Mental stimulation and multimodal trials to prevent cognitive impairment and Alzheimer ́s disease

Theoretical models of dynamic biomarkers underlying the development of Alzheimer´s Disease (AD) acknowledge that there is inter-individual variability in the cognitive performance associated with any level of AD pathology. Mentally stimulating activities such as schooling, occupation, and leisure activities, may contribute to this variability, but it is yet unclear how this can be best assessed, and how such effects can vary across AD severity and among individuals at-risk for cognitive impairment. The association between mental stimulation and cognitive performance also suggests that it is important to account for mental stimulation levels in randomized clinical trials (RCTs) comparing rates of cognitive change between interventions (i.e., drugs, lifestyle interventions) and controls. The aim of this thesis was to investigate a) how pre-existing levels of occupational complexity affect the cognitive outcomes of a multimodal lifestyle-based RCT among older adults at increased risk for dementia based on a validated risk score b) if occupational complexity is associated to cognitive performance among individuals at-risk for dementia, including individuals in the early stages of symptomatic AD (prodromal AD) and c) if occupational complexity is associated with resilience to AD pathology, measured with validated biomarkers and neuroimaging among individuals at-risk for cognitive impairment and with prodromal AD. The four studies in this thesis were based on data from the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER), the Karolinska University Hospital electronic database and biobank for clinical research (GEDOC) and The Multimodal Prevention Trial for Alzheimer´s Disease (MIND-ADmini). Study I. This study used data from the FINGER study (N=1026) to investigate if preexisting levels of occupational complexity were associated with cognitive function at baseline, and if occupational complexity was associated with the rate of change in cognition during the 2-year intervention period. For all measures of occupational complexity, higher levels of complexity were associated with better cognitive outcomes at baseline. Occupational complexity was not associated with the rate of cognitive change during the intervention, except for the executive function outcome, for which higher levels of complexity with data predicted increased improvement ((ß[SE]: .028[.014], p=.044). Study II. This study used data from the FINGER neuroimaging cohort, to investigate if the association between occupational complexity and cognition was moderated by measures of brain integrity, both in terms of magnetic resonance imaging (MRI, N=126) and Pittsburgh-B Compound – Positron Emission Tomography (PiB-PET, N=41). The results showed that higher levels of occupational complexity were associated with better cognitive performance for some outcomes after adjusting for Alzheimer’s Disease Signature (ADS) and medial temporal atrophy (MTA). However, for most types of neuropathology and cognitive outcomes, moderation effects indicated that higher occupational complexity levels were associated with better cognitive performance only in people with higher brain integrity, suggesting lack of occupational complexity-related resilience mechanisms. Study III. This study investigated the association between mental stimulation (occupational complexity and education) and validated AD biomarkers, Aβ1–42, p-tau and t-tau measured in cerebrospinal fluid (CSF). Using data from the GEDOC database, 174 individuals with prodromal AD were included, and analyses were adjusted for cognitive function. The results indicated that both higher occupational complexity and education were associated with higher levels of p-tau and t-tau. For education the association with tau pathology was age dependent. No association was found with Aβ1– 42. This suggests that higher education and occupational complexity may provide resilience against tau-related pathology in prodromal AD. Study IV. This study used data from FINGER, GEDOC, and MIND-ADmini, thus including a total of 1410 individuals, 1207 at-risk for dementia and 203 with Prodromal AD. The aim was to to compare the two most common rating systems for occupational complexity, the Occupation Information Network (O*NET) and the Dictionary of Occupational Titles (DOT) and assess if there was an association between occupational complexity and episodic memory performance among individuals at-risk for dementia. The study found that higher occupational complexity was only associated with memory performance in the FINGER cohort but not the two prodromal AD cohorts. The correlation between the two rating systems was moderate to strong, and highly significant (Spearman’s rho = 0.5-0.6, p <.001). Conclusions. Higher levels of Occupational complexity are associated with better cognitive performance among older individuals at-risk for dementia (and with no substantial cognitive impairment), but does not affect the intervention effect in the FINGER multidomain lifestyle-based RCT, apart from the effect on executive function. Occupational complexity does not seem to provide strong resilience against neuropathology among individuals at-risk for cognitive impairment. Among individuals with prodromal AD, higher levels of occupational complexity do seem to provide resilience to tau-related pathology measured with CSF markers but is not associated with better episodic memory performance. Measuring occupational complexity with the DOT or O*NET system seems to yield similar results, as the two systems scores are correlated

The influence of attachment on implicit affective opinions towards caregivers

The influence of attachment quality and style on implicit emotional opinions towards caregivers was measured using an affective priming task very similar to a lexical decision task. The reaction time in milliseconds for each prime and target word combination was recorded and used and indication of associative strength between the two. Two attachment tests was administered, the ASQ-Sw questionnaire, a self-report questionnaire with 40 questions measuring attachment style on five different dimensions and an electronic version of the SBST test, which is a narrative-based test measuring the presence of an secure-base script. The priming task had four different primes, mother and father and two control primes and a total of 128 different negative and positive target words. A total of 33 participants completed all of the tests and results show that one of the attachment styles indicating an insecure attachment had an influence on the participants implicit emotional opinions towards their caregivers, the other attachment styles did not, the two attachment tests was positively linked to each other and showed similar results, gender differences in regard to attachment was also found. The priming task reveled that participants in general had more positive than negative emotional opinions towards their caregivers, especially towards mothers. The participants also had more positive than negative emotional opinions towards the control prime Gandhi but no difference was found for Hitler.Anknytningens påverkan på implicita emotionella åsikter gentemot vårdnadsgivare studerades genom ett experiment som innehöll en affektiv priming uppgift liknande den välkända lexikala beslutsuppgiften ”lexical decision task” (LDT). Reaktionstiden i millisekunder för varje prime och mål ord kombination registrerades och användes som indikator för den associativa styrkan mellan de två. Två anknytningstest administrerades, dels ASQ-Sw testet, som är ett självfrågeformulär innehållande 40 frågor som mäter anknytning på fem olika dimensioner samt en elektronisk version av SBST testet, vilket är ett narrativt test för att mäta förekomsten av säker bas skript. Priming testet hade fyra olika primes, mamma och pappa samt två kontroll primes och totalt 128 stycken olika positiva och negativa mål ord. 33 stycken deltagare genomförda samtliga tre tester och resultaten visade att en av anknytningsstilarna som indikerar en osäker anknytning påverkade deltagarnas implicita emotionella åsikter gentemot deras vårdnadsgivare, de andra anknytningsstilarna uppvisade inget sammanband. De två anknytningstesten som användes var positivt sammanlänkade och visade liknande resultat, könsskillnader i anknytning hittades också. Priming testet visade att deltagarna generellt hade mer positiva än negativa åsikter om deras vårdnadsgivare, speciellt gentemot deras mammor, deltagarna hade också mer positiva än negativa åsikter gentemot Gandhi medan inga skillnader fanns för Hitle

Proton translocating nicotinamide nucleotide transhydrogenase from E. coli. Mechanism of action deduced from its structural and catalytic properties11This review is dedicated to the memory of Professor Lars Ernster.

AbstractTranshydrogenase couples the stereospecific and reversible transfer of hydride equivalents from NADH to NADP+ to the translocation of proton across the inner membrane in mitochondria and the cytoplasmic membrane in bacteria. Like all transhydrogenases, the Escherichia coli enzyme is composed of three domains. Domains I and III protrude from the membrane and contain the binding site for NAD(H) and NADP(H), respectively. Domain II spans the membrane and constitutes at least partly the proton translocating pathway. Three-dimensional models of the hydrophilic domains I and III deduced from crystallographic and NMR data and a new topology of domain II are presented. The new information obtained from the structures and the numerous mutation studies strengthen the proposition of a binding change mechanism, as a way to couple the reduction of NADP+ by NADH to proton translocation and occurring mainly at the level of the NADP(H) binding site

Role of regulatory T cells in acute myeloid leukemia patients undergoing relapse-preventive immunotherapy

Regulatory T cells (Tregs) have been proposed to dampen functions of anti-neoplastic immune cells and thus promote cancer progression. In a phase IV trial (Re:Mission Trial, NCT01347996, http://www.clinicaltrials.gov ) 84 patients (age 18-79) with acute myeloid leukemia (AML) in first complete remission (CR) received ten consecutive 3-week cycles of immunotherapy with histamine dihydrochloride (HDC) and low-dose interleukin-2 (IL-2) to prevent relapse of leukemia in the post-consolidation phase. This study aimed at defining the features, function and dynamics of Foxp3+CD25highCD4+ Tregs during immunotherapy and to determine the potential impact of Tregs on relapse risk and survival. We observed a pronounced increase in Treg counts in peripheral blood during initial cycles of HDC/IL-2. The accumulating Tregs resembled thymic-derived natural Tregs (nTregs), showed augmented expression of CTLA-4 and suppressed the cell cycle proliferation of conventional T cells ex vivo. Relapse of AML was not prognosticated by Treg counts at onset of treatment or after the first cycle of immunotherapy. However, the magnitude of Treg induction was diminished in subsequent treatment cycles. Exploratory analyses implied that a reduced expansion of Tregs in later treatment cycles and a short Treg telomere length were significantly associated with a favorable clinical outcome. Our results suggest that immunotherapy with HDC/IL-2 in AML entails induction of immunosuppressive Tregs that may be targeted for improved anti-leukemic efficiency

Occupational complexity and cognition in the FINGER multidomain intervention trial

Introduction Lifetime exposure to occupational complexity is linked to late-life cognition, and may affect benefits of preventive interventions. Methods In the 2-year multidomain Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER), we investigated, through post hoc analyses (N = 1026), the association of occupational complexity with cognition. Occupational complexity with data, people, and substantive complexity were classified through the Dictionary of Occupational Titles. Results Higher levels of occupational complexity were associated with better baseline cognition. Measures of occupational complexity had no association with intervention effects on cognition, except for occupational complexity with data, which was associated with the degree of intervention-related gains for executive function. Discussion In older adults at increased risk for dementia, higher occupational complexity is associated with better cognition. The cognitive benefit of the FINGER intervention did not vary significantly among participants with different levels of occupational complexity. These exploratory findings require further testing in larger studies.Peer reviewe

The fog is cleared : energy survey at Halmstad University

Samhällets normer och riktlinjer är att dagens byggnader ska minska sinenergianvändning för att erhålla en bättre energiprestanda. För att möjliggöra detta harnya lagar tagits fram för att säkerställa att så är fallet. Högskolan i Halmstad (HH) beståridag av 18 byggnadskroppar, var och en med sin egna unika energianvändning. För att fåen helhetsblick över HHs energisituation har mätvärden för fjärrvärme, kyla samt el tagitsfram. Uppgiften att få fram dessa mätvärden har varit mödosam då flera instanser frånbåde HH, leverantören samt fastighetsförvaltaren har behövt rådfrågas. Dessa mätvärdenhar behandlats utefter riktlinjer från Boverket angående hur energideklarationer skautfärdas. Där har dock funnits mätvärden som ej har kunnat erhållas, detta beroende av attflera byggnader delade på samma anslutningspunkt, detta har gjort att en uppdelning påhur mycket energi varje byggnad använder sig av har varit omöjlig att svara på. Vid dessasituationer har de byggnadernas energianvändning samt ytor slagits samman för att sedanbli behandlade som en byggnad. Ytterliggare förenklingar har förekommit frånleverantören då flera kunder har delat på samma anslutningspunkt där separata mätareinte har existerat. Vid dessa tillfällen har leverantören fördelat energianvändningenprocentuellt mellan kunderna, en fördelning som uppfattas som hämmande förenergieffektiviserings åtgärder. Fördelning av denna typ påvisar inte den verkligaenergianvändningen i en specifik byggnad. Vid jämförelse av de mätvärden sominhämtats från leverantören och de utförda energideklarationerna har flera felaktigheterpåträffats. I energideklarationerna har förväxling av ytor förekommit. Även renaförsummande av kyla har förekommit. Det slutgiltiga resultatet visar på att HHsbyggnader har högre energianvändning än vad de dokument som enligt samhället skasäkerställa den energiprestanda varje byggnad innehar.Society's standards and guidelines say that today's buildings shall reduce their energyconsumption to obtain a better energy performance. To make this possible new laws havebeen formulated to ensure that this is the case. Halmstad University (HH) consists of 18building cells, each with has its own unique energy usage. To get an overall image overHH’s energy situation, the values for heating, cooling and electricity have been collected.The task of obtaining these values has been difficult were multiple instances in HH, theenergy provider and the property manager has been consulted. These values have beentreated along the guidelines of the National Housing Board on how the energyconsumption documents should be created. There have been some values that areunobtainable, the reason for this is because several buildings shared the same connectionpoint for heating, cooling and energy, because of this a breakdown of how much energyeach building uses have been impossible to answer. In these situations all of the buildingsenergy consumptions and surfaces have been pooled and then been treated as onebuilding. Further simplification has been made. In some instances many differentcustomers have shared the same connection point even though separate meters for eachcustomer have not existed. On these occasions the energy provider has divided the energyconsumption between the energy customers only with the means of a fixed percentage, adistribution that is perceived as a disincentive to energy efficiency measures.Distributions of this type do not show the actual energy usage in a specific building.When comparing the values obtained from the energy provider and the energyconsumption documents, several errors were found. Some of the building surfaces havebeen switched. Even pure neglections have occurred. The final result shows that HH’sbuildings have higher energy consumption than the documents that society refers to tooensure that the energy performance of each building is known

X-ray structure of domain I of the proton-pumping membrane protein transhydrogenase from Escherichia coli.

The dimeric integral membrane protein nicotinamide nucleotide transhydrogenase is required for cellular regeneration of NADPH in mitochondria and prokaryotes, for detoxification and biosynthesis purposes. Under physiological conditions, transhydrogenase couples the reversible reduction of NADP+ by NADH to an inward proton translocation across the membrane. Here, we present crystal structures of the NAD(H)-binding domain I of transhydrogenase from Escherichia coli, in the absence as well as in the presence of oxidized and reduced substrate. The structures were determined at 1.9-2.0 A resolution. Overall, the structures are highly similar to the crystal structure of a previously published NAD(H)-binding domain, from Rhodospirillum rubrum transhydrogenase. However, this particular domain is unique, since it is covalently connected to the integral-membrane part of transhydrogenase. Comparative studies between the structures of the two species reveal extensively differing surface properties and point to the possible importance of a rigid peptide (PAPP) in the connecting linker for conformational coupling. Further, the kinetic analysis of a deletion mutant, from which the protruding beta-hairpin was removed, indicates that this structural element is important for catalytic activity, but not for domain I:domain III interaction or dimer formation. Taken together, these results have important implications for the enzyme mechanism of the large group of transhydrogenases, including mammalian enzymes, which contain a connecting linker between domains I and II