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1.	Imtiaz, Bushra, et al. (författare) Oophorectomy, Hysterectomy, and Risk of Alzheimer's Disease : A Nationwide Case-Control Study 2014 Ingår i: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 42:2, s. 575-581 Tidskriftsartikel (refereegranskat)abstract Background: Association between oophorectomy and/or hysterectomy and dementia in context of hormone therapy (HT) use is ambiguous. Objective: To assess whether oophorectomy, hysterectomy, and hysterectomy with bilateral oophorectomy are related to risk of Alzheimer's disease (AD), whether the possible indication for surgery plays a role, and if the associations are modified by HT. Methods: Our nationwide register based case-control (1 : 1) study included all women with clinically-verified AD diagnoses, residing in Finland on December 31, 2005 (n of cases = 19,043, n of controls = 19,043). AD cases, diagnosed according to NINCS-ADRDA and the DSM-IV criteria, were identified from Special Reimbursement Register. Information on HT use was collected from national prescription register, and data on surgery and uterine/ovarian/cervical cancer were obtained from the hospital discharge register. Most of the women (91.8%) were over 51 years of age when the surgery was performed. Results: Oophorectomy, hysterectomy, and hysterectomy with bilateral oophorectomy were associated with lower risk of AD (OR/95% CI: 0.85/0.75-0.97, 0.89/0.81-0.97 and 0.85/0.75-0.98, respectively) among women without the history of uterine/ovarian/cervical cancer, although the absolute risk difference was small. The association was not evident in women with uterine/ovarian/cervical cancer history (3.00 /0.20-44.87 for all surgeries). The associations were not modified by HT use, which was independently associated with AD risk, with longer use showing protective association. Conclusion: Our findings indicate that oophorectomy with or without hysterectomy after commencement of natural menopause is not an important determinant of AD risk in older age and support the critical window hypothesis for HT use.
2.	Adedeji, Dickson O., et al. (författare) Longitudinal study of Alzheimer's disease biomarkers, allostatic load, and cognition among memory clinic patients 2023 Ingår i: Brain, Behavior, and Immunity - Health. - : Elsevier. - 2666-3546. ; 28 Tidskriftsartikel (refereegranskat)abstract Background: Allostatic load (AL) is defined as the cumulative dysregulation of neuroendocrine, immunological, metabolic, and cardiovascular systems that increases the susceptibility to stress-related health problems. Several dementia and Alzheimer's disease (AD) risk factors have been identified, yet little is known about the role of AL and its associations with AD biomarkers (e.g., beta-amyloid (Aβ) or tau) and cognitive function among memory clinic patients. Hence, this study aims to assess the association between AL and AD biomarkers, cognitive performance, and cognitive decline after 3-years of follow-up.Methods: Data from 188 memory clinic patients were derived from the Cortisol and Stress in AD (Co-STAR) study in Sweden. Participants underwent baseline assessments including blood tests for AL measures (including cortisol, thyroid stimulating hormone, cobalamin, homocysteine, leukocytes, glycated hemoglobin, albumin, high-density and low-density lipoprotein cholesterol, triglycerides, and creatinine), cerebrospinal fluid (CSF) sampling for AD biomarkers and neuropsychological tests including five cognitive domains. Linear regressions were conducted, adjusting for age, sex, and education.Results: Higher AL was associated with lower CSF Aβ1-42 levels (β = −0.175, p = 0.025), reflecting higher brain levels of Aβ1-42. Stratified analyses suggested a significant association among women but not men, although the AL-sex interaction was not statistically significant. AL was not significantly associated with T-tau level (β = −0.030, p = 0.682) and P-tau level (β = 0.091, p = 0.980). There were no significant associations between AL and cognition or cognitive decline after 3 years.Conclusion: This study showed that higher AL was associated with increased brain amyloid accumulation. This suggests that AL may play a role in AD/dementia pathophysiology. Potential sex-related differences should be assessed in further larger studies.
3.	Adedeji, Dickson O., et al. (författare) Longitudinal study of Alzheimer's disease biomarkers, allostatic load, and cognition among memory clinic patients 2023 Ingår i: Brain, Behavior, and Immunity - Health. - : Elsevier BV. - 2666-3546. ; 28 Tidskriftsartikel (refereegranskat)abstract Background: Allostatic load (AL) is defined as the cumulative dysregulation of neuroendocrine, immunological, metabolic, and cardiovascular systems that increases the susceptibility to stress-related health problems. Several dementia and Alzheimer's disease (AD) risk factors have been identified, yet little is known about the role of AL and its associations with AD biomarkers (e.g., beta-amyloid (Aβ) or tau) and cognitive function among memory clinic patients. Hence, this study aims to assess the association between AL and AD biomarkers, cognitive performance, and cognitive decline after 3-years of follow-up.Methods: Data from 188 memory clinic patients were derived from the Cortisol and Stress in AD (Co-STAR) study in Sweden. Participants underwent baseline assessments including blood tests for AL measures (including cortisol, thyroid stimulating hormone, cobalamin, homocysteine, leukocytes, glycated hemoglobin, albumin, high-density and low-density lipoprotein cholesterol, triglycerides, and creatinine), cerebrospinal fluid (CSF) sampling for AD biomarkers and neuropsychological tests including five cognitive domains. Linear regressions were conducted, adjusting for age, sex, and education.Results: Higher AL was associated with lower CSF Aβ1-42 levels (β = −0.175, p = 0.025), reflecting higher brain levels of Aβ1-42. Stratified analyses suggested a significant association among women but not men, although the AL-sex interaction was not statistically significant. AL was not significantly associated with T-tau level (β = −0.030, p = 0.682) and P-tau level (β = 0.091, p = 0.980). There were no significant associations between AL and cognition or cognitive decline after 3 years.Conclusion: This study showed that higher AL was associated with increased brain amyloid accumulation. This suggests that AL may play a role in AD/dementia pathophysiology. Potential sex-related differences should be assessed in further larger studies.
4.	Akenine, Ulrika, et al. (författare) Attitudes of at-risk older adults about prevention of cardiovascular disease and dementia using eHealth : a qualitative study in a European context 2020 Ingår i: BMJ Open. - 2044-6055. ; 10:8 Tidskriftsartikel (refereegranskat)abstract Objectives Prevention of cardiovascular disease (CVD) and dementia is a key health priority among older adults. Understanding individuals’ attitudes to, the prevention of these conditions, particularly when delivered through novel eHealth tools, could help in designing effective prevention programmes. The aim of the study was to explore the attitudes of older adults at increased risk of CVD and dementia regarding engagement in eHealth self-management prevention programmes, and to describe the facilitators and barriers.Design A qualitative research approach was used. Data were collected through eight focus groups in Finland, France and the Netherlands. Data were analysed following the principles of grounded theory.Setting and participants Forty-four community-dwellers aged 65+ at risk of CVD were recruited from a previous trial cohort in Finland, and through general practices in France and the Netherlands.Results The study identified three categories: access to reliable information, trust in the healthcare providers and burden and stigma of dementia. A core category was also identified: the interactive process of the three categories influencing engagement in self-management prevention programme. The categories were interconnected through an interactive process and influenced by the local healthcare culture and context which shaped them differently, becoming either facilitators or barriers to engage in eHealth self-management prevention programmes.Conclusions The study emphasises the importance of considering the interactions between the identified categories in this study, grounded in the local healthcare culture and context in further developments of eHealth self-management interventions that aim to prevent CVD and dementia.
5.	Aspö, Malin, et al. (författare) Transitions : Experiences of younger persons recently diagnosed with Alzheimer-type dementia 2023 Ingår i: Dementia. - : Sage Publications. - 1471-3012 .- 1741-2684. ; 22:3, s. 610-627 Tidskriftsartikel (refereegranskat)abstract Receiving a diagnosis of dementia before the age of 65 has a huge impact on everyday life. Previously, the disease trajectory has mainly been described from the perspective of older persons. However, young persons with dementia are confronted with specific challenges, influencing the type of life-changing events, or 'critical points' that they may experience. The aim of this study was therefore to describe experiences of persons recently being diagnosed with young-onset dementia. In total, 14 participants with dementia due to Alzheimer's disease (10 woman/4 men) with an average age of 59 were included in the study. Interviews were conducted within 2 months after receiving the diagnosis and analyzed using qualitative content analysis with an inductive approach, resulting in three categories: (1) A life changing moment, (2) An ongoing process, and (3) Remaining in control. The findings show that receiving such a diagnosis was experienced by participants as a life changing moment, followed by them seeking to come to terms with the diagnosis and reflecting on its meaning, in which various strategies were adopted to remain in control. The current study highlights three critical points considering the diagnosis of young-onset dementia that warrant special attention and provides insight into factors related to delay in healthy transitioning after receiving the diagnosis, as well as factors that may facilitate successful transitions.
6.	Ballin, Marcel, et al. (författare) Excess Mortality After COVID-19 in Swedish Long-Term Care Facilities 2021 Ingår i: Journal of the American Medical Directors Association. - : Elsevier. - 1525-8610 .- 1538-9375. ; 22:8, s. 1574-1580.e8 Tidskriftsartikel (refereegranskat)abstract Objective: To compare 30-day mortality in long-term care facility (LTCF) residents with and without COVID-19 and to investigate the impact of 31 potential risk factors for mortality in COVID-19 cases.Design: Retrospective cohort study.Setting and Participants: All residents of LTCFs registered in Senior Alert, a Swedish national database of health examinations in older adults, during 2019-2020.Methods: We selected residents with confirmed COVID-19 until September 15, 2020, along with time-dependent propensity score–matched controls without COVID-19. Exposures were COVID-19, age, sex, comorbidities, medications, and other patient characteristics. The outcome was all-cause 30-day mortality.Results: A total of 3731 residents (median age 87 years, 64.5% female) with COVID-19 were matched to 3731 controls without COVID-19. Thirty-day mortality was 39.9% in COVID-19 cases and 5.7% in controls [relative risk 7.05, 95% confidence interval (CI) 6.10-8.14]. In COVID-19 cases, the odds ratio (OR) for 30-day mortality was 2.44 (95% CI 1.57-3.81) in cases aged 80-84 years, 2.99 (95% CI 1.93-4.65) in cases aged 85-89 years, and 3.28 (95% CI 2.11-5.10) in cases aged ≥90 years, as compared with cases aged <70 years. Other risk factors for mortality among COVID-19 cases included male sex (OR, 2.60, 95% CI 2.22-3.05), neuropsychological conditions (OR, 2.18; 95% CI 1.76-2.71), impaired walking ability (OR, 1.45, 95% CI 1.17-1.78), urinary and bowel incontinence (OR 1.51, 95% CI 1.22-1.85), diabetes (OR 1.36, 95% CI 1.14-1.62), chronic kidney disease (OR 1.37, 95% CI 1.11-1.68) and previous pneumonia (OR 1.57, 95% CI 1.32-1.85). Nutritional factors, cardiovascular diseases, and antihypertensive medications were not significantly associated with mortality.Conclusions and Implications: In Swedish LTCFs, COVID-19 was associated with a large excess in mortality after controlling for an extensive number of risk factors. Beyond older age and male sex, several prevalent clinical risk factors independently contributed to higher mortality. These findings suggest that reducing transmission of COVID-19 in LTCFs will likely prevent a considerable number of deaths.
7.	Ballin, Marcel, et al. (författare) Time-varying risk of death after SARS-CoV-2 infection in Swedish long-term care facility residents: a matched cohort study 2022 Ingår i: BMJ Open. - : BMJ Publishing Group Ltd. - 2044-6055. ; 12:11 Tidskriftsartikel (refereegranskat)abstract OBJECTIVES: To evaluate whether SARS-CoV-2 infection in residents of long-term care (LTC) facilities is associated with higher mortality after the acute phase of infection, and to estimate survival in uninfected residents.DESIGN: Extended follow-up of a previous, propensity score-matched, retrospective cohort study based on the Swedish Senior Alert register.SETTING: LTC facilities in Sweden.PARTICIPANTS: n=3604 LTC residents with documented SARS-CoV-2 until 15 September 2020 matched to 3604 uninfected controls using time-dependent propensity scores on age, sex, health status, comorbidities, prescription medications, geographical region and Senior Alert registration time. In a secondary analysis (n=3731 in each group), geographical region and Senior Alert registration time were not matched for in order to increase the follow-up time in controls and allow for an estimation of median survival.PRIMARY OUTCOME MEASURES: All-cause mortality until 24 October 2020, tracked using the National Cause of Death Register.RESULTS: Median age was 87 years and 65% were women. Excess mortality peaked at 5 days after documented SARS-CoV-2-infection (HR 21.5, 95% CI 15.9 to 29.2), after which excess mortality decreased. From the second month onwards, mortality rate became lower in infected residents than controls. The HR for death during days 61-210 of follow-up was 0.76 (95% CI 0.62 to 0.93). The median survival of uninfected controls was 1.6 years, which was much lower than the national life expectancy in Sweden at age 87 (5.05 years in men, 6.07 years in women).CONCLUSIONS: The risk of death after SARS-CoV-2 infection in LTC residents peaked after 5 days and decreased after 2 months, probably because the frailest residents died during the acute phase, leaving healthier residents remaining. The limited life expectancy in this population suggests that LTC resident status should be accounted for when estimating years of life lost due to COVID-19.
8.	Barbera, Mariagnese, et al. (författare) A multimodal precision-prevention approach combining lifestyle intervention with metformin repurposing to prevent cognitive impairment and disability: the MET-FINGER randomised controlled trial protocol 2024 Ingår i: Alzheimer's Research & Therapy. - : BioMed Central Ltd. - 1758-9193. ; 16 Tidskriftsartikel (refereegranskat)abstract Background: Combining multimodal lifestyle interventions and disease-modifying drugs (novel or repurposed) could provide novel precision approaches to prevent cognitive impairment. Metformin is a promising candidate in view of the well-established link between type 2 diabetes (T2D) and Alzheimer’s Disease and emerging evidence of its potential neuro-protective effects (e.g. vascular, metabolic, anti-senescence). MET-FINGER aims to test a FINGER 2.0 multimodal intervention, combining an updated FINGER multidomain lifestyle intervention with metformin, where appropriate, in an APOE ε4-enriched population of older adults (60–79 years) at increased risk of dementia.Methods: MET-FINGER is an international randomised, controlled, parallel-group, phase-IIb proof-of-concept clinical trial, where metformin is included through a trial-within-trial design. 600 participants will be recruited at three sites (UK, Finland, Sweden). Participants at increased risk of dementia based on vascular risk factors and cognitive screening, will be first randomised to the FINGER 2.0 intervention (lifestyle + metformin if eligible; active arm) or to receive regular health advice (control arm). Participants allocated to the FINGER 2.0 intervention group at risk indicators of T2D will be additionally randomised to receive metformin (2000 mg/day or 1000 mg/day) or placebo. The study duration is 2 years. The changes in global cognition (primary outcome, using a Neuropsychological Test Battery), memory, executive function, and processing speed cognitive domains; functional status; lifestyle, vascular, metabolic, and other dementia-related risk factors (secondary outcomes), will be compared between the FINGER 2.0 intervention and the control arm. The feasibility, potential interaction (between-groups differences in healthy lifestyle changes), and disease-modifying effects of the lifestyle-metformin combination will be exploratory outcomes. The lifestyle intervention is adapted from the original FINGER trial (diet, physical activity, cognitive training, monitoring of cardiovascular/metabolic risk factors, social interaction) to be consistently delivered in three countries. Metformin is administered as Glucophage®XR/SR 500, (500 mg oral tablets). The metformin/placebo treatment will be double blinded. Conclusion: MET-FINGER is the first trial combining a multimodal lifestyle intervention with a putative repurposed disease-modifying drug for cognitive impairment prevention. Although preliminary, its findings will provide crucial information for innovative precision prevention strategies and form the basis for a larger phase-III trial design and future research in this field.
9.	Barbera, Mariagnese, et al. (författare) Designing an Internet-Based Multidomain Intervention for the Prevention of Cardiovascular Disease and Cognitive Impairment in Older Adults : The HATICE Trial 2018 Ingår i: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 62:2, s. 649-663 Tidskriftsartikel (refereegranskat)abstract Background: Many dementia and cardiovascular disease (CVD) cases in older adults are attributable to modifiable vascular and lifestyle-related risk factors, providing opportunities for prevention. In the Healthy Aging Through Internet Counselling in the Elderly (HATICE) randomized controlled trial, an internet-based multidomain intervention is being tested to improve the cardiovascular risk (CVR) profile of older adults. Objective: To design a multidomain intervention to improve CVR, based on the guidelines for CVR management, and administered through a coach-supported, interactive, platform to over 2500 community-dwellers aged 65+ in three European countries. Methods: A comparative analysis of national and European guidelines for primary and secondary CVD prevention was performed. Results were used to define the content of the intervention. Results: The intervention design focused on promoting awareness and self-management of hypertension, dyslipidemia, diabetes mellitus, and overweight, and supporting smoking cessation, physical activity, and healthy diet. Overall, available guidelines lacked specific recommendations for CVR management in older adults. The comparative analysis of the guidelines showed general consistency for lifestyle-related recommendations. Key differences, identified mostly in methods used to assess the overall CVR, did not hamper the intervention design. Minor country-specific adaptations were implemented to maximize the intervention feasibility in each country. Conclusion: Despite differences inCVRmanagement within the countries considered, itwas possible to design and implement the HATICE multidomain intervention. The study can help define preventative strategies for dementia and CVD that are applicable internationally.
10.	Beishuizen, Cathrien R. L., et al. (författare) Web-Based Interventions Targeting Cardiovascular Risk Factors in Middle-Aged and Older People : A Systematic Review and Meta-Analysis 2016 Ingår i: Journal of Medical Internet Research. - : JMIR Publications Inc.. - 1438-8871. ; 18:3 Forskningsöversikt (refereegranskat)abstract Background: Web-based interventions can improve single cardiovascular risk factors in adult populations. In view of global aging and the associated increasing burden of cardiovascular disease, older people form an important target population as well.Objective: In this systematic review and meta-analysis, we evaluated whether Web-based interventions for cardiovascular risk factor management reduce the risk of cardiovascular disease in older people.Methods: Embase, Medline, Cochrane and CINAHL were systematically searched from January 1995 to November 2014. Search terms included cardiovascular risk factors and diseases (specified), Web-based interventions (and synonyms) and randomized controlled trial. Two authors independently performed study selection, data-extraction and risk of bias assessment. In a meta-analysis, outcomes regarding treatment effects on cardiovascular risk factors (blood pressure, glycated hemoglobin A1c (HbA1C), low-density lipoprotein (LDL) cholesterol, smoking status, weight and physical inactivity) and incident cardiovascular disease were pooled with random effects models.Results: A total of 57 studies (N=19,862) fulfilled eligibility criteria and 47 studies contributed to the meta-analysis. A significant reduction in systolic blood pressure (mean difference -2.66 mmHg, 95% CI -3.81 to -1.52), diastolic blood pressure (mean difference -1.26 mmHg, 95% CI -1.92 to -0.60), HbA1c level (mean difference -0.13%, 95% CI -0.22 to -0.05), LDL cholesterol level (mean difference -2.18 mg/dL, 95% CI -3.96 to -0.41), weight (mean difference -1.34 kg, 95% CI -1.91 to -0.77), and an increase of physical activity (standardized mean difference 0.25, 95% CI 0.10-0.39) in the Web-based intervention group was found. The observed effects were more pronounced in studies with short (<12 months) follow-up and studies that combined the Internet application with human support (blended care). No difference in incident cardiovascular disease was found between groups (6 studies).Conclusions: Web-based interventions have the potential to improve the cardiovascular risk profile of older people, but the effects are modest and decline with time. Currently, there is insufficient evidence for an effect on incident cardiovascular disease. A focus on long-term effects, clinical endpoints, and strategies to increase sustainability of treatment effects is recommended for future studies.
11.	Bergman, Jonathan, 1993- (författare) Benefits and harms of Bisphosphonates : an observational study 2022 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract Background: Bisphosphonates are first-line treatment for osteoporosis, but osteoporosis is considered an undertreated disease. The general aim of this dissertation was to further study the benefits and harms of bisphosphonates. There were four specific research questions: (1) Do bisphosphonates reduce the risk of new fractures in older adults who have a history of fracture? (2) Do bisphosphonates reduce the risk of fracture in people taking glucocorticoids? (3) Does confounding explain why bisphosphonates are associated with lower mortality in observational studies? (4) Do bisphosphonates increase the risk of non-jaw osteonecrosis?Methods: To answer these questions, we used Swedish register data on deaths, diagnoses, and prescription medications to conduct four matched cohort studies of bisphosphonate users and nonusers. The cohorts were selected from patients registered in the Hip Fracture Register and from all residents of Sweden who were aged 50 years or older on December 31, 2005.Results: (1) Bisphosphonate users had an initially increased risk of sustaining new fractures, which appeared to be due to an underlying high risk of fracture. This increased risk diminished over time, which is consistent with a gradual treatment effect, but it is also consistent with a bias known as depletion of susceptibles. (2) Bisphosphonate users had a lower risk of fracture during glucocorticoid therapy. (3) Bisphosphonate users had a lower mortality rate from day 2 of treatment. Although such an early treatment effect cannot be ruled out, this finding is consistent with confounding. (4) Bisphosphonate users had an increased risk of developing non-jaw osteonecrosis. Conclusion: Most of the results were difficult to interpret as true benefits or harms of bisphosphonates because alternative explanations, arising from bias or confounding, were likely. The exception was the results of Study 2, where alternative explanations are more difficult to find. Therefore, Study 2 suggests that bisphosphonates reduce the risk of fractures in glucocorticoid-treated patients. Further research is needed to clarify the potential effects of bisphosphonates on mortality, non-jaw osteonecrosis, and new fractures after a previous fracture.
12.	Bruinsma, Jeroen, et al. (författare) Social activities in multidomain dementia prevention interventions: insights from practice and a blueprint for the future 2024 Ingår i: Frontiers in Psychiatry. - : Frontiers. - 1664-0640. ; 15 Tidskriftsartikel (refereegranskat)abstract Introduction: Social activities are important for health and act as a driver of cognitive reserve during aging. In this perspective paper, we describe challenges and outline future (research) endeavors to establish better operationalization of social activities in multidomain interventions to prevent dementia.Body: We first address the lack of conceptual clarity, which makes it difficult to measure engagement in social activities. Second, drawing from our experience with the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER), we discuss social activities in multidomain dementia prevention interventions. Using qualitative data from the Multimodal Preventive Trial for Alzheimer’s Disease (MIND-ADmini), we reflect on participant experiences with social activities. Third, we address the potential and challenges of digital solutions in promoting social activities in interventions for dementia prevention. Finally, we share insights from a workshop on digital technology, where we consulted with individuals with and without cognitive impairment who have been involved in three European projects (i.e., EU-FINGERS, Multi-MeMo, and LETHE).Discussion: Based on these insights, we advocate for research that strengthens and accelerates the integration of social activities into multidomain interventions for dementia prevention. We propose several ways to achieve this: (a) by conducting mixed methods research to formulate a broadly accepted definition and instructions to measure social activities; (b) by focusing on promoting engagement in social activities beyond the intervention setting; and (c) by exploring the needs and preferences of older adults towards digitally-supported interventions and co-design of new technologies that enrich in-person social activities.
13.	Bunce, David, et al. (författare) Apolipoprotein E, B vitamins, and cognitive function in older adults. 2005 Ingår i: Journal of Gerontology: Psychological Sciences. - 1079-5014. ; 60B:1, s. 41-48 Tidskriftsartikel (refereegranskat)abstract Recognition of dated and contemporary famous faces, short-term memory, and visuospatial abilities were investigated in adults aged 75 years and older as a function of apolipoprotein E (APOE) genotype, ε4 or not ε4, and whether participants recorded normal or low levels of B vitamins. No associations between B vitamins and APOE were identified in respect to short-term memory or visuospatial skills, or for contemporary famous faces. However, in respect to the recognition of dated famous faces, deficits in persons carrying the ε4 allele who also recorded low vitamin B12 values were found. The results suggest that the neurological structures and processes supporting face recognition may be vulnerable to the combined influence of the APOE ε4 allele and low levels of vitamin B12. This finding was unrelated to incipient dementia up to 6 years following testing. The results are discussed with reference to the neuroanatomical reserves that epsilon4 carriers may possess.
14.	Daniilidou, Makrina, et al. (författare) Alzheimer's disease biomarker profiling in a memory clinic cohort without common comorbidities. 2023 Ingår i: Brain communications. - 2632-1297. ; 5:5 Tidskriftsartikel (refereegranskat)abstract Alzheimer's disease is a multifactorial disorder with large heterogeneity. Comorbidities such as hypertension, hypercholesterolaemia and diabetes are known contributors to disease progression. However, less is known about their mechanistic contribution to Alzheimer's pathology and neurodegeneration. The aim of this study was to investigate the relationship of several biomarkers related to risk mechanisms in Alzheimer's disease with the well-established Alzheimer's disease markers in a memory clinic population without common comorbidities. We investigated 13 molecular markers representing key mechanisms underlying Alzheimer's disease pathogenesis in CSF from memory clinic patients without diagnosed hypertension, hypercholesterolaemia or diabetes nor other neurodegenerative disorders. An analysis of covariance was used to compare biomarker levels between clinical groups. Associations were analysed by linear regression. Two-step cluster analysis was used to determine patient clusters. Two key markers were analysed by immunofluorescence staining in the hippocampus of non-demented control and Alzheimer's disease individuals. CSF samples from a total of 90 participants were included in this study: 30 from patients with subjective cognitive decline (age 62.4 ± 4.38, female 60%), 30 with mild cognitive impairment (age 65.6 ± 7.48, female 50%) and 30 with Alzheimer's disease (age 68.2 ± 7.86, female 50%). Angiotensinogen, thioredoxin-1 and interleukin-15 had the most prominent associations with Alzheimer's disease pathology, synaptic and axonal damage markers. Synaptosomal-associated protein 25kDa and neurofilament light chain were increased in mild cognitive impairment and Alzheimer's disease patients. Grouping biomarkers by biological function showed that inflammatory and survival components were associated with Alzheimer's disease pathology, synaptic dysfunction and axonal damage. Moreover, a vascular/metabolic component was associated with synaptic dysfunction. In the data-driven analysis, two patient clusters were identified: Cluster 1 had increased CSF markers of oxidative stress, vascular pathology and neuroinflammation and was characterized by elevated synaptic and axonal damage, compared with Cluster 2. Clinical groups were evenly distributed between the clusters. An analysis of post-mortem hippocampal tissue showed that compared with non-demented controls, angiotensinogen staining was higher in Alzheimer's disease and co-localized with phosphorylated-tau. The identification of biomarker-driven endophenotypes in cognitive disorder patients further highlights the biological heterogeneity of Alzheimer's disease and the importance of tailored prevention and treatment strategies.
15.	Dong, Huan-Ji, 1981- (författare) Health Maintenance in Very Old Age : Medical Conditions, Functional Outcome and Nutritional Status 2014 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract The overall aim of this thesis was to provide better understanding of the underlying factors related to health maintenance in very old people, with a focus on medical conditions, functional outcome and nutritional status. Data were gathered from the ELSA 85 project (Elderly in Linköping Screening Assessment). The ELSA 85 project was started in 2007 with a population-based survey of 85-year-old individuals (n = 650) residing in Linköping municipality, Sweden. During the study period from 2007 to 2010, we conducted surveys by postal questionnaire, home visits, geriatric clinic visits, and reviews of electronic medical records as well as the database of health service consumption. A series of cross-sectional analyses were performed on multimorbidity, health service consumption, activities of daily living (ADLs), physical functioning and nutritional status.Of 650 eligible individuals, 496 (78% of those alive) completed the questionnaire (Paper I). Despite the prevalence of multimorbidity (68%) and frequent use of assistive technology for mobility (40%), the majority managed self-care (85%), usual activities (74%) and had high self-rated health (>60/100, visual analogue scale). Factors associated with in-patient care were an increased number of general practitioner visits, more use of assistive technology, community assistance, multimorbidity (≥2 chronic diseases) and/or heart failure and arrhythmia.Cluster analyses (n = 496, Paper II) revealed five clusters: vascular, cardiopulmonary, cardiac (only for men), somatic–mental (only for men), mental disease (only for women), and three other clusters related to ageing (one for men and two for women). Heart failure in men (odds ratio [OR], 2.4; 95% confidence interval [CI], 1–5.7) and women (OR, 3; 95% CI, 1.3–6.9) as a single morbidity explained more variance than morbidity clusters in models of emergency room visits. Men’s cardiac cluster (OR, 1.6; 95% CI, 1–2.7) and women’s cardiopulmonary cluster (OR, 1.7; 95% CI, 1.2–2.4) were significantly associated with hospitalization. The combination of the cardiopulmonary cluster with the men’s cardiac cluster (OR, 1.6; 95% CI, 1–2.4) and one of the women’s ageing clusters (OR, 0.5; 95% CI, 0.3–0.8) showed interaction effects on hospitalization.In Paper III, overweight (body mass index [BMI], 25–29.9 kg/m2) and obese (BMI, ≥30 kg/m2) individuals (n = 333) perceived more difficulty performing instrumental ADL (IADL) and had more comorbidities than their normal weight counterparts (BMI, 18.5–24.9 kg/m2). After controlling for socio-demographic factors, obese but not overweight individuals were more likely to perceive increased difficulty in performing outdoor activities (OR, 2.1; 95% CI, 1.1–4) and cleaning (OR, 2.2; 95% CI, 1.2–4.2) than their normal weight counterparts. Although obesity was also associated with multimorbidity (OR, 3; 95% CI, 1.2–8), the health service cost of each case of multimorbidity (n = 251) was highest in individuals of normal weight and nearly three times as much as in obese individuals (ratio, 2.9; 95% CI, 1.1–8.1).In Paper IV, 88-year-old obese women (n = 83) had greater absolute waist circumference, fat mass (FM) and fat-free mass (FFM), and lower handgrip strength (HS) corrected for FFM and HS-based ratios (HS/weight (Wt), HS/BMI, HS/FFM and HS/FM) than their normal weight and overweight counterparts. After adjusting for physical activity levels and the number of chronic diseases, the HS-based ratios explained more variance in physical functioning in Short Form-36 (R2, 0.52–0.54) than other single anthropometric or body composition parameters (R2, 0.45–0.51). Waist circumference, HS, and two HS-based ratios (HS/Wt and HS/FFM) were also associated with the number of IADL with no difficulty.In conclusion, the ELSA 85 population showed a fairly positive image of healthy perception, good functional ability as well as low use of health care among the majority of participants. Patterns of cardiac and pulmonary conditions were better associated than any single morbidity with hospitalization. Heart failure as a single morbidity was better associated than multimorbidity patterns with emergency room visits. For 85-year-olds, being obese, as opposed to overweight, was associated with self-reported activity limitations and comorbidities. Overweight elderly living in their own homes in this population had similar well-being to those of normal weight. In the cohort of 88-year-olds, obese women had high waist circumference, but their HS was relatively low in relation to their Wt and FFM. These parameters were better than BMI for predicting physical function and independent daily living.
16.	Ekman, Sirkka-Liisa, et al. (författare) Alzheimer 2011 Rapport (övrigt vetenskapligt/konstnärligt)
17.	Ekman, Urban, et al. (författare) Evaluation of a Novel Psychological Intervention Tailored for Patients With Early Cognitive Impairment (PIPCI) : Study Protocol of a Randomized Controlled Trial 2020 Ingår i: Frontiers in Psychology. - : Frontiers Media SA. - 1664-1078. ; 11 Tidskriftsartikel (refereegranskat)abstract Background: Individuals with early phase cognitive impairment are frequently affected by existential distress, social avoidance and associated health issues (including symptoms of stress, anxiety, and depression). The demand for efficient psychological support is crucial from both an individual and a societal perspective. We have developed a novel psychological intervention (Psychological Intervention tailored for Patients with Cognitive Impairment, PIPCI) manual for providing a non-medical path to enhanced psychological health in the cognitively impaired population. The current article provides specific information on the randomized controlled trial (RCT)-design and methods. The main hypothesis is that participants receiving PIPCI will increase their psychological flexibility (the ability to notice and accept interfering thoughts, emotions, and bodily sensations without acting on them, when this serves action in line with personal values) compared to participants in the active control (cognitive training) group and the waiting list control group. The secondary hypotheses are that participants receiving PIPCI will improve psychological health (stress measures, quality of life, depression, and general health) compared to participants in the active control group and the waiting list control group.Materials and Methods: This three-arm RCT will recruit participants from the cognitive centers at Karolinska University Hospital in Stockholm and randomize approximately 120 individuals in the early phase of cognitive impairment to either an experimental group (psychological intervention once a week for 10 weeks), an active control group (cognitive training once a week for 10 weeks) or a waiting list control group. Intervention outcome will be evaluated with self-report questionnaires on physical and psychological aspects of health, cognitive assessment, biological markers (obtained from blood and saliva) and health care costs. Assessments will be performed at pre- (1 week before the interventions) and post-intervention (1 week after the interventions), as well as at a 6-month follow-up.Discussion: The development of a potentially feasible and effective psychological intervention tailored for early phase cognitive impairment (PIPCI) has the potential to advance the non-pharmacological intervention field. This is especially important given the extensive burden for many affected individuals and their families and the current lack of effective treatments. If the psychological intervention discussed here shows feasibility and efficacy, there is potential for far-reaching healthcare implications for patients with early cognitive impairment at risk of developing dementia.
18.	Enache, Daniela, et al. (författare) CAIDE Dementia Risk Score and biomarkers of neurodegeneration in memory clinic patients without dementia 2016 Ingår i: Neurobiology of Aging. - : Elsevier BV. - 0197-4580 .- 1558-1497. ; 42, s. 124-131 Tidskriftsartikel (refereegranskat)abstract The aim of this study was to explore cross-sectional associations between Cardiovascular Risk Factors, Aging and Dementia Study (CAIDE) Dementia Risk Score and dementia-related cerebrospinal fluid and neuroimaging biomarkers in 724 patients without dementia from the Memory Clinic at Karolinska University Hospital, Huddinge, Sweden. We additionally evaluated the score's capacity to predict dementia. Two risk score versions were calculated: one including age, gender, obesity, hyperlipidemia, and hypertension; and one additionally including apolipoprotein E (APOE) ε4 carrier status. Cerebrospinal fluid was analyzed for amyloid β (Aβ), total tau, and phosphorylated tau. Visual assessments of medial temporal lobe atrophy (MTA), global cortical atrophy-frontal subscale, and Fazekas scale for white matter changes (WMC) were performed. Higher CAIDE Dementia Risk Score (version without APOE) was significantly associated with higher total tau, more severe MTA, WMC, and global cortical atrophy-frontal subscale. Higher CAIDE Dementia Risk Score (version with APOE) was associated with reduced Aβ, more severe MTA, and WMC. CAIDE Dementia Risk Score version with APOE seemed to predict dementia better in this memory clinic population with short follow-up than the version without APOE.
19.	Eskelinen, Marjo H, et al. (författare) Midlife healthy-diet index and late-life dementia and Alzheimer's disease 2011 Ingår i: Dementia and Geriatric Cognitive Disorders Extra. - Basel : S. Karger. - 1664-5464. ; 1:1, s. 103-112 Tidskriftsartikel (refereegranskat)abstract AIM: To study long-term effects of dietary patterns on dementia and Alzheimer's disease (AD). METHODS: Of 525 subjects randomly selected from population-based cohorts surveyed at midlife, a total of 385 (73%) subjects were re-examined 14 years later in the CAIDE study. A healthy-diet index (range 0-17) was constructed including both healthy and unhealthy dietary components. RESULTS: Persons with a healthy diet (healthy-diet index >8 points) had a decreased risk of dementia (OR 0.12, 95% CI 0.02-0.85) and AD (OR 0.08, 95% CI 0.01-0.89) compared with persons with an unhealthy diet (0-8 points), adjusting for several possible confounders. CONCLUSIONS: Healthy diet at midlife is associated with a decreased risk of dementia/AD in late life. These findings highlight the importance of dietary patterns and may make more effective measures for dementia/AD prevention or postponement possible.
20.	Exalto, Lieza G, et al. (författare) Midlife risk score for the prediction of dementia four decades later 2013 Ingår i: Alzheimer's & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 10:5, s. 562-570 Tidskriftsartikel (refereegranskat)abstract ObjectiveThe objective of this study was to obtain external validation of the only available midlife dementia risk score cardiovascular risk factors , aging and dementia study (CAIDE) constituting age, education, hypertension, obesity, and hyperlipidemia in a larger, more diverse population. Our second aim was to improve the CAIDE risk score by additional midlife risk factors.MethodsThis retrospective cohort study was conducted in an integrated health care delivery system. A total of 9480 Kaiser Permanente members who participated in a health survey study (age range, 40–55 years) from 1964 to 1973 were included in this study. Dementia diagnoses from primary care and medical specialist visits were collected from January 1, 1994 to January 16, 2006, using International Classification of Diseases 9 codes 290.0, 290.1 for “possible dementia,” and 331.0 and 290.4 for “specialist confirmed dementia.” Risk model prediction and validation were examined with the C statistic, net reclassification improvement, and integrated discrimination improvement. Dementia risk per sum score was calculated with Kaplan-Meier estimates.ResultsA total of 2767 participants (25%) were diagnosed with any type of dementia, of which 1011 diagnoses (10.7%) were specialist-confirmed diagnoses. Average time between midlife examination and end of follow-up was 36.1 years. The CAIDE risk score replicated well with a C statistic of 0.75, quite similar to the original CAIDE C statistic of 0.78. The CAIDE score also predicted well within different race strata. Other midlife risk factors (central obesity, depressed mood, diabetes mellitus, head trauma, lung function, and smoking) did not improve predictability. The risk score allowed stratification of participants into those with 40-year low (9%) and high (29%) dementia risk.ConclusionsA combination of modifiable vascular risk factors in midlife is highly predictive of the likelihood of dementia decades later. Possible dementia prevention strategies should point to a life course perspective on maintaining vascular health.
21.	Feldman, H H, et al. (författare) Randomized controlled trial of atorvastatin in mild to moderate Alzheimer disease : LEADe 2010 Ingår i: Neurology. - Minneapolis ; New York : Lancet ; Ovid. - 0028-3878 .- 1526-632X. ; 74:12, s. 956-964 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: There is some evidence that statins may have a protective and symptomatic benefit in Alzheimer disease (AD). The LEADe study is a randomized controlled trial (RCT) evaluating the efficacy and safety of atorvastatin in patients with mild to moderate AD.METHODS: This was an international, multicenter, double-blind, randomized, parallel-group study. Subjects had mild to moderate probable AD (Mini-Mental State Examination score 13-25), were aged 50-90 years, and were taking donepezil 10 mg daily for > or 3 months prior to screening. Entry low-density lipoprotein cholesterol levels (LDL-C) were > 95 and < 195 mg/dL. Patients were randomized to atorvastatin 80 mg/day or placebo for 72 weeks followed by a double-blind, 8-week atorvastatin withdrawal phase. Coprimary endpoints were changes in cognition (Alzheimer's Disease Assessment Scale-Cognitive Subscale [ADAS-Cog]) and global function (Alzheimer's Disease Cooperative Study Clinical Global Impression of Change [ADCS-CGIC]) at 72 weeks.RESULTS: A total of 640 patients were randomized in the study. There were no significant differences in the coprimary endpoints of ADAS-cog or ADCS-CGIC or the secondary endpoints. Atorvastatin was generally well-tolerated.CONCLUSIONS: In this large-scale randomized controlled trial evaluating statin therapy as a treatment for mild to moderate Alzheimer disease, atorvastatin was not associated with significant clinical benefit over 72 weeks. This treatment was generally well-tolerated without unexpected adverse events. Classification of evidence: This study provides Class II evidence that intensive lipid lowering with atorvastatin 80 mg/day in patients with mild to moderate probable Alzheimer disease (aged 50-90), taking donepezil, with low-density lipoprotein cholesterol levels between 95 and 195 mg/dL over 72 weeks does not benefit cognition (as measured by Alzheimer's Disease Assessment Scale-Cognitive Subscale) (p = 0.26) or global function (as measured by Alzheimer's Disease Cooperative Study Clinical Global Impression of Change) (p = 0.73) compared with placebo.
22.	Forouzanfar, Mohammad H., et al. (författare) Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2015 : a systematic analysis for the Global Burden of Disease Study 2015 2016 Ingår i: The Lancet. - : Elsevier BV. - 0140-6736 .- 1474-547X. ; 388:10053, s. 1659-1724 Tidskriftsartikel (refereegranskat)abstract Background The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context.Methods We used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. We developed a metric that allows comparisons of exposure across risk factors-the summary exposure value. Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to a Socio-demographic Index (SDI).Findings Between 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25%. Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25% over the same period. All risks jointly evaluated in 2015 accounted for 57.8% (95% CI 56.6-58.8) of global deaths and 41.2% (39.8-42.8) of DALYs. In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211.8 million [192.7 million to 231.1 million] global DALYs), smoking (148.6 million [134.2 million to 163.1 million]), high fasting plasma glucose (143.1 million [125.1 million to 163.5 million]), high BMI (120.1 million [83.8 million to 158.4 million]), childhood undernutrition (113.3 million [103.9 million to 123.4 million]), ambient particulate matter (103.1 million [90.8 million to 115.1 million]), high total cholesterol (88.7 million [74.6 million to 105.7 million]), household air pollution (85.6 million [66.7 million to 106.1 million]), alcohol use (85.0 million [77.2 million to 93.0 million]), and diets high in sodium (83.0 million [49.3 million to 127.5 million]). From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines. Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa.Interpretation Declines in some key environmental risks have contributed to declines in critical infectious diseases. Some risks appear to be invariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention. Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden.
23.	Forouzanfar, Mohammad H, et al. (författare) Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks in 188 countries, 1990-2013 : a systematic analysis for the Global Burden of Disease Study 2013. 2015 Ingår i: The Lancet. - 0140-6736 .- 1474-547X. ; 386:10010, s. 2287-2323 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: The Global Burden of Disease, Injuries, and Risk Factor study 2013 (GBD 2013) is the first of a series of annual updates of the GBD. Risk factor quantification, particularly of modifiable risk factors, can help to identify emerging threats to population health and opportunities for prevention. The GBD 2013 provides a timely opportunity to update the comparative risk assessment with new data for exposure, relative risks, and evidence on the appropriate counterfactual risk distribution.METHODS: Attributable deaths, years of life lost, years lived with disability, and disability-adjusted life-years (DALYs) have been estimated for 79 risks or clusters of risks using the GBD 2010 methods. Risk-outcome pairs meeting explicit evidence criteria were assessed for 188 countries for the period 1990-2013 by age and sex using three inputs: risk exposure, relative risks, and the theoretical minimum risk exposure level (TMREL). Risks are organised into a hierarchy with blocks of behavioural, environmental and occupational, and metabolic risks at the first level of the hierarchy. The next level in the hierarchy includes nine clusters of related risks and two individual risks, with more detail provided at levels 3 and 4 of the hierarchy. Compared with GBD 2010, six new risk factors have been added: handwashing practices, occupational exposure to trichloroethylene, childhood wasting, childhood stunting, unsafe sex, and low glomerular filtration rate. For most risks, data for exposure were synthesised with a Bayesian meta-regression method, DisMod-MR 2.0, or spatial-temporal Gaussian process regression. Relative risks were based on meta-regressions of published cohort and intervention studies. Attributable burden for clusters of risks and all risks combined took into account evidence on the mediation of some risks such as high body-mass index (BMI) through other risks such as high systolic blood pressure and high cholesterol.FINDINGS: All risks combined account for 57·2% (95% uncertainty interval [UI] 55·8-58·5) of deaths and 41·6% (40·1-43·0) of DALYs. Risks quantified account for 87·9% (86·5-89·3) of cardiovascular disease DALYs, ranging to a low of 0% for neonatal disorders and neglected tropical diseases and malaria. In terms of global DALYs in 2013, six risks or clusters of risks each caused more than 5% of DALYs: dietary risks accounting for 11·3 million deaths and 241·4 million DALYs, high systolic blood pressure for 10·4 million deaths and 208·1 million DALYs, child and maternal malnutrition for 1·7 million deaths and 176·9 million DALYs, tobacco smoke for 6·1 million deaths and 143·5 million DALYs, air pollution for 5·5 million deaths and 141·5 million DALYs, and high BMI for 4·4 million deaths and 134·0 million DALYs. Risk factor patterns vary across regions and countries and with time. In sub-Saharan Africa, the leading risk factors are child and maternal malnutrition, unsafe sex, and unsafe water, sanitation, and handwashing. In women, in nearly all countries in the Americas, north Africa, and the Middle East, and in many other high-income countries, high BMI is the leading risk factor, with high systolic blood pressure as the leading risk in most of Central and Eastern Europe and south and east Asia. For men, high systolic blood pressure or tobacco use are the leading risks in nearly all high-income countries, in north Africa and the Middle East, Europe, and Asia. For men and women, unsafe sex is the leading risk in a corridor from Kenya to South Africa.INTERPRETATION: Behavioural, environmental and occupational, and metabolic risks can explain half of global mortality and more than one-third of global DALYs providing many opportunities for prevention. Of the larger risks, the attributable burden of high BMI has increased in the past 23 years. In view of the prominence of behavioural risk factors, behavioural and social science research on interventions for these risks should be strengthened. Many prevention and primary care policy options are available now to act on key risks.FUNDING: Bill & Melinda Gates Foundation.
24.	Gil-Bea, Francisco J, et al. (författare) Insulin levels are decreased in the cerebrospinal fluid of women with prodomal Alzheimer's disease 2010 Ingår i: Journal of Alzheimer's Disease. - Amsterdam; Washington : IOS Press. - 1387-2877 .- 1875-8908. ; 22:2, s. 405-413 Tidskriftsartikel (refereegranskat)abstract Previous studies have failed to reach consensus on insulin levels in cerebrospinal fluid of Alzheimer's disease (AD) patients and on its relation to pathological features. We performed a new analysis in patients at different stages of AD, and investigated the relationship of insulin levels with biochemical disease markers and with cognitive score. We included 99 patients from our Memory Clinic (Karolinska University Hospital, Sweden), including: 27 patients with mild AD, 13 that progressed from mild cognitive impairment (MCI) to AD in two years time, 26 with MCI stable after two years, and 33 with subjective cognitive impairment. Insulin was significantly decreased in the cerebrospinal fluid of both women and men with mild AD. Insulin deficits were seen in women belonging to both MCI groups, suggesting that this occurs earlier than in men. Insulin was positively associated with amyloid-β 1-42 (Aβ1-42) levels and cognitive score. Furthermore, total-tau/(Aβ1-42*insulin) ratio showed strikingly better sensitivity and specificity than the total-tau/Aβ1-42 ratio for early AD diagnosis in women.
25.	Hachinski, Vladimir, et al. (författare) Stroke: Working Toward a Prioritized World Agenda 2010 Ingår i: Stroke: a journal of cerebral circulation. - 1524-4628. ; 41:6, s. 1084-1099 Tidskriftsartikel (refereegranskat)abstract Background and Purpose-The aim of the Synergium was to devise and prioritize new ways of accelerating progress in reducing the risks, effects, and consequences of stroke. Methods-Preliminary work was performed by 7 working groups of stroke leaders followed by a synergium (a forum for working synergistically together) with approximately 100 additional participants. The resulting draft document had further input from contributors outside the synergium. Results-Recommendations of the Synergium are: Basic Science, Drug Development and Technology: There is a need to develop: (1) New systems of working together to break down the prevalent "silo" mentality; (2) New models of vertically integrated basic, clinical, and epidemiological disciplines; and (3) Efficient methods of identifying other relevant areas of science. Stroke Prevention: (1) Establish a global chronic disease prevention initiative with stroke as a major focus. (2) Recognize not only abrupt clinical stroke, but subtle subclinical stroke, the commonest type of cerebrovascular disease, leading to impairments of executive function. (3) Develop, implement and evaluate a population approach for stroke prevention. (4) Develop public health communication strategies using traditional and novel (eg, social media/marketing) techniques. Acute Stroke Management: Continue the establishment of stroke centers, stroke units, regional systems of emergency stroke care and telestroke networks. Brain Recovery and Rehabilitation: (1) Translate best neuroscience, including animal and human studies, into poststroke recovery research and clinical care. (2) Standardize poststroke rehabilitation based on best evidence. (3) Develop consensus on, then implementation of, standardized clinical and surrogate assessments. (4) Carry out rigorous clinical research to advance stroke recovery. Into the 21st Century: Web, Technology and Communications: (1) Work toward global unrestricted access to stroke-related information. (2) Build centralized electronic archives and registries. Foster Cooperation Among Stakeholders (large stroke organizations, nongovernmental organizations, governments, patient organizations and industry) to enhance stroke care. Educate and energize professionals, patients, the public and policy makers by using a "Brain Health" concept that enables promotion of preventive measures. Conclusions-To accelerate progress in stroke, we must reach beyond the current status scientifically, conceptually, and pragmatically. Advances can be made not only by doing, but ceasing to do. Significant savings in time, money, and effort could result from discontinuing practices driven by unsubstantiated opinion, unproven approaches, and financial gain. Systematic integration of knowledge into programs coupled with careful evaluation can speed the pace of progress.
26.	Hachinski, Vladimir, et al. (författare) Stroke: Working toward a Prioritized World Agenda 2010 Ingår i: Cerebrovascular Diseases. - : S. Karger AG. - 1421-9786 .- 1015-9770. ; 30:2, s. 127-147 Tidskriftsartikel (refereegranskat)abstract Background and Purpose: The aim of the Synergium was to devise and prioritize new ways of accelerating progress in reducing the risks, effects, and consequences of stroke. Methods: Preliminary work was performed by 7 working groups of stroke leaders followed by a synergium (a forum for working synergistically together) with approximately 100 additional participants. The resulting draft document had further input from contributors outside the synergium. Results: Recommendations of the Synergium are: Basic Science, Drug Development and Technology: There is a need to develop: (1) New systems of working together to break down the prevalent 'silo' mentality; (2) New models of vertically integrated basic, clinical, and epidemiological disciplines; and (3) Efficient methods of identifying other relevant areas of science. Stroke Prevention: (1) Establish a global chronic disease prevention initiative with stroke as a major focus. (2) Recognize not only abrupt clinical stroke, but subtle subclinical stroke, the commonest type of cerebrovascular disease, leading to impairments of executive function. (3) Develop, implement and evaluate a population approach for stroke prevention. (4) Develop public health communication strategies using traditional and novel (e. g., social media/marketing) techniques. Acute Stroke Management: Continue the establishment of stroke centers, stroke units, regional systems of emergency stroke care and telestroke networks. Brain Recovery and Rehabilitation: (1) Translate best neuroscience, including animal and human studies, into poststroke recovery research and clinical care. (2) Standardize poststroke rehabilitation based on best evidence. (3) Develop consensus on, then implementation of, standardized clinical and surrogate assessments. (4) Carry out rigorous clinical research to advance stroke recovery. Into the 21st Century: Web, Technology and Communications: (1) Work toward global unrestricted access to stroke-related information. (2) Build centralized electronic archives and registries. Foster Cooperation Among Stakeholders (large stroke organizations, nongovernmental organizations, governments, patient organizations and industry) to enhance stroke care. Educate and energize professionals, patients, the public and policy makers by using a 'Brain Health' concept that enables promotion of preventive measures. Conclusions: To accelerate progress in stroke, we must reach beyond the current status scientifically, conceptually, and pragmatically. Advances can be made not only by doing, but ceasing to do. Significant savings in time, money, and effort could result from discontinuing practices driven by unsubstantiated opinion, unproven approaches, and financial gain. Systematic integration of knowledge into programs coupled with careful evaluation can speed the pace of progress. Copyright (C) 2010 American Heart Association. Inc., S. Karger AG, Basel, and John Wiley & Sons, Inc.
27.	Hachinski, Vladimir, et al. (författare) Stroke: working toward a prioritized world agenda 2010 Ingår i: International Journal of Stroke. - : SAGE Publications. - 1747-4949 .- 1747-4930. ; 5:4, s. 238-256 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract Background and Purpose The aim of the Synergium was to devise and prioritize new ways of accelerating progress in reducing the risks, effects, and consequences of stroke. Methods Preliminary work was performed by seven working groups of stroke leaders followed by a synergium (a forum for working synergistically together) with approximately 100 additional participants. The resulting draft document had further input from contributors outside the synergium. Results Recommendations of the Synergium are: Basic Science, Drug Development and Technology: There is a need to develop: (1) New systems of working together to break down the prevalent 'silo' mentality; (2) New models of vertically integrated basic, clinical, and epidemiological disciplines; and (3) Efficient methods of identifying other relevant areas of science. Stroke Prevention: (1) Establish a global chronic disease prevention initiative with stroke as a major focus. (2) Recognize not only abrupt clinical stroke, but subtle subclinical stroke, the commonest type of cerebrovascular disease, leading to impairments of executive function. (3) Develop, implement and evaluate a population approach for stroke prevention. (4) Develop public health communication strategies using traditional and novel (eg, social media/marketing) techniques. Acute Stroke Management: Continue the establishment of stroke centers, stroke units, regional systems of emergency stroke care and telestroke networks. Brain Recovery and Rehabilitation: (1) Translate best neuroscience, including animal and human studies, into poststroke recovery research and clinical care. (2) Standardize poststroke rehabilitation based on best evidence. (3) Develop consensus on, then implementation of, standardized clinical and surrogate assessments. (4) Carry out rigorous clinical research to advance stroke recovery. Into the 21st Century: Web, Technology and Communications: (1) Work toward global unrestricted access to stroke-related information. (2) Build centralized electronic archives and registries. Foster Cooperation Among Stakeholders (large stroke organizations, nongovernmental organizations, governments, patient organizations and industry) to enhance stroke care. Educate and energize professionals, patients, the public and policy makers by using a 'Brain Health' concept that enables promotion of preventive measures. Conclusions To accelerate progress in stroke, we must reach beyond the current status scientifically, conceptually, and pragmatically. Advances can be made not only by doing, but ceasing to do. Significant savings in time, money, and effort could result from discontinuing practices driven by unsubstantiated opinion, unproven approaches, and financial gain. Systematic integration of knowledge into programs coupled with careful evaluation can speed the pace of progress.
28.	Hagg, Sara, et al. (författare) Age, Frailty, and Comorbidity as Prognostic Factors for Short-Term Outcomes in Patients With Coronavirus Disease 2019 in Geriatric Care 2020 Ingår i: Journal of the American Medical Directors Association. - : ELSEVIER SCIENCE INC. - 1525-8610 .- 1538-9375. ; 21:11, s. 1555-1559 Tidskriftsartikel (refereegranskat)abstract Objectives: To analyze whether frailty and comorbidities are associated with in-hospital mortality and discharge to home in older adults hospitalized for coronavirus disease 2019 (COVID-19). Design: Single-center observational study. Setting and Participants: Patients admitted to geriatric care in a large hospital in Sweden between March 1 and June 11, 2020; 250 were treated for COVID-19 and 717 for other diagnoses. Methods: COVID-19 diagnosis was clinically confirmed by positive reverse transcription polymerase chain reaction test or, if negative, by other methods. Patient data were extracted from electronic medical records, which included Clinical Frailty Scale (CFS), and were further used for assessments of the Hospital Frailty Risk Score (HFRS) and the Charlson Comorbidity Index (CCI). In-hospital mortality and home discharge were followed up for up to 25 and 28 days, respectively. Multivariate Cox regression models adjusted for age and sex were used. Results: Among the patients with COVID-19, in-hospital mortality rate was 24% and home discharge rate was 44%. Higher age was associated with in-hospital mortality (hazard ratio [HR] 1.05 per each year, 95% confidence interval [CI] 1.01.1.08) and lower probability of home discharge (HR 0.97, 95% CI 0.95.0.99). CFS (>5) and CCI, but not HFRS, were predictive of in-hospital mortality (HR 1.93, 95% CI 1.02.3.65 and HR 1.27, 95% CI 1.02.1.58, respectively). Patients with CFS >5 had a lower probability of being discharged home (HR 0.38, 95% CI 0.25.0.58). CCI and HFRS were not associated with home discharge. In general, effects were more pronounced in men. Acute kidney injury was associated with in-hospital mortality and hypertension with discharge to home. Other comorbidities (diabetes, cardiovascular disease, lung diseases, chronic kidney disease and dementia) were not associated with either outcome. Conclusions and Implications: Of all geriatric patients with COVID-19, 3 out of 4 survived during the study period. Our results indicate that in addition to age, the level of frailty is a useful predictor of short-term COVID-19 outcomes in geriatric patients. (C) 2020 AMDA - The Society for Post-Acute and Long-Term Care Medicine.
29.	Hagman, Göran, et al. (författare) Midlife hopelessness and white matter lesions two decades later : A population-based study 2010 Ingår i: Alzheimer's & Dementia. - : Elsevier. - 1552-5260 .- 1552-5279. ; 7:4, Supplement, s. 595-595 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract Background: Hopelessness has been associated with increased cardiovas- cular disease mortality and morbidity, subclinical atherosclerosis and meta- bolic syndrome. This study investigates the relation between midlife hopelessness and white matter lesions (WMLs) 20 years later in a Finnish population of men and women. Methods: Participants of the Cardiovascular Risk Factors, Aging and Incidence of Dementia (CAIDE) study in Finland were derived from random, population-based samples previously surveyed in 1972,1977, 1982 or 1987. In 1998, 1449 (73%) individuals aged 65-79 years participated in the re-examination. A subgroup (n1⁄4112, including 39 dementia cases, 31 mild cognitive impairment (MCI) cases and 42 con- trols) underwent 1.5T MRI scanning at re-examination, and WMLs were as- sessed from FLAIR-images using a semi-quantitative visual rating scale. Hopelessness was measured by 2 questionnaire items (expectations about future and reaching goals). Results: Subjects with increased hopelessness had a significantly higher risk of developing more severe WMLs two de- cades later. OR (95% CI) was 4.35 (1.36-13.46) in ordinal regression anal- yses adjusted for age, sex education, follow-up time, presence of the APOEe4 allele, systolic blood pressure, BMI, history of stroke, heart infarct, smoking and level of midlife leisure physical activity. Conclusions: Higher levels of hopelessness at midlife seem to be related to more severe WMLs later in life. Since WMLs may contribute to late-life cognitive impairment, lifestyle management of midlife vascular risk factors (which also increase the risk of dementia and cognitive impairment) may have better effects if people’s expectations are more thoroughly discussed.
30.	Hampel, Harald, et al. (författare) Advances in the therapy of Alzheimer's disease : targeting amyloid beta and tau and perspectives for the future 2015 Ingår i: Expert Review of Neurotherapeutics. - : Informa UK Limited. - 1473-7175 .- 1744-8360. ; 15:1, s. 83-105 Forskningsöversikt (refereegranskat)abstract Worldwide multidisciplinary translational research has led to a growing knowledge of the genetics and molecular pathogenesis of Alzheimer's disease (AD) indicating that pathophysiological brain alterations occur decades before clinical signs and symptoms of cognitive decline can be diagnosed. Consequently, therapeutic concepts and targets have been increasingly focused on early-stage illness before the onset of dementia; and distinct classes of compounds are now being tested in clinical trials. At present, there is a growing consensus that therapeutic progress in AD delaying disease progression would significantly decrease the expanding global burden. The evolving hypothesis- and evidence-based generation of new diagnostic research criteria for early-stage AD has positively impacted the development of clinical trial designs and the characterization of earlier and more specific target populations for trials in prodromal as well as in pre- and asymptomatic at-risk stages of AD.
31.	Hartikainen, Päivi, et al. (författare) Cortical thickness in frontotemporal dementia, mild cognitive impairment, and Alzheimer's disease 2012 Ingår i: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 30:4, s. 857-874 Tidskriftsartikel (refereegranskat)abstract Cortical thickness analysis has been proposed as a potential diagnostic measure in memory disorders. In this retrospective study, we compared the cortical thickness values of 24 patients with frontotemporal dementia (FTD) to those of 25 healthy controls, 45 symptomatic subjects with stable mild cognitive impairment (S-MCI), 15 subjects with progressive mild cognitive impairment (P-MCI), and 36 patients with Alzheimer's disease (AD). The patterns of regions of thinning in FTD when compared to controls and also S-MCI patients showed similar trends; thinning of the bilateral frontal poles and bilateral medial temporal lobe structures, especially the anterior part of the gingulum, the uncus, and parahippocampal gyri. Cortical thinning in FTD was also found on the boundary regions of parietal and occipital lobes. In the P-MCI group compared to FTD, the trend of thinning in small distinct areas of the parietal and occipital lobes was observed. The FTD and AD groups did not differ statistically, but we found trends toward thinning in FTD of the left cingulate gyrus, and the left occipitotemporal gyri, and in AD of the inferior parietal, occipitoparietal, and the pericalcarine regions, more in the right hemisphere. In FTD, increased slowness in the executive test (Trail-Making A) correlated with the thinner cortex, whereas the language tests showed the lower scores, the thinner cortex in the left hemisphere. Cortical thickness might be a tool for detecting subtle changes in brain atrophy in screening of dementia prior to the development of diffuse or lobar atrophies.
32.	Hoevenaar-Blom, Marieke P., et al. (författare) Improving data sharing in research with context-free encoded missing data 2017 Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 12:9 Tidskriftsartikel (refereegranskat)abstract Lack of attention to missing data in research may result in biased results, loss of power and reduced generalizability. Registering reasons for missing values at the time of data collection, or-in the case of sharing existing data-before making data available to other teams, can save time and efforts, improve scientific value and help to prevent erroneous assumptions and biased results. To ensure that encoding of missing data is sufficient to understand the reason why data are missing, it should ideally be context-free. Therefore, 11 context-free codes of missing data were carefully designed based on three completed randomized controlled clinical trials and tested in a new randomized controlled clinical trial by an international team consisting of clinical researchers and epidemiologists with extended experience in designing and conducting trials and an Information System expert. These codes can be divided into missing due to participant and/or participation characteristics (n = 6), missing by design (n = 4), and due to a procedural error (n = 1). Broad implementation of context-free missing data encoding may enhance the possibilities of data sharing and pooling, thus allowing more powerful analyses using existing data.
33.	Holleman, Jasper, et al. (författare) Cortisol, cognition and Alzheimer's disease biomarkers among memory clinic patients 2022 Ingår i: BMJ Neurology Open. - : BMJ Publishing Group Ltd. - 2632-6140. ; 4:2 Tidskriftsartikel (refereegranskat)abstract ObjectiveThis study aims to investigate the relationship between diurnal cortisol patterns, cognition and Alzheimer's disease (AD) biomarkers in memory clinic patients.MethodMemory clinic patients were recruited from Karolinska University Hospital in Sweden (n=155). Diurnal cortisol patterns were assessed using five measures: awakening levels, cortisol awakening response, bedtime levels, the ratio of awakening to bedtime levels (AM/PM ratio) and total daily output. Cognition was measured in five domains: memory, working memory, processing speed, perceptual reasoning and overall cognition. AD biomarkers A beta(42), total tau and phosphorylated tau were assessed from cerebrospinal fluid (CSF). Cognition was measured at follow-up (average 32 months) in a subsample of participants (n=57).ResultsIn assessing the associations between cortisol and cognition, higher awakening cortisol levels were associated with greater processing speed at baseline. No relationship was found between diurnal cortisol patterns and change in cognition over time or CSF AD biomarkers in the total sample. After stratification by CSF A beta(42) levels, higher awakening cortisol levels were associated with worse memory performance in amyloid-positive participants. In amyloid-negative participants, higher bedtime cortisol levels and a lower AM/PM ratio were associated with lower overall cognition, greater awakening cortisol levels were associated with better processing speed, and a higher AM/PM ratio was associated with better perceptual reasoning. Additionally, higher awakening cortisol levels were associated with lower CSF A beta(42) levels in amyloid-positive participants, while higher bedtime cortisol levels and a lower AM/PM ratio were associated with higher CSF total tau in amyloid-negative participants.ConclusionsOur findings suggest that diurnal cortisol patterns are associated with cognitive function and provide new insights into the association between diurnal cortisol patterns and AD-related CSF biomarkers. Further research is needed to examine the complex relationship between cortisol, cognition and brain pathology.
34.	Holleman, Jasper, et al. (författare) Diurnal cortisol, neuroinflammation, and neuroimaging visual rating scales in memory clinic patients 2024 Ingår i: Brain, behavior, and immunity. - : Elsevier. - 0889-1591 .- 1090-2139. ; 118, s. 499-509 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: Neuroinflammation is a hallmark of the Alzheimer's disease (AD) pathogenic process. Cortisol dysregulation may increase AD risk and is related to brain atrophy. This cross-sectional study aims to examine interactions of cortisol patterns and neuroinflammation markers in their association with neuroimaging correlates.METHOD: 134 participants were recruited from the Karolinska University Hospital memory clinic (Stockholm, Sweden). Four visual rating scales were applied to magnetic resonance imaging or computed tomography scans: medial temporal lobe atrophy (MTA), global cortical atrophy (GCA), white matter lesions (WML), and posterior atrophy. Participants provided saliva samples for assessment of diurnal cortisol patterns, and underwent lumbar punctures for cerebrospinal fluid (CSF) sampling. Three cortisol measures were used: the cortisol awakening response, total daily output, and the ratio of awakening to bedtime levels. Nineteen CSF neuroinflammation markers were categorized into five composite scores: proinflammatory cytokines, other cytokines, angiogenesis markers, vascular injury markers, and glial activation markers. Ordinal logistic regressions were conducted to assess associations between cortisol patterns, neuroinflammation scores, and visual rating scales, and interactions between cortisol patterns and neuroinflammation scores in relation to visual rating scales.RESULT: Higher levels of angiogenesis markers were associated with more severe WML. Some evidence was found for interactions between dysregulated diurnal cortisol patterns and greater neuroinflammation-related biomarkers in relation to more severe GCA and WML. No associations were found between cortisol patterns and visual rating scales.CONCLUSION: This study suggests an interplay between diurnal cortisol patterns and neuroinflammation in relation to brain structure. While this cross-sectional study does not provide information on causality or temporality, these findings suggest that neuroinflammation may be involved in the relationship between HPA-axis functioning and AD.
35.	Holleman, Jasper, et al. (författare) Life-course stress, cognition, and diurnal cortisol in memory clinic patients without dementia 2024 Ingår i: Archives of gerontology and geriatrics (Print). - : Elsevier. - 0167-4943 .- 1872-6976. ; 119 Tidskriftsartikel (refereegranskat)abstract AIMS: To examine associations of life-course stress with cognition and diurnal cortisol patterns in older adulthood, as well as potential mediation effects of diurnal cortisol patterns and perceived stress on the association between life-course stress and cognition.METHODS: 127 participants without dementia were selected from a cohort of Swedish memory clinic patients. Cross-sectional associations between scores on two chronic stress questionnaires (perceived stress, stressful life events (SLEs)), five cognitive domains (overall cognition, memory, working memory, processing speed, perceptual reasoning), and two measures of diurnal cortisol patterns (total daily output, diurnal cortisol slope), as well as potential mediation effects of diurnal cortisol patterns and perceived stress on associations between life-course stress and cognition, were assessed using linear regressions.RESULTS: Greater lifetime exposure to SLEs was associated with worse memory, working memory, and processing speed performance, but not with diurnal cortisol patterns. A greater number of SLEs in late childhood was associated with worse working memory and processing speed, while a greater number of SLEs in non-recent adulthood were associated with better overall cognition and perceptual reasoning. Greater perceived stress was associated with a flattened diurnal cortisol slope, but not with cognition. No evidence for interplay between self-reported and physiological stress markers was found in relation to cognition, although there appeared to be a significant positive indirect association between economic/legal SLEs and the diurnal cortisol slope via perceived stress.CONCLUSIONS: The associations between SLEs and cognition depend on the period during which SLEs occur, but seem independent of late-life cortisol dysregulation.
36.	Hooshmand, Babak, et al. (författare) Association of Methionine to Homocysteine Status With Brain Magnetic Resonance Imaging Measures and Risk of Dementia 2019 Ingår i: JAMA psychiatry. - : American Medical Association (AMA). - 2168-6238 .- 2168-622X. ; 76:11, s. 1198-1205 Tidskriftsartikel (refereegranskat)abstract IMPORTANCE Impairment of methylation status (ie, methionine to homocysteine ratio) may be a modifiable risk factor for structural brain changes and incident dementia.OBJECTIVE To investigate the association of serum markers of methylation status and sulfur amino acids with risk of incident dementia, Alzheimer disease (AD), and the rate of total brain tissue volume loss during 6 years.DESIGN, SETTING, AND PARTICIPANTS This population-based longitudinal study was performed from March 21, 2001, to October 10, 2010, in a sample of 2570 individuals aged 60 to 102 years from the Swedish Study on Aging and Care in Kungsholmen who were dementia free at baseline and underwent comprehensive examinations and structural brain magnetic resonance imaging (MRI) on 2 to 3 occasions during 6 years. Data analysis was performed from March 1, 2018, to October 1, 2018.MAIN OUTCOMES AND MEASURES Incident dementia, AD, and the rate of total brain volume loss.RESULTS This study included 2570 individuals (mean [SD] age, 73.1 [10.4] years; 1331 [56.5%] female). The methionine to homocysteine ratio was higher in individuals who consumed vitamin supplements (median, 1.9; interquartile range [IQR], 1.5-2.6) compared with those who did not (median, 1.8; IQR, 1.3-2.3; P<.001) and increased per each quartile increase of vitamin B-12 or folate. In the multiadjusted model, an elevated baseline serum total homocysteine level was associated with an increased risk of dementia and AD during 6 years: for the highest homocysteine quartile compared with the lowest, the hazard ratios (HRs) were 1.60 (95% CI, 1.01-2.55) for dementia and 2.33 (95% CI, 1.26-4.30) for AD. In contrast, elevated concentrations of methionine were associated with a decreased risk of dementia (HR, 0.54; 95% CI, 0.36-0.81) for the highest quartile compared with the lowest. Higher values of the methionine to homocysteine ratio were significantly associated with lower risk of dementia and AD: for the fourth methionine-homocysteine quartile compared with the first quartile, the HR was 0.44 (95% CI, 0.27-0.71) for incident dementia and 0.43 (95% CI, 0.23-0.80) for AD. In the multiadjusted linear mixed models, a higher methionine to homocysteine ratio was associated with a decreased rate of total brain tissue volume loss during the study period (beta [SE] per 1-SD increase, 0.038 [0.014]; P=.007).CONCLUSIONS AND RELEVANCE The methionine to homocysteine status was associated with dementia development and structural brain changes during the 6-year study period, suggesting that a higher methionine to homocysteine ratio may be important in reducing the rate of brain atrophy and decreasing the risk of dementia in older adults.
37.	Hooshmand, Babak, et al. (författare) Association of Vitamin B-12, Folate, and Sulfur Amino Acids With Brain Magnetic Resonance Imaging Measures in Older Adults A Longitudinal Population-Based Study 2016 Ingår i: JAMA psychiatry. - : American Medical Association (AMA). - 2168-6238 .- 2168-622X. ; 73:6, s. 606-613 Tidskriftsartikel (refereegranskat)abstract IMPORTANCE Vitamin B-12, folate, and sulfur amino acids may be modifiable risk factors for structural brain changes that precede clinical dementia. OBJECTIVE To investigate the association of circulating levels of vitamin B-12, red blood cell folate, and sulfur amino acids with the rate of total brain volume loss and the change in white matter hyperintensity volume as measured by fluid-attenuated inversion recovery in older adults. DESIGN, SETTING, AND PARTICIPANTS The magnetic resonance imaging subsample of the Swedish National Study on Aging and Care in Kungsholmen, a population-based longitudinal study in Stockholm, Sweden, was conducted in 501 participants aged 60 years or older who were free of dementia at baseline. A total of 299 participants underwent repeated structural brain magnetic resonance imaging scans from September 17, 2001, to December 17, 2009. MAIN OUTCOMES AND MEASURES The rate of brain tissue volume loss and the progression of total white matter hyperintensity volume. RESULTS In the multi-adjusted linear mixed models, among 501 participants (300 women [59.9%]; mean [SD] age, 70.9 [9.1] years), higher baseline vitamin B-12 and holotranscobalamin levels were associated with a decreased rate of total brain volume loss during the study period: for each increase of 1 SD, beta (SE) was 0.048 (0.013) for vitamin B-12 (P < .001) and 0.040 (0.013) for holotranscobalamin (P = .002). Increased total homocysteine levels were associated with faster rates of total brain volume loss in the whole sample (beta [SE] per 1-SD increase, -0.035 [0.015]; P = .02) and with the progression of white matter hyperintensity among participants with systolic blood pressure greater than 140mmHg (beta [SE] per 1-SD increase, 0.000019 [0.00001]; P = .047). No longitudinal associations were found for red blood cell folate and other sulfur amino acids. CONCLUSIONS AND RELEVANCE This study suggests that both vitamin B-12 and total homocysteine concentrations may be related to accelerated aging of the brain. Randomized clinical trials are needed to determine the importance of vitamin B-12 supplementation on slowing brain aging in older adults.
38.	Hooshmand, Babak, et al. (författare) Associations between serum homocysteine, holotranscobalamin, folate and cognition in the elderly : a longitudinal study 2012 Ingår i: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 271:2, s. 204-212 Tidskriftsartikel (refereegranskat)abstract 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.
39.	Hooshmand, Babak, et al. (författare) Homocysteine and holotranscobalamin and the risk of Alzheimer disease : a longitudinal study 2010 Ingår i: Neurology. - 0028-3878 .- 1526-632X. ; 75:16, s. 1408-1414 Tidskriftsartikel (refereegranskat)abstract OBJECTIVE: To examine the relation between serum levels of homocysteine (tHcy) and holotranscobalamin (holoTC), the active fraction of vitamin B12, and risk of incident Alzheimer disease (AD) in a sample of Finnish community-dwelling elderly. METHODS: A dementia-free sample of 271 subjects aged 65-79 years derived from the Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) study was followed up for 7 years to detect incident AD. The association between serum tHcy and holoTC with AD was analyzed with multiple logistic regression after adjusting for several potential confounders, including common vascular risk factors. RESULTS: The odds ratios (ORs) (95% confidence interval [CI]) for AD were 1.16 (1.04-1.31) per increase of 1 μmol/L of tHcy at baseline and 0.980 (0.965-0.995) for each increase of 1 pmol/L baseline holoTC. Adjustment for several potential confounders including age, sex, education, APOE ε4 allele, body mass index, Mini-Mental State Examination, smoking, stroke, and blood pressure did not alter the associations: ORs (95% CI) for AD became 1.19 (1.01-1.39) for tHcy and 0.977 (0.958-0.997) for holoTC. Adjusting for holoTC attenuated the tHcy-AD link (OR changed from 1.16 to 1.10, 95% CI 0.96-1.25). The holoTC-AD relationship was less influenced by controlling for tHcy (OR changed from 0.980 to 0.984, 95% CI 0.968-1.000). Addition of folate did not change any of the results. CONCLUSIONS: This study suggests that both tHcy and holoTC may be involved in the development of AD. The tHcy-AD link may be partly explained by serum holoTC. The role of holoTC in AD should be further investigated.
40.	Hooshmand, Babak, et al. (författare) Plasma homocysteine, Alzheimer and cerebrovascular pathology : a population-based autopsy study 2013 Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 136, s. 2707-2716 Tidskriftsartikel (refereegranskat)abstract Elevated plasma total homocysteine is associated with increased risk of dementia/Alzheimer's disease, but underlying pathophysiological mechanisms are not fully understood. This study investigated possible links between baseline homocysteine, and post-mortem neuropathological and magnetic resonance imaging findings up to 10 years later in the Vantaa 85+ population including people aged epsilon 85 years. Two hundred and sixty-five individuals had homocysteine and autopsy data, of which 103 had post-mortem brain magnetic resonance imaging scans. Methenamine silver staining was used for amyloid-beta and modified Bielschowsky method for neurofibrillary tangles and neuritic plaques. Macroscopic infarcts were identified from cerebral hemispheres, brainstem and cerebellum slices. Standardized methods were used to determine microscopic infarcts, cerebral amyoloid angiopathy, and alpha-synuclein pathology. Magnetic resonance imaging was used for visual ratings of the degree of medial temporal lobe atrophy, and periventricular and deep white matter hyperintensities. Elevated baseline homocysteine was associated with increased neurofibrillary tangles count at the time of death: for the highest homocysteine quartile, odds ratio (95% confidence interval) was 2.60 (1.28-5.28). The association was observed particularly in people with dementia, in the presence of cerebral infarcts, and with longer time between the baseline homocysteine assessment and death. Also, elevated homocysteine tended to relate to amyloid-beta accumulation, but this was seen only with longer baseline-death interval: odds ratio (95% confidence interval) was 2.52 (0.88-7.19) for the highest homocysteine quartile. On post-mortem magnetic resonance imaging, for the highest homocysteine quartile odds ratio (95% confidence interval) was 3.78 (1.12-12.79) for more severe medial temporal atrophy and 4.69 (1.14-19.33) for more severe periventricular white matter hyperintensities. All associations were independent of several potential confounders, including common vascular risk factors. No relationships between homocysteine and cerebral macro- or microinfarcts, cerebral amyoloid angiopathy or alpha-synuclein pathology were detected. These results suggest that elevated homocysteine in adults aged epsilon 85 years may contribute to increased Alzheimer-type pathology, particularly neurofibrillary tangles burden. This effect seems to be more pronounced in the presence of cerebrovascular pathology. Randomized controlled trials are needed to determine the impact of homocysteine-lowering treatments on dementia-related pathology.
41.	Hooshmand, Babak, et al. (författare) Serum Insulin and Cognitive Performance in Older Adults : A Longitudinal Study 2019 Ingår i: American Journal of Medicine. - : Elsevier BV. - 0002-9343 .- 1555-7162. ; 132:3, s. 367-373 Tidskriftsartikel (refereegranskat)abstract PurposeThe aim of this study was to examine the association of serum glucose, insulin, and insulin resistance with cognitive functioning 7 years later in a longitudinal population-based study of Finnish older adults.MethodsSerum glucose and insulin were measured at baseline in 269 dementia-free individuals aged 65-79 years, from the Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) study. Insulin resistance was estimated with the homeostasis model assessment (HOMA-IR). Participants were reexamined 7 years later, and global cognition, episodic memory, executive functioning, verbal expression, and psychomotor speed were assessed, both at baseline and at follow-up. Multiple linear regression was used to investigate the associations with cognitive performance at follow-up, after adjusting for several potential confounders, including common vascular risk factors.ResultsIn the multivariable-adjusted linear regression models, no associations of insulin resistance with cognitive functioning were observed. After excluding 19 incident dementia cases, higher baseline HOMA-IR values were related to worse performance in global cognition (beta [standard error (SE)] -.050 [0.02]; P =.043) and psychomotor speed (beta [SE] -.064 [. 03]; P = [.043]) 7 years later. Raised serum insulin levels were associated with lower scores on global cognition (b [SE] -.054 [.03]; P =.045) and tended to relate to poorer performance in psychomotor speed (beta [SE] -.061 [.03]; P =.070).ConclusionsSerum insulin and insulin resistance may be independent predictors of cognitive performance 7 years later in elderly individuals without dementia. Randomized controlled trials are needed to determine this issue.
42.	Hooshmand, Babak, et al. (författare) Vitamin D in Relation to Cognitive Impairment, Cerebrospinal Fluid Biomarkers, and Brain Volumes 2014 Ingår i: The journals of gerontology. Series A, Biological sciences and medical sciences. - : Oxford University Press (OUP). - 1079-5006 .- 1758-535X. ; 69:9, s. 1132-1138 Tidskriftsartikel (refereegranskat)abstract Background. Low vitamin D status is associated with poorer cognitive function in older adults, but little is known about the potential impact on cerebrospinal fluid (CSF) biomarkers and brain volumes. The objective of this study was to examine the relations between plasma 25-hydroxyvitamin D (25(OH)D) and cognitive impairment, CSF biomarkers of Alzheimer's disease (AD), and structural brain tissue volumes. Methods. A total of 75 patients (29 with subjective cognitive impairment, 28 with mild cognitive impairment, 18 with AD) referred to the Memory Clinic at Karolinska University Hospital, Huddinge, Sweden were recruited. Plasma 25(OH)D, CSF levels of amyloid beta (A beta(1-42)), total-tau, and phosphorylated tau, and brain tissue volumes have been measured. Results. After adjustment for several potential confounders, the odds ratios (95% confidence interval) for cognitive impairment were as follows: 0.969 (0.948-0.990) per increase of 1 nmol/L of 25(OH) D and 4.19 (1.30-13.52) for 24(OH) D values less than 50 nmol/L compared with values greater than or equal to 50 nmol/L. Adjusting for CSF A beta(1-42) attenuated the 25(OH) D-cognition link. In a multiple linear regression analysis, higher 25(OH)D levels were related to higher concentrations of CSF A beta(1-42) and greater brain volumes (eg, white matter, structures belonging to medial temporal lobe). The associations between 25(OH)D and tau variables were not significant. Conclusions. This study suggests that vitamin D may be associated with cognitive status, CSF A beta(1-42) levels, and brain tissue volumes.
43.	Håkansson, Krister, 1952-, et al. (författare) Association between mid-life marital status and cognitive function in later life : population based cohort study 2009 Ingår i: The BMJ. - : BMJ. - 1756-1833 .- 0959-8138 .- 1468-5833. ; 339:July, s. Article number: b2462- Tidskriftsartikel (refereegranskat)abstract Objectives To evaluate whether mid-life marital status is related to cognitive function in later life. Design Prospective population based study with an average follow-up of 21 years. Setting Kuopio and Joensuu regions in eastern Finland. Participants Participants were derived from random, population based samples previously investigated in 1972, 1977, 1982, or 1987; 1449 individuals (73%), aged 65-79, underwent re-examination in 1998. Main outcome measures Alzheimer's disease and mild cognitive impairment. Results People cohabiting with a partner in mid-life (mean age 50.4) were less likely than all other categories (single, separated, or widowed) to show cognitive impairment later in life at ages 65-79. Those widowed or divorced in mid-life and still so at follow-up had three times the risk compared with married or cohabiting people. Those widowed both at mid-life and later life had an odds ratio of 7.67 (1.6 to 40.0) for Alzheimer's disease compared with married or cohabiting people. The highest increased risk for Alzheimer's disease was in carriers of the apolipoprotein E e4 allele who lost their partner before mid-life and were still widowed or divorced at follow-up. The progressive entering of several adjustment variables from mid-life did not alter these associations. Conclusions Living in a relationship with a partner might imply cognitive and social challenges that have a protective effect against cognitive impairment later in life, consistent with the brain reserve hypothesis. The specific increased risk for widowed and divorced people compared with single people indicates that other factors are needed to explain parts of the results. A sociogenetic disease model might explain the dramatic increase in risk of Alzheimer's disease for widowed apolipoprotein E e4 carriers.
44.	Håkansson, Krister, 1952-, et al. (författare) BDNF Responses in Healthy Older Persons to 35 Minutes of Physical Exercise, Cognitive Training, and Mindfulness : Associations with Working Memory Function 2017 Ingår i: Journal of Alzheimer's Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 55:2, s. 645-657 Tidskriftsartikel (refereegranskat)abstract Brain-derived neurotrophic factor (BDNF) has a central role in brain plasticity by mediating changes in cortical thickness and synaptic density in response to physical activity and environmental enrichment. Previous studies suggest that physical exercise can augment BDNF levels, both in serum and the brain, but no other study has examined how different types of activities compare with physical exercise in their ability to affect BDNF levels. By using a balanced cross over experimental design, we exposed nineteen healthy older adults to 35-minute sessions of physical exercise, cognitive training, and mindfulness practice, and compared the resulting changes in mature BDNF levels between the three activities. We show that a single bout of physical exercise has significantly larger impact on serum BDNF levels than either cognitive training or mindfulness practice in the same persons. This is the first study on immediate BDNF effects of physical activity in older healthy humans and also the first study to demonstrate an association between serum BDNF responsivity to acute physical exercise and working memory function. We conclude that the BDNF increase we found after physical exercise more probably has a peripheral than a central origin, but that the association between post-intervention BDNF levels and cognitive function could have implications for BDNF responsivity in serum as a potential marker of cognitive health.
45.	Håkansson, Krister, 1952-, et al. (författare) Feelings of Hopelessness in Midlife and Cognitive Health in Later Life : A Prospective Population-Based Cohort Study. 2015 Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:10, s. 1-16 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: Several studies have found depression and depressive feelings to be associated with subsequent dementia. As dementias typically have a long preclinical development phase, it has been difficult to determine whether depression and depressive feelings reflect a concurrent underlying dementia disease, rather than playing a causative role. Our aim was to investigate hopelessness, one dimension of depressive feelings, and evaluate the likelihood of a prodromal versus a causative role of hopelessness feelings in dementia development.METHODS: We invited a random sample of 2000 survivors from a representative population in Eastern Finland, originally investigated in midlife between 1972 and 1987, for re-examination an average of 21 years later. The age of the 1449 persons who accepted the invitation was between 39 and 64 years (mean 50.4 years) in midlife and between 65 and 80 (mean 71.3) at follow-up. To measure feelings of hopelessness in midlife and at follow-up, the participants indicated their level of agreement to two statements about their own possible future. We used logistic regression to investigate the association between the combined scores from these two items and cognitive health at follow-up, while adjusting for several health and life-style variables from midlife and for apolipoprotein E4 (ApoE4) status, depression and hopelessness feelings at follow-up. We compared the associations with late-life cognitive health when feelings of hopelessness were either measured in midlife or at the follow-up. In addition we analyzed the changes in hopelessness scores from midlife to follow-up in participants who were either cognitively healthy or impaired at follow-up.RESULTS: We found higher levels of hopelessness in midlife, but not at follow-up, to be associated with cognitive impairment at follow-up; the adjusted odds ratio for each step of the five-level hopelessness scale was 1.30 (95% confidence interval 1.11-1.51) for any cognitive impairment and 1.37 (1.05-1.78) for Alzheimer's disease. These associations remained significant also after the final adjustments for depressive feelings and for hopelessness at follow-up. The individual changes in hopelessness scores between midlife and follow-up were not systematically related to cognitive health at the follow-up.CONCLUSION: Our results suggest that feelings of hopelessness already in midlife may have long-term implications for cognitive health and increase the risk of Alzheimer's disease in later life.
46.	Håkansson, Krister, 1952-, et al. (författare) Feelings of hopelessness in midlife are associated with dementia risk in later life 2012 Ingår i: 12th International Stockholm/Springfield Symposium on Advances in Alzheimer Therapy. ; , s. 165-165 Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract Background: Although an association between depressive feelings and dementia has been estab- lished previously, the nature of this relation remains unclear. Establishing causality has been com- plicated by the typical use of a short follow-up and aged participants already at baseline. The aim with this study was to investigate the association between feelings of hopelessness in midlife and cognitive impairment in later life.Methods: From a representative population in Eastern Finland, originally investigated between 1972-1987, a random sample of 2000 survivors was invited for re-examination in 1998, averagely 21 years later. The mean age of the 1449 persons who accepted the invitation was 50.4 (range 39-64) at baseline and 71.3 years (range 65-80) at follow-up. Baseline scores of hopelessness were related to cognitive status at follow-up, mainly through logistic regression. Adjustments were made for age, years of education, gender, APOE4 and a number of health and life style factors at baseline. In addition we analyzed differences in hopelessness scores between baseline and follow-up within the different outcome groups.Results: Participants with high levels of hopelessness at midlife had more than a doubled risk of cognitive impairment in later life as expressed by an odds ratio of 2.24 (1.4-3.6), even higher spe- cifically for Alzheimers disease. Persons with high levels of hopelessness at midlife and who in addition carried the apolipoprotein allele 4 (ApoE ε4) had a highly elevated risk of Alzheimers dis- ease. There were no significant differences in levels of hopelessness between baseline and follow-up within any of the outcome groups.Conclusions: The results confirm previous studies showing elevated scores of depressive feelings in persons diagnosed with dementia, compared to cognitively healthy persons. On the other hand, the results also suggest that the major portion of this difference could have existed already decades before the dementia diagnosis; Carrying feelings of hopelessness in midlife may have long-term implications for cognitive health in later life. Background: Although an association between depressive feelings and dementia has been estab- lished previously, the nature of this relation remains unclear. Establishing causality has been com- plicated by the typical use of a short follow-up and aged participants already at baseline. The aim with this study was to investigate the association between feelings of hopelessness in midlife and cognitive impairment in later life.Methods: From a representative population in Eastern Finland, originally investigated between 1972-1987, a random sample of 2000 survivors was invited for re-examination in 1998, averagely 21 years later. The mean age of the 1449 persons who accepted the invitation was 50.4 (range 39-64) at baseline and 71.3 years (range 65-80) at follow-up. Baseline scores of hopelessness were related to cognitive status at follow-up, mainly through logistic regression. Adjustments were made for age, years of education, gender, APOE4 and a number of health and life style factors at baseline. In addition we analyzed differences in hopelessness scores between baseline and follow-up within the different outcome groups.Results: Participants with high levels of hopelessness at midlife had more than a doubled risk of cognitive impairment in later life as expressed by an odds ratio of 2.24 (1.4-3.6), even higher spe- cifically for Alzheimers disease. Persons with high levels of hopelessness at midlife and who in addition carried the apolipoprotein allele 4 (ApoE ε4) had a highly elevated risk of Alzheimers dis- ease. There were no significant differences in levels of hopelessness between baseline and follow-up within any of the outcome groups.Conclusions: The results confirm previous studies showing elevated scores of depressive feelings in persons diagnosed with dementia, compared to cognitively healthy persons. On the other hand, the results also suggest that the major portion of this difference could have existed already decades before the dementia diagnosis; Carrying feelings of hopelessness in midlife may have long-term implications for cognitive health in later life.
47.	Håkansson, Krister, 1952-, et al. (författare) Perceived marital problems in midlife are associated with cognitive health in later life 2010 Ingår i: Alzheimer's & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 7:4, Supplement, s. 595-595 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
48.	Håkansson, Krister, et al. (författare) Robot-assisted detection of subclinical dementia : progress report and preliminary findings 2020 Ingår i: In <em>2020 Alzheimer's Association International Conference</em>. ALZ.. Konferensbidrag (refereegranskat)
49.	Håkansson, Krister, 1952-, et al. (författare) The Patient with Cognitive Impairment 2018 Ingår i: Treatable and Potentially Preventable Dementias. - New York : Cambridge University Press. - 9781107157460 ; , s. 52-80 Bokkapitel (refereegranskat)
50.	Håkansson, Krister, 1952- (författare) The role of socio-emotional factors for cognitive health in later life 2016 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract With increasing life expectancies in most parts of the world, the prevalence of dementia and other age-related chronic diseases is growing. Several factors affect future projections and are discussed in this thesis, including possible limits to a continued growth of life expectancy. A related question is to what extent healthy ageing per se affects cognitive functions in old persons. Previous studies have generally exaggerated ageing effects on cognition, by applying study designs that did not account for common confounders, such as birth cohort differences, and the effects of terminal decline and subclinical dementia. In contrast to healthy ageing, dementia neuropathologies dramatically reduce cognitive performance, and proposed mechanisms behind dementia are briefly discussed with focus on Alzheimer’s disease (AD), on the role of genetic factors and on life course exposures. Three studies (study 1-3) investigated how cohabitant status and feelings of loneliness and hopelessness in midlife were associated with cognitive health in later life. Neurotrophic factors could potentially be involved in the biological mechanisms behind these and other associations between life-style factors and cognitive health. The fourth study aimed to explore how levels of brain-derived neurotrophic factor (BDNF), measured in serum, were affected by performing different activities; physical exercise, cognitive training, and mindfulness.THE FOUR STUDIESStudy 1-3 were epidemiological association studies based on the Cardiovascular Risk Factor, Ageing and Dementia (CAIDE) Study, a population based cohort study on 1511 persons in eastern Finland, who at baseline were 50.4 years. Two re-examinations have been performed in the CAIDE Study, in 1998 when the participants were between 65 and 80 years, and between 2005-2008, averagely 25.3 years after the baseline examinations. The first two studies were based on the 1409 persons who fully participated in the first re-examination and the third study on the 1511 persons who participated in one or both re-examinations. In the first two studies logistic regression was the main statistical method with any cognitive impairment versus no cognitive impairment as outcome. In addition we performed analyses with mild cognitive impairment and Alzheimer’s disease as separate outcomes. In Study 1 and 2 we also analysed how apolipoprotein epsilon 4 (ApoE4) status affected the associations with Alzheimer’s disease. The statistical method in Study 3 was survival model analysis (Kaplan-Meyer and Cox regression) and the outcome variable was dementia, without subtyping. We compared the results from the analysis on the 1511 participants with the results when we used the total sample (by including register linked data on dementia diagnoses). We adjusted the associations for several potential confounding variables in all three studies.In Study 4 we used 19 elderly healthy volunteers who were between 65 and 80 years (mean = 70.8 years). They performed three different activities during 35 minutes on separate occasions, i.e. a within-subject cross-over experimental design where we randomized the order of the three conditions between the participants. We sampled blood from a suitablelower arm vein directly before and after each activity session and in addition at 20 and 60 minutes after the session had ended. After the serum had been analysed for BDNF levels, we used repeated measures ANOVA to calculate the differences in the effect of BDNF levels between the three conditions.MAIN RESULTSWe found that living alone in midlife was associated with approximately a doubled risk of cognitive impairment during the re-examination. Among the non-cohabitants the risk increase was especially high for persons who were widowed in midlife and who had continued to live alone until the re-examination (odds ratio (OR) 7.67, 95% confidence interval (CI) 1.6 – 40.0). Feelings of loneliness were common both among cohabitants and non-cohabitants, but we found that such feelings were only associated with an increased dementia risk if these persons had also been living alone. Feelings of hopelessness in midlife, but not at follow-up, were associated with increased risk of cognitive impairment at the re-examination, especially of Alzheimer’s disease (OR 2.90, CI 1.4 – 5.9). When we adjusted the association from midlife also for depression and hopelessness at the re-examination, this association was still statistically significant. Participants with a diagnosis of cognitive impairment had higher feelings of hopelessness at the re-examination, compared to the cognitively healthy group, but this difference between the groups existed already when they were in midlife. When we stratified the participants with reference to ApoE4 status, we found that participants who were also ApoE4 carriers had a dramatically increased risk of Alzheimer’s disease compared to non-carriers without feelings of hopelessness, even after final adjustment for depression (OR 6.48, CI 2.4 –17.5). A similar stratification for ApoE4 status in Study 1 showed an even more dramatic increase in the association for persons who had lost their partner (widowed or divorced/separated) if they in addition were ApoE4 carriers.In Study 4 we found that physical exercise, but not cognitive training or mindfulness, led to a statistically significant increase in BDNF levels of around 25%, compared to baseline. We also found that the individual differences in BDNF levels after the physical exercise correlated with working memory performance, measured on a separate occasion.CONCLUSIONSSocial and emotional factors can have long-term consequences for cognitive health in later life. The long follow-up time in Study 1-3 suggests that the associations we found with dementia could reflect a causal, rather than a prodromal, relation. As other studies have found a range of adverse ill health consequences from both living alone and from depressive feelings, a possible mechanism behind the associations we found could be related to a systemic biological impact, and that the specific ill health outcome could be a result of individual vulnerability where genetic dispositions could play an important role. This conclusion seems consistent with the dramatic risk increases we found for AD when ApoE4status was combined with the social factor of living alone and with the emotional dimension of hopelessness. At the micro level, as synaptic dysfunction and loss is characteristic of Alzheimer’s disease, and as BDNF has a central role for synaptogenesis, impaired BDNF functionality could play a role in the development of Alzheimer’s disease. More research is needed to further explore the role of BDNF in Alzheimer’s disease and if the disease can be prevented, or the disease process halted, by activities that stimulate BDNF expression in the brain.

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