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  • 1.
    Arama, Charles
    et al.
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. University of Sciences Techniques and Technologies of Bamako, Mali.
    Troye-Blomberg, Marita
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    The path of malaria vaccine development: challenges and perspectives2014In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 275, no 5, p. 456-466Article, review/survey (Refereed)
    Abstract [en]

    Malaria is a life-threatening disease caused by parasites of the Plasmodium genus. In many parts of the world, the parasites have developed resistance to a number of antimalarial agents. Key interventions to control malaria include prompt and effective treatment with artemisinin-based combination therapies, use of insecticidal nets by individuals at risk and active research into malaria vaccines. Protection against malaria through vaccination was demonstrated more than 30years ago when individuals were vaccinated via repeated bites by Plasmodium falciparum-infected and irradiated but still metabolically active mosquitoes. However, vaccination with high doses of irradiated sporozoites injected into humans has long been considered impractical. Yet, following recent success using whole-organism vaccines, the approach has received renewed interest; it was recently reported that repeated injections of irradiated sporozoites increased protection in 80 vaccinated individuals. Other approaches include subunit malaria vaccines, such as the current leading candidate RTS,S (consisting of fusion between a portion of the P.falciparum-derived circumsporozoite protein and the hepatitis B surface antigen), which has been demonstrated to induce reasonably good protection. Although results have been encouraging, the level of protection is generally considered to be too low to achieve eradication of malaria. There is great interest in developing new and better formulations and stable delivery systems to improve immunogenicity. In this review, we will discuss recent strategies to develop efficient malaria vaccines.

  • 2.
    Calderón-Larrañaga, Amaia
    et al.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Santoni, Giola
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Wang, Hui Xin
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Welmer, Anna-Karin
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Rizzuto, Debora
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Vetrano, Davide L.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). University of Rome, Italy.
    Marengoni, Alessandra
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). University of Brescia, Italy.
    Fratiglioni, Laura
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Stockholm Gerontology Research Center, Sweden.
    Rapidly developing multimorbidity and disability in older adults: does social background matter?2018In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 283, no 5, p. 489-499Article in journal (Refereed)
    Abstract [en]

    Background. Multimorbidity is among the most disabling geriatric conditions. In this study, we explored whether a rapid development of multi morbidity potentiates its impact on the functional independence of older adults, and whether different sociodemographic factors play a role beyond the rate of chronic disease accumulation. Methods. A random sample of persons aged >= 60 years (n = 2387) from the Swedish National study on Aging and Care in Kungsholmen (SNAC-K) was followed over 6 years. The speed of multimorbidity development was estimated as the rate of chronic disease accumulation (linear mixed models) and further dichotomized into the upper versus the three lower rate quartiles. Binomial negative mixed models were used to analyse the association between speed of multimorbidity development and disability (impaired basic and instrumental activities of daily living), expressed as the incidence rate ratio (IRR). The effect of sociodemographic factors, including sex, education, occupation and social network, was investigated. Results. The risk of new activity impairment was higher among participants who developed multi morbidity faster (IRR 2.4, 95% Cl 1.9-3.1) compared with those who accumulated diseases more slowly overtime, even after considering the baseline number of chronic conditions. Only female sex (IRR for women vs. men 1.6, 95% Cl 1.2-2.0) and social network (IRR for poor vs. rich social network 1.7, 95% Cl 1.3-2.2) showed an effect on disability beyond the rate of chronic disease accumulation. Conclusions. Rapidly developing multimorbidity is a negative prognostic factor for disability. However, sociodemographic factors such as sex and social network may determine older adults' reserves of functional ability, helping them to live independently despite the rapid accumulation of chronic conditions.

  • 3.
    Calderón-Larrañaga, Amaia
    et al.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Vetrano, Davide L.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Catholic University of the Sacred Heart, Italy; Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Italy.
    Ferrucci, L.
    Mercer, S. W.
    Marengoni, A.
    Onder, G.
    Eriksdotter, M.
    Fratiglioni, Laura
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Stockholm Gerontology Research Center, Sweden.
    Multimorbidity and functional impairment-bidirectional interplay, synergistic effects and common pathways2019In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 285, no 3, p. 255-271Article, review/survey (Refereed)
    Abstract [en]

    This review discusses the interplay between multimorbidity (i.e. co-occurrence of more than one chronic health condition in an individual) and functional impairment (i.e. limitations in mobility, strength or cognition that may eventually hamper a person's ability to perform everyday tasks). On the one hand, diseases belonging to common patterns of multimorbidity may interact, curtailing compensatory mechanisms and resulting in physical and cognitive decline. On the other hand, physical and cognitive impairment impact the severity and burden of multimorbidity, contributing to the establishment of a vicious circle. The circle may be further exacerbated by people's reduced ability to cope with treatment and care burden and physicians' fragmented view of health problems, which cause suboptimal use of health services and reduced quality of life and survival. Thus, the synergistic effects of medical diagnoses and functional status in adults, particularly older adults, emerge as central to assessing their health and care needs. Furthermore, common pathways seem to underlie multimorbidity, functional impairment and their interplay. For example, older age, obesity, involuntary weight loss and sedentarism can accelerate damage accumulation in organs and physiological systems by fostering inflammatory status. Inappropriate use or overuse of specific medications and drug-drug and drug-disease interactions also contribute to the bidirectional association between multimorbidity and functional impairment. Additionally, psychosocial factors such as low socioeconomic status and the direct or indirect effects of negative life events, weak social networks and an external locus of control may underlie the complex interactions between multimorbidity, functional decline and negative outcomes. Identifying modifiable risk factors and pathways common to multimorbidity and functional impairment could aid in the design of interventions to delay, prevent or alleviate age-related health deterioration; this review provides an overview of knowledge gaps and future directions.

  • 4.
    Drefahl, Sven
    et al.
    Stockholm University, Faculty of Social Sciences, Department of Sociology.
    Lundström, Hans
    Modig, Karin
    Ahlbom, Anders
    The era of centenarians: mortality of the oldest old in Sweden2012In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 272, no 1, p. 100-102Article in journal (Refereed)
  • 5.
    Hernández-Neuta, Iván
    et al.
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Neumann, Felix
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Brightmeyer, J.
    Tis, T. Ba
    Madaboosi, Narayanan
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Wei, Q.
    Ozcan, A.
    Nilsson, Mats
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics. Stockholm University, Science for Life Laboratory (SciLifeLab).
    Smartphone-based clinical diagnostics: towards democratization of evidence-based health care2019In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 285, no 1, p. 19-39Article, review/survey (Refereed)
    Abstract [en]

    Recent advancements in bioanalytical techniques have led to the development of novel and robust diagnostic approaches that hold promise for providing optimal patient treatment, guiding prevention programs and widening the scope of personalized medicine. However, these advanced diagnostic techniques are still complex, expensive and limited to centralized healthcare facilities or research laboratories. This significantly hinders the use of evidence-based diagnostics for resource-limited settings and the primary care, thus creating a gap between healthcare providers and patients, leaving these populations without access to precision and quality medicine. Smartphone-based imaging and sensing platforms are emerging as promising alternatives for bridging this gap and decentralizing diagnostic tests offering practical features such as portability, cost-effectiveness and connectivity. Moreover, towards simplifying and automating bioanalytical techniques, biosensors and lab-on-a-chip technologies have become essential to interface and integrate these assays, bringing together the high precision and sensitivity of diagnostic techniques with the connectivity and computational power of smartphones. Here, we provide an overview of the emerging field of clinical smartphone diagnostics and its contributing technologies, as well as their wide range of areas of application, which span from haematology to digital pathology and rapid infectious disease diagnostics.

  • 6.
    Hooshmand, Babak
    et al.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Ulm University Hospital, Germany.
    Polvikoski, T.
    Kivipelto, M.
    Tanskanen, M.
    Myllykangas, L.
    Mäkelä, M.
    Oinas, M.
    Paetau, A.
    Solomon, A.
    CAIDE Dementia Risk Score, Alzheimer and cerebrovascular pathology: a population-based autopsy study2018In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 283, no 6, p. 597-603Article in journal (Refereed)
    Abstract [en]

    Background. CAIDE Dementia Risk Score is a tool for estimating dementia risk in the general population. Its longitudinal associations with Alzheimer or vascular neuropathology in the oldest old are not known. Aim. To explore the relationship between CAIDE Dementia Risk Score at baseline and neuritic plaques, neurofibrillary tangles, cerebral infarcts and cerebral amyloid angiopathy (CAA) after up to 10-year follow-up in the Vantaa 85+ population. Methods. Study population included 149 participants aged 85 years, without dementia at baseline, and with available clinical and autopsy data. Methenamine silver staining was used for beta-amyloid and modified Bielschowsky method for neurofibrillary tangles and neuritic plaques. Macroscopic infarcts were identified from cerebral hemispheres, brain-stem and cerebellum slices. Standardized methods were used to determine microscopic infarcts, CAA and alpha-synuclein pathologies. The CAIDE Dementia Risk Score was calculated based on scores for age, sex, BMI, total cholesterol, systolic blood pressure, physical activity and APOE epsilon 4 carrier status (range 0-18 points). Results. A CAIDE Dementia Risk Score above 11 points was associated with more cerebral infarctions up to 10 years later: OR (95% CI) was 2.10 (1.06-4.16). No associations were found with other neuropathologies. Conclusion. In a population of elderly aged 85 years, higher CAIDE Dementia Risk Score was associated with increased risk of cerebral infarcts.

  • 7.
    Hooshmand, Babak
    et al.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Solomon, Alina
    Kåreholt, Ingemar
    Centrum för forskning om äldre och åldrande (ARC), (tills m KI), Aging Research Center (ARC), (together with KI).
    Rusanen, Minna
    Hänninen, Tuomo
    Leiviskä, Jaana
    Winblad, Bengt
    Laatikainen, Tiina
    Soininen, Hilkka
    Kivipelto, Miia
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Associations between serum homocysteine, holotranscobalamin, folate and cognition in the elderly: a longitudinal study2012In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 271, no 2, p. 204-212Article in journal (Refereed)
    Abstract [en]

    Objectives:  To examine the associations of serum homocysteine (tHcy), Holotranscobalamin (holoTC), the biologically active fraction of vitamin B12, and folate with cognitive functioning in a longitudinal population-based study of Finnish elderly. Subjects and design:  tHcy, holoTC, and folate were measured at baseline in 274 dementia-free subjects aged 65-79 years derived from the Cardiovascular Risk Factors, Aging and Dementia (CAIDE) study. Subjects were re-investigated 7 years later and global cognition, episodic memory, executive functioning, verbal expression, and psychomotor speed were assessed. Results:  Higher baseline tHcy values were associated with poorer performance on global cognition: relative difference (95% confidence interval) was: 0.90 (0.81 - 0.99); episodic memory: 0.87 (0.77 - 0.99); executive functions: 0.86 (0.75 - 0.98), and verbal expression: 0.89 (0.81 - 0.97) at follow-up. Increased holoTC levels were related to better performance on global cognition: 1.09 (1.00 - 1.19), executive functions: 1.11 (1.01 - 1.21), and psychomotor speed: 1.13 (1.01 - 1.26). After excluding 20 incident dementia cases, increased tHcy remained associated with poorer performance in episodic memory, execution functions, and verbal expression. Higher holoTC values tended to relate to better performance in executive functions and psychomotor speed while elevated serum folate concentrations were significantly related to higher scores in global cognition and verbal expression tests. Conclusions:  tHcy, holoTC, and folate measured 7 years earlier are related to cognitive performance even in non-demented elderly. Randomized trials are needed to determine the impact of vitamin B12 and folate supplementations on preventing cognitive decline in the elderly.

  • 8.
    Kivipelto, Miia
    et al.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Mangialasche, Francesca
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Solomon, Alina
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Johansson, G
    Lannfelt, L
    Fratiglioni, Laura
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Winblad, B
    9th Key symposium introduction: updating Alzheimer's disease diagnosis implications for prevention and treatment.2014In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 275, no 3, p. 202-203Article in journal (Refereed)
  • 9. Kulmala, J.
    et al.
    Solomon, Alina
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). University of Eastern Finland, Finland; Karolinska Institutet, Sweden.
    Kåreholt, Ingmar
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Jönköping University, Sweden.
    Ngandu, T.
    Rantanen, T.
    Laatikainen, T.
    Soininen, H.
    Tuomilehto, J.
    Kivipelto, Miia
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). University of Eastern Finland, Finland; Karolinska Institutet, Sweden; National Institute for Health and Welfare, Finland.
    Association between mid- to late life physical fitness and dementia: evidence from the CAIDE study2014In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 276, no 3, p. 296-307Article in journal (Refereed)
    Abstract [en]

    Objectives. This study investigated the association between perceived physical fitness at midlife, changes in perceived fitness during the three decades from mid-to late life and dementia risk. Design. Prospective cohort study. Setting. Cardiovascular risk factors, ageing and incidence of dementia (CAIDE) study. Subjects. Subjects were selected from four independent, random samples of population-based cardiovascular surveys and were first examined in 1972, 1977, 1982 or 1987, when they were on average 50 years old. The CAIDE target population included 3559 individuals. A random sample of 2000 individuals still alive in 1997 was drawn for re-examinations (performed in 1998 and 2005-2008) that consisted of cognitive assessments, with 1511 subjects participating in at least one re-examination. Dementia diagnoses were also confirmed from national registers for the entire target population. Main outcome measure. All-cause dementia. Results. Poor physical fitness at midlife was associated with increased dementia risk in the entire target population [hazard ratio (HR), 1.5; 95% confidence interval (CI), 1.1-2.0]. In participants, odds ratio (OR) was 2.0 (95% CI, 0.9-4.0). This association was significant in apolipoprotein E epsilon 4 allele (APO epsilon 4) noncarriers (OR, 4.3; 95% CI, 1.4-13.3), men (HR, 1.8; 95% CI, 1.1-3.0) and people with chronic conditions (HR, 2.9; 95% CI, 1.3-6.6). A decline in fitness after midlife was also associated with dementia (OR, 3.0; 95% CI, 1.7-5.1), which was significant amongst both men and women and more pronounced in APOE epsilon 4 carriers (OR, 4.4; 95% CI, 2.1-9.1). Conclusions. Perceived poor physical fitness reflects a combination of biological and lifestyle-related factors that can increase dementia risk. A simple question about perceived physical fitness may reveal at-risk individuals who could benefit from preventive interventions.

  • 10. Li, X.
    et al.
    Westman, E.
    Ståhlbom, A. K.
    Thordardottir, S.
    Almkvist, Ove
    Stockholm University, Faculty of Social Sciences, Department of Psychology. Karolinska Institutet, Sweden.
    Blennow, K.
    Wahlund, L. -O.
    Graff, C.
    White matter changes in familial Alzheimer's disease2015In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 278, no 2, p. 211-218Article in journal (Refereed)
    Abstract [en]

    BackgroundFamilial Alzheimer's disease (FAD) resulting from gene mutations in PSEN1, PSEN2 and APP is associated with changes in the brain. ObjectiveThe aim of this study was to investigate changes in grey matter (GM), white matter (WM) and the cerebrospinal fluid (CSF) in FAD. SubjectsTen mutation carriers (MCs) with three different mutations in PSEN1 and APP and 20 noncarriers (NCs) were included in the study. Three MCs were symptomatic and seven were presymptomatic (pre-MCs). MethodsWhole-brain GM volume as well as fractional anisotropy (FA) and mean diffusivity (MD) using voxel-based morphometry and tract-based spatial statistics analyses, respectively, were compared between MCs and NCs. FA and MD maps were obtained from diffusion tensor imaging. ResultsA significant increase in MD was found in the left inferior longitudinal fasciculus, cingulum and bilateral superior longitudinal fasciculus in pre-MCs compared with NCs. After inclusion of the three symptomatic MCs in the analysis, the regions became wider. The mean MD of these regions showed significant negative correlation with the CSF level of A42, and positive correlations with P-tau(181p) and T-tau. No differences were observed in GM volume and FA between the groups. ConclusionsThe results of this study suggest that FAD gene mutations affect WM diffusivity before changes in GM volume can be detected. The WM changes observed were related to changes in the CSF, with similar patterns previously observed in sporadic Alzheimer's disease.

  • 11.
    Mangialasche, Francesca
    et al.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Westman, E.
    Kivipelto, Miia
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Muehlboeck, J. -S.
    Cecchetti, R.
    Baglioni, M.
    Tarducci, R.
    Gobbi, G.
    Floridi, P.
    Soininen, H.
    Ktoszewska, I.
    Tsolaki, M.
    Vellas, B.
    Spenger, C.
    Lovestone, S.
    Wahlund, L. -O.
    Simmons, A.
    Mecocci, P.
    Classification and prediction of clinical diagnosis of Alzheimer's disease based on MRI and plasma measures of α-/γ-tocotrienols and γ-tocopherol.2013In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 273, no 6, p. 602-621Article in journal (Refereed)
    Abstract [en]

    Background: The aim of this study was to evaluate the accuracy of combined structural magnetic resonance imaging (MRI) measures and plasma levels of vitamin E forms, including all eight natural vitamin E congeners (four tocopherols and four tocotrienols) and markers of vitamin E oxidative/nitrosative damage, in differentiating individuals with Alzheimer's disease (AD) and mild cognitive impairment (MCI) from cognitively intact control (CTL) subjects.

    Methods: Overall, 81 patients with AD, 86 with MCI and 86 CTL individuals were enrolled from the longitudinal multicentre AddNeuroMed study. MRI and plasma vitamin E data were acquired at baseline. MRI scans were analysed using Freesurfer, an automated segmentation scheme which generates regional volume and cortical thickness measures. Orthogonal partial least squares to latent structures (OPLS), a multivariate data analysis technique, was used to analyse MRI and vitamin E measures in relation to AD and MCI diagnosis.

    Results: The joint evaluation of MRI and plasma vitamin E measures enhanced the accuracy of differentiating individuals with AD and MCI from CTL subjects: 98.2% (sensitivity 98.8%, specificity 97.7%) for AD versus CTL, and 90.7% (sensitivity 91.8%, specificity 89.5%) for MCI versus CTL. This combination of measures also identified 85% of individuals with MCI who converted to clinical AD at follow-up after 1 year.

    Conclusions: Plasma levels of tocopherols and tocotrienols together with automated MRI measures can help to differentiate AD and MCI patients from CTL subjects, and to prospectively predict MCI conversion into AD. Our results suggest the potential role of nutritional biomarkers detected in plasma–tocopherols and tocotrienols–as indirect indicators of AD pathology, and the utility of a multimodality approach.

  • 12. Muth, C.
    et al.
    Blom, J. W.
    Smith, S. M.
    Johnell, Kristina
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Gonzalez-Gonzalez, A. I.
    Nguyen, T. S.
    Brueckle, M. -S.
    Cesari, M.
    Tinetti, M. E.
    Valderas, J. M.
    Evidence supporting the best clinical management of patients with multimorbidity and polypharmacy: a systematic guideline review and expert consensus2019In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 285, no 3, p. 272-288Article, review/survey (Refereed)
    Abstract [en]

    The complexity and heterogeneity of patients with multimorbidity and polypharmacy renders traditional disease-oriented guidelines often inadequate and complicates clinical decision making. To address this challenge, guidelines have been developed on multimorbidity or polypharmacy. To systematically analyse their recommendations, we conducted a systematic guideline review using the Ariadne principles for managing multimorbidity as analytical framework. The information synthesis included a multistep consensus process involving 18 multidisciplinary experts from seven countries. We included eight guidelines (four each on multimorbidity and polypharmacy) and extracted about 250 recommendations. The guideline addressed (i) the identification of the target population (risk factors); (ii) the assessment of interacting conditions and treatments: medical history, clinical and psychosocial assessment including physiological status and frailty, reviews of medication and encounters with healthcare providers highlighting informational continuity; (iii) the need to incorporate patient preferences and goal setting: eliciting preferences and expectations, the process of shared decision making in relation to treatment options and the level of involvement of patients and carers; (iv) individualized management: guiding principles on optimization of treatment benefits over possible harms, treatment communication and the information content of medication/care plans; (v) monitoring and follow-up: strategies in care planning, self-management and medication-related aspects, communication with patients including safety instructions and adherence, coordination of care regarding referral and discharge management, medication appropriateness and safety concerns. The spectrum of clinical and self-management issues varied from guiding principles to specific recommendations and tools providing actionable support. The limited availability of reliable risk prediction models, feasible interventions of proven effectiveness and decision aids, and limited consensus on appropriate outcomes of care highlight major research deficits. An integrated approach to both multimorbidity and polypharmacy should be considered in future guidelines.

  • 13. Nyberg, S. T.
    et al.
    Heikkilä, K.
    Fransson, E. I.
    Alfredsson, L.
    De Bacquer, D.
    Bjorner, J. B.
    Bonenfant, S.
    Borritz, M.
    Burr, H.
    Casini, A.
    Clays, E.
    Dragano, N.
    Erbel, R.
    Geuskens, G. A.
    Goldberg, M.
    Hooftman, W. E.
    Houtman, I. L.
    Jöckel, K-H
    Kittel, F.
    Knutsson, A.
    Koskenvuo, M.
    Leineweber, Constanze
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Lunau, T.
    Madsen, I. E. H.
    Magnusson Hanson, Linda. L.
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Marmot, M. G.
    Nielsen, M. L.
    Nordin, M.
    Oksanen, T.
    Pentti, J.
    Rugulies, R.
    Siegrist, J.
    Suominen, S.
    Vahtera, J.
    Virtanen, M.
    Westerholm, P.
    Westerlund, Hugo
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Karolinska Institutet, Sweden; University College London, UK.
    Zins, M.
    Ferrie, J. E.
    Theorell, Töres
    Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Steptoe, A.
    Hamer, M.
    Singh-Manoux, A.
    Batty, G. D.
    Kivimäki, M.
    Job strain in relation to body mass index: pooled analysis of 160 000 adults from 13 cohort studies2012In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 272, no 1, p. 65-73Article in journal (Refereed)
    Abstract [en]

    Job strain in relation to body mass index: pooled analysis of 160 000 adults from 13 cohort studies. J Intern Med 2012; 272: 6573. Background. Evidence of an association between job strain and obesity is inconsistent, mostly limited to small-scale studies, and does not distinguish between categories of underweight or obesity subclasses. Objectives. To examine the association between job strain and body mass index (BMI) in a large adult population. Methods. We performed a pooled cross-sectional analysis based on individual-level data from 13 European studies resulting in a total of 161 746 participants (49% men, mean age, 43.7 years). Longitudinal analysis with a median follow-up of 4 years was possible for four cohort studies (n = 42 222). Results. A total of 86 429 participants were of normal weight (BMI 18.524.9 kg m-2), 2149 were underweight (BMI < 18.5 kg m-2), 56 572 overweight (BMI 25.029.9 kg m-2) and 13 523 class I (BMI 3034.9 kg m-2) and 3073 classes II/III (BMI = 35 kg m-2) obese. In addition, 27 010 (17%) participants reported job strain. In cross-sectional analyses, we found increased odds of job strain amongst underweight [odds ratio 1.12, 95% confidence interval (CI) 1.001.25], obese class I (odds ratio 1.07, 95% CI 1.021.12) and obese classes II/III participants (odds ratio 1.14, 95% CI 1.011.28) as compared with participants of normal weight. In longitudinal analysis, both weight gain and weight loss were related to the onset of job strain during follow-up. Conclusions. In an analysis of European data, we found both weight gain and weight loss to be associated with the onset of job strain, consistent with a U-shaped cross-sectional association between job strain and BMI. These associations were relatively modest; therefore, it is unlikely that intervention to reduce job strain would be effective in combating obesity at a population level.

  • 14.
    Pan, K-Y.
    et al.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Xu, W.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Mangialasche, F.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Fratiglioni, L.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Stockholm Gerontology Research Center, Sweden.
    Wang, Hui Xin
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Work-related psychosocial stress and the risk of type 2 diabetes in later life2017In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 281, no 6, p. 601-610Article in journal (Refereed)
    Abstract [en]

    Objectives: Although work-related psychosocial stress and type 2 diabetes mellitus (T2DM) have been investigated, the association between lifelong work stress and T2DM in later life remains unclear. This study examined whether high work stress increased the risk of T2DM risk in later life, accounting also for other sources of stress outside work, such as burden from household chores.

    Methods: From the population-based prospective study SNAC-K, 2719 diabetes-free participants aged 60 years were identified and followed up for 6 years. T2DM was ascertained by glycated haemoglobin level, self-report, hypoglycaemic medication use and clinical records. Levels of job control and demands over the whole working life were assessed by a validated matrix. Household chores load was assessed by hours spent on such chores. Multivariate logistic regression models were used to estimate the association between job strain and T2DM.

    Results: During the 6-year follow-up, 154 incident cases of T2DM were identified. High job strain was associated with T2DM occurrence amongst the 60-year-old cohort (OR = 3.14, 95% CI: 1.27-7.77), and only amongst women (OR = 6.18, 95% CI: 1.22-31.26), but not in men. When taking into account household chores load, a more pronounced risk of T2DM was associated with high job strain in combination with heavy household chores load in women aged 60 years at baseline (OR = 9.45, 95% CI: 1.17-76.53).

    Conclusion: Work-related psychosocial stress may increase the risk of T2DM only amongst women in their early 60s. The risk can be amplified by high household chores load.

  • 15. Petersen, R. C.
    et al.
    Caracciolo, Barbara
    Stockholm University, Faculty of Social Sciences, Stress Research Institute. Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Brayne, C.
    Gauthier, S.
    Jelic, V.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Fratiglioni, L.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Mild cognitive impairment: a concept in evolution2014In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 275, no 3, p. 214-228Article in journal (Refereed)
    Abstract [en]

    The construct of mild cognitive impairment (MCI) has evolved over the past 10years since the publication of the new MCI definition at the Key Symposium in 2003, but the core criteria have remained unchanged. The construct has been extensively used worldwide, both in clinical and in research settings, to define the grey area between intact cognitive functioning and clinical dementia. A rich set of data regarding occurrence, risk factors and progression of MCI has been generated. Discrepancies between studies can be mostly explained by differences in the operationalization of the criteria, differences in the setting where the criteria have been applied, selection of subjects and length of follow-up in longitudinal studies. Major controversial issues that remain to be further explored are algorithmic versus clinical classification, reliability of clinical judgment, temporal changes in cognitive performances and predictivity of putative biomarkers. Some suggestions to further develop the MCI construct include the tailoring of the clinical criteria to specific populations and to specific contexts. The addition of biomarkers to the clinical phenotypes is promising but requires deeper investigation. Translation of findings from the specialty clinic to the population setting, although challenging, will enhance uniformity of outcomes. More longitudinal population-based studies on cognitive ageing and MCI need to be performed to clarify all these issues.

  • 16. Schneider, L. S.
    et al.
    Mangialasche, F.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Andreasen, N.
    Feldman, H.
    Giacobini, E.
    Jones, R.
    Mantua, V.
    Mecocci, P.
    Pani, L.
    Winblad, B.
    Kivipelto, M.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Clinical trials and late-stage drug development for Alzheimer's disease: an appraisal from 1984 to 20142014In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 275, no 3, p. 251-283Article in journal (Refereed)
    Abstract [en]

    The modern era of drug development for Alzheimer's disease began with the proposal of the cholinergic hypothesis of memory impairment and the 1984 research criteria for Alzheimer's disease. Since then, despite the evaluation of numerous potential treatments in clinical trials, only four cholinesterase inhibitors and memantine have shown sufficient safety and efficacy to allow marketing approval at an international level. Although this is probably because the other drugs tested were ineffective, inadequate clinical development methods have also been blamed for the failures. Here, we review the development of treatments for Alzheimer's disease during the past 30years, considering the drugs, potential targets, late-stage clinical trials, development methods, emerging use of biomarkers and evolution of regulatory considerations in order to summarize advances and anticipate future developments. We have considered late-stage Alzheimer's disease drug development from 1984 to 2013, including individual clinical trials, systematic and qualitative reviews, meta-analyses, methods, commentaries, position papers and guidelines. We then review the evolution of drugs in late clinical development, methods, biomarkers and regulatory issues. Although a range of small molecules and biological products against many targets have been investigated in clinical trials, the predominant drug targets have been the cholinergic system and the amyloid cascade. Trial methods have evolved incrementally: inclusion criteria have largely remained focused on mild-to-moderate Alzheimer's disease criteria, recently extending to early or prodromal Alzheimer disease or mild cognitive impairment due to Alzheimer's disease', for drugs considered to be disease modifying. The duration of trials has remained at 6-12months for drugs intended to improve symptoms; 18- to 24-month trials have been established for drugs expected to attenuate clinical course. Cognitive performance, activities of daily living, global change and severity ratings have persisted as the primary clinically relevant outcomes. Regulatory guidance and oversight have evolved to allow for enrichment of early-stage Alzheimer's disease trial samples using biomarkers and phase-specific outcomes. In conclusion, validated drug targets for Alzheimer's disease remain to be developed. Only drugs that affect an aspect of cholinergic function have shown consistent, but modest, clinical effects in late-phase trials. There is opportunity for substantial improvements in drug discovery and clinical development methods.

  • 17.
    Shang, Ying
    et al.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Marseglia, Anna
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Fratiglioni, Laura
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Stockholm Gerontology Research Center, Sweden.
    Welmer, Anna-Karin
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Karolinska University Hospital, Sweden.
    Wang, Rui
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Wang, Hui-Xin
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Stockholm University, Faculty of Social Sciences, Stress Research Institute.
    Xu, Weili
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI). Tianjin Medical University, China.
    Natural history of prediabetes in older adults from a population-based longitudinal study2019In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 286, no 3, p. 326-340Article in journal (Refereed)
    Abstract [en]

    Background. The natural history of prediabetes in older adults remains unknown.

    Objectives. To assess the rate at which prediabetes progresses to diabetes, leads to death or reverts to normoglycaemia in older adults and to identify prognostic factors related to different outcomes of prediabetes.

    Methods. In the Swedish National Study on Aging and Care-Kungsholmen, 2575 diabetes-free participants aged >= 60 years were examined at baseline and followed for up to 12 years. At each wave, diabetes was diagnosed via medical examination, antidiabetic drug use, medical records or glycated haemoglobin (HbA1c) >= 6.5%. Prediabetes was defined as HbA1c >= 5.7% and normoglycaemia as HbA1c <5.7% in diabetes-free participants. Data were analysed with multinomial logistic regression.

    Results. At baseline, 918 (36%) individuals had prediabetes. Of them, 204 (22%) reverted to normoglycaemia (3.4/100 person-years, 95% CI 5.6-12.3), 119 (13%) developed diabetes (2.0/100 person-years, 95% CI 1.7-2.4) and 215 (23%) died (13.0/100 person-years, 95% CI 11.4-14.9) during the 12-year follow-up. The rates of reversion, progression and mortality were higher in the first 6-year than in the second 6-year follow-up, albeit not statistically significant. Lower systolic blood pressure (SBP), absence of heart diseases and weight loss promoted the reversion from prediabetes to normoglycaemia, whilst obesity accelerated its progression to diabetes.

    Conclusions. During a 12-year follow-up, most of older adults with prediabetes remained stable or reverted to normoglycaemia, whereas only one-third developed diabetes or died. Lower SBP, no heart diseases and weight management may promote reversion to normoglycaemia, suggesting possible strategies for achieving normoglycaemia in older adults with prediabetes.

  • 18. Solomon, A.
    et al.
    Mangialasche, F.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Richard, E.
    Andrieu, S.
    Bennett, D. A.
    Breteler, M.
    Fratiglioni, L.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Hooshmand, B.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Khachaturian, A. S.
    Schneider, L. S.
    Skoog, I.
    Kivipelto, M.
    Stockholm University, Faculty of Social Sciences, Aging Research Center (ARC), (together with KI).
    Advances in the prevention of Alzheimer's disease and dementia2014In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 275, no 3, p. 229-250Article in journal (Refereed)
    Abstract [en]

    BackgroundDefinitions and diagnostic criteria for all medical conditions are regularly subjected to reviews and revisions as knowledge advances. In the field of Alzheimer's disease (AD) research, it has taken almost three decades for diagnostic nomenclature to undergo major re-examination. The shift towards presymptomatic and pre-dementia stages of AD has brought prevention and treatment trials much closer to each other than before. MethodsHere we discuss: (i) the impact of diagnostic reliability on the possibilities for developing preventive strategies for AD; (ii) the scientific evidence to support moving from observation to action; (iii) ongoing intervention studies; and (iv) the methodological issues and prospects for balancing strategies for high-risk individuals with those for broad population-based prevention. ResultsThe associations between neuropathology and cognition are still not entirely clear. In addition, the risk factors for AD dementia and the neuropathological hallmarks of AD may not necessarily be the same. Cognitive impairment has a clearer clinical significance and should therefore remain the main focus of prevention. Risk/protective factors for dementia/AD need to be studied from a life-course perspective. New approaches in prevention trials include enrichment strategies based on genetic risk factors or beta-amyloid biomarkers (at least four ongoing pharmacological trials), and multidomain interventions simultaneously targeting various vascular and lifestyle-related risk factors (at least three ongoing trials). Experience from prevention programmes in other chronic diseases can provide additional methodological improvements. ConclusionsBuilding infrastructures for international collaborations is necessary for managing the worldwide public health problem of AD and dementia. The International Database on Aging and Dementia (IDAD) and the European Dementia Prevention Initiative (EDPI) are examples of ongoing international efforts aiming to improve the methodology of preventive studies and provide the basis for larger intervention trials.

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