on uniapnean tärkein riskitekijä, löysimme painoindeksistä riippumattoman lokuksen, joka oli spesifi uniapneadiagnoosille, ja joka yhdistyi masennuslääkeostoihin. Tätä tulosta emme kuitenkaan onnistuneet toistamaan itsenäisissä aineistoissa. Havaitsimme voimakkaita geneettisiä korrelaatioita uniapnean ja sen liitännäissairauksien, kuten verenpainetaudin, tyypin 2 diabeteksen, koronaaritaudin, depression, kilpirauhasen vajaatoiminnan, astman ja inflammatoristen reumasairauksien välillä. Lisäksi geneettiset korrelaatiot olivat vahvoja uniapean ja päiväväsymyksen sekä unen tehokkuuden välillä. Nämä havainnot viittaavat siihen, että uniapnea on heterogeeninen sairaus, johon liittyy useita eri tauteja, jotka tulisi huomioida uniapneapotilaita hoidettaessa. Tarkastelimme lisäksi uniapnean aiheauttamaa riskiä vakavalle COVID-19-infektiolle ja mahdollisesti uniapneapotilaiden suurentunutta riskiä saada infektio. Hyödyntämällä FinnGen-kohorttia (N=260,405) aineistomme sisälsi 445 COVID-19 positiivista henkilöä, joista 38:lla oli lisäksi uniapneadiagnoosi. Heistä 19 tarvitsi sairaalahoitoa COVID-19 aiheuttaman infektion vuoksi. Uniapnea liittyi 2.93-kertaiseen riskiin vakavalle infektiolle riippumatta muista riskitekijöistä, kuten iäistä, sukupuolesta, painoindeksistä, verenpainetaudista, tyypin 2 diabeteksesta, koronaaritaudista, keuhkoahtaumataudista ja astmasta. Lisäksi teimme meta-analyysin, joka sisälsi 15 835 COVID-19 positiiviseksi testattua henkilöä vahvistaen tietoutta uniapnean aiheuttamasta kohonneesta riskistä. Keräsimme uniapneapotilaiden hoitotietoja ennen sairastumista COVID-19-infektioon ja havaitsimme, että vaikka suurin osa uniapneapotilaista oli hoidettu, vaativat he silti sairaalahoitoa. Tämä antaa viitteitä siitä, että keskivaikea ja vaikea uniapnea on hoidettunakin riskitekijä vakavalle COVID-19-infektiolle. Tämä väitöskirja tutkii uniapnean yhteyttä kardiometabolisten sairauksien ilmaantuvuuteen ja niiden riskitekijöihin. Samalla se selvittää geneettistä vaihtelua uniapneapotilaiden ja ei-uniapneapotilaiden välillä tarkastellen lisäksi uniapnean geneettistä yhteyttä sen liitännäissairauksiin hyödyntämällä laajoja kansallisia aineistoja epidemiologisesta ja geneettisestä näkökulmasta luoden katsauksen uniapneasta suomalaisessa väestössä. Tutkimuksissa on hyödynnetty niin pitkittäistutkimukseen soveltuvia kuin uusimpia geneettiseen laskentaan kehiteltyjä menetelmiä. Lisäksi keskivaikean ja vaikean uniapnean yhteys COVID-19-infetion vakavaan muotoon nostaa sen hyvin ajankohtaiseksi aiheeksi pandemian aikana

LITERATURE MINING SUSTAINS AND ENHANCES KNOWLEDGE DISCOVERY FROM OMIC STUDIES

Genomic, proteomic and other experimentally generated data from studies of biological systems aiming to discover disease biomarkers are currently analyzed without sufficient supporting evidence from the literature due to complexities associated with automated processing. Extracting prior knowledge about markers associated with biological sample types and disease states from the literature is tedious, and little research has been performed to understand how to use this knowledge to inform the generation of classification models from ‘omic’ data. Using pathway analysis methods to better understand the underlying biology of complex diseases such as breast and lung cancers is state-of-the-art. However, the problem of how to combine literature-mining evidence with pathway analysis evidence is an open problem in biomedical informatics research. This dissertation presents a novel semi-automated framework, named Knowledge Enhanced Data Analysis (KEDA), which incorporates the following components: 1) literature mining of text; 2) classification modeling; and 3) pathway analysis. This framework aids researchers in assigning literature-mining-based prior knowledge values to genes and proteins associated with disease biology. It incorporates prior knowledge into the modeling of experimental datasets, enriching the development process with current findings from the scientific community. New knowledge is presented in the form of lists of known disease-specific biomarkers and their accompanying scores obtained through literature mining of millions of lung and breast cancer abstracts. These scores can subsequently be used as prior knowledge values in Bayesian modeling and pathway analysis. Ranked, newly discovered biomarker-disease-biofluid relationships which identify biomarker specificity across biofluids are presented. A novel method of identifying biomarker relationships is discussed that examines the attributes from the best-performing models. Pathway analysis results from the addition of prior information, ultimately lead to more robust evidence for pathway involvement in diseases of interest based on statistically significant standard measures of impact factor and p-values. The outcome of implementing the KEDA framework is enhanced modeling and pathway analysis findings. Enhanced knowledge discovery analysis leads to new disease-specific entities and relationships that otherwise would not have been identified. Increased disease understanding, as well as identification of biomarkers for disease diagnosis, treatment, or therapy targets should ultimately lead to validation and clinical implementation

Genetic and Epigenetic Determinants of Thrombin Generation Potential : an epidemiological approach

Thrombin Generation Potential (TGP) is a promising in vitro measurement that allows quantifying thrombin activity, in a close way to what happens in vivo. It is sensitive to coagulation factors deficiencies, anticoagulant proteins and is associated to thrombotic disorders. There exists two polymorphisms located in the F2 (prothrombin) gene known to influence TGP levels, and altogether they explain 11.3% of the TGP inter-individual variability. With the aims of identifying novel genetic and epigenetic factors that influence TGP variability, I have performed two different studies in the present work. First, I conducted the first genome-wide association study for the three TGP biomarkers (ETP, Peak and Lagtime) using imputation data from two French studies. The most significant single nucleotide polymorphisms (SNPs) were then replicated in two independent French studies. This analysis lead to the discovery of ORM1 as a new gene participating to the control of TGP. Second, I followed a similar strategy using this time whole blood DNA methylation levels at CpG sites to identify DNA methylation marks involved in TGP variability. I analyzed the association between methylation-wide patterns from a French study and a French-Canadian families measured for TGP. Unfortunately, I did not identify robust associations between whole DNA methylation levels and thrombin generation.Le potentiel de génération thrombine (TGP en anglais) est une nouvelle mesure qui permet de quantifier in vitro l'activité globale de la thrombine reflétant bien les mécanismes in vivo de la coagulation. Ce méthode de dosage est sensible aux déficits de facteurs de coagulation, à la prise d'anti-coagulants et à de nombreux troubles de la coagulation. Au moment où j'ai débuté ma thèse, seuls deux polymorphismes génétiques, tous les deux situés dans le gène F2 codant pour la prothrombine, étaient connus pour influencer la variabilité plasmatique du TGP. Mon projet de thèse avait pour objectifs d'identifier de nouveaux facteurs génétiques, mais également épigénétiques, pouvant influencer les taux plasmatiques de TGP. Dans une première partie, j'ai mené la toute première étude d'association génome-entier (GWAS pour Genome Wide Association Study en anglais) sur 3 biomarqueurs (temps de latence, quantité totale de thrombine produite et niveau maximal de thrombine produite) du TGP dans deux études françaises rassemblant 1267 sujets et j'ai répliqué les résultats les plus significatifs dans deux autres études françaises indépendantes de 1344 sujets. Cette stratégie a permis de mettre en évidence qu'un polymorphisme génétique du gène ORM1 était associé de manière robuste au temps de latence, biomarqueur caractérisant le temps nécessaire pour initier la coagulation après induction. Dans la seconde partie de ma thèse, en suivant une stratégie similaire mais cette fois-ci en étudiant non plus des polymorphismes génétiques mais des marques de méthylation d'ADN, j'ai recherché si des niveaux de méthylation de site CpG, mesurés à partir d'ADN sanguin et couvrant l'ensemble du génome, pouvaient être associés à la variabilité des 3 mêmes biomarqueurs de TGP. Malheureusement, à partir de deux échantillons mis à ma disposition et rassemblant 425 sujets, je n'ai pas pu mettre en évidence d'association robuste entre des marques de méthylation sanguine et la génération trombine

Liver Tumors

This book is oriented towards clinicians and scientists in the field of the management of patients with liver tumors. As many unresolved problems regarding primary and metastatic liver cancer still await investigation, I hope this book can serve as a tiny step on a long way that we need to run on the battlefield of liver tumors

Effects of an 8-week Swedish massage program on quality of life, sleep, stress, fatigue, cortisol, c-reactive protein and cytokines in breast cancer survivors

Background: Many women who have received treatment for breast cancer have a high risk of developing late side effects or persistent cancer-related symptoms (CRS). Although massage therapy (MT) showed to provide positive results in the management of CRS, only a few studies have been conducted to examine persistent CRS in breast cancer survivors (BCS). Additionally, more robust examinations of the biological effects of most integrative therapies, including MT, remains needed. Objective: To investigate the effects of an 8-week Swedish massage program on quality of life (QoL), sleep, stress, fatigue, cortisol, c-reactive protein (CRP) and pro-inflammatory cytokines in BCS. Methodology: Females over 18 years who were diagnosed with breast cancer - stages I to III and have completed the treatment in the last six months were recruited. Participants underwent a one-hour session of MT once a week. Subjects were assessed for QoL, fatigue, stress, sleep and inflammatory markers before the beginning of the study (baseline), every two weeks during intervention period (assessment 1 and 2) and one week after the program (endpoint). The Functional Assessment of Cancer Therapy Fatigue was chosen to measure QoL and fatigue, and the Perceived Stress Scale was used to measure stress. Circadian sleep-wake rhythms were measured noninvasively through Actigraphy. Saliva was collected to detect the following markers: cortisol, CRP, IL-1β, IL-6, TNF-α and IFN-. Oximetry, heart rate and blood pressure were measured pre and post every MT session. Results: A total of 24 participants completed the study. The average age of participants was 56.9 (±9.3). QoL improvements were significantly associated with time after cancer treatment completion and cancer stage. Changes in fatigue scores were significantly associated with sleep aids in use and comorbidities. Stress levels significantly improved at endpoint in comparison to baseline, regardless of any covariates tested. Wake after sleep onset showed improvement at endpoint. Sleep onset latency improvement was only significant for Stage III patients. Sleep duration did not show any significant improvement. Subjects showed superior sleep efficiency at the end of the program, however, changes did not attain statistical significance. Overall, all the biomarkers decreased at endpoint in comparison to baseline; however, only cortisol, IL-1β and TNF-α reached significant changes, with IL-1β showing important associations with cancer stage and hormone therapy. Heart rate and oxygen levels improved right after sessions, and blood pressure slightly increased. Conclusion: This study reveals evidence of a positive effect of MT in QoL, fatigue, stress, some sleep parameters, oxygen levels, heart rate, cortisol, IL-1β and TNF-α

Cardiovascular risk factors since childhood and cognitive performance in midlife: The Cardiovascular Risk in Young Finns Study

According to the World Health Organization, dementia and cognitive deficits are major global health and social care challenges in the 21st century. As the population ages, the need for preventive means against cognitive deficits becomes crucial. The risk of cognitive deficits is influenced by e.g., cardiovascular risk factors, which may begin to exert their influence decades before any detectable cognitive symptoms. This thesis aims to close the existing knowledge gap on the association between the cardiovascular risk factors since childhood and cognitive performance in midlife. The specific aim is to study how 1) physical activity accumulation since childhood; 2) blood pressure, serum lipids, obesity, and their accumulation since childhood; and 3) serum creatinine since adulthood are associated with cognitive performance. This thesis is a part of the prospective population-based Cardiovascular Risk in Young Finns Study that focuses on cardiovascular risk factors from childhood to adulthood with a follow-up time of over 30 years. The baseline study was conducted in 1980, with 3,596 randomly selected boys and girls aged between three and 18 participating in clinical examinations. The follow-up studies were conducted in three- to nine-year intervals. In the follow-up study conducted in 2011, the cognitive performance of 2,026 subjects aged between 34 and 49 was assessed using computerized cognitive testing. In this thesis, low physical activity, high blood pressure, elevated total cholesterol and LDL cholesterol, and overweight and obesity since childhood and low serum creatinine since adulthood were observed to be associated with poorer cognitive performance in midlife. Especially, cardiovascular risk factor accumulation (blood pressure, total cholesterol, and obesity) was observed to be associated with poorer cognitive performance in a dose-responsive manner. If these associations turn out to be causal, the observations can be utilized for aiming to better cognitive health in adulthood by targeting preventive means against cardiovascular risk factors already in childhood and adolescence. Hence, those individuals with a worse cardiovascular risk factor profile since childhood might especially benefit from, for example, adopting healthier lifestyle

2012 IMSAloquium, Student Investigation Showcase

Through SIR and its partnerships, IMSA students engage in rich opportunities to pursue compelling questions of interest, conduct investigations, engage with extraordinary advisors, communicate findings, and ultimately impact society.https://digitalcommons.imsa.edu/archives_sir/1004/thumbnail.jp