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The role of socio-emotional factors for cognitive health in later life
Karolinska Institutet.ORCID iD: 0000-0002-0057-0308
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

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 STUDIES

Study 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 suitable

lower 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 RESULTS

We 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.

CONCLUSIONS

Social 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 ApoE4

status 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.

Place, publisher, year, edition, pages
Stockholm: Karolinska Institutet , 2016. , p. 78
National Category
Public Health, Global Health, Social Medicine and Epidemiology
Research subject
Health and Caring Sciences
Identifiers
URN: urn:nbn:se:lnu:diva-59566ISBN: 978-91-7676-449-7 (print)OAI: oai:DiVA.org:lnu-59566DiVA, id: diva2:1061486
Public defence
2016-10-28, Petren, Karolinska Institutet, Nobels väg 12B, Karolinska Institutet, Solna, Solna, 14:15 (English)
Opponent
Supervisors
Available from: 2017-01-10 Created: 2017-01-02 Last updated: 2017-01-10Bibliographically approved
List of papers
1. BDNF Responses in Healthy Older Persons to 35 Minutes of Physical Exercise, Cognitive Training, and Mindfulness: Associations with Working Memory Function
Open this publication in new window or tab >>BDNF Responses in Healthy Older Persons to 35 Minutes of Physical Exercise, Cognitive Training, and Mindfulness: Associations with Working Memory Function
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2017 (English)In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 55, no 2, p. 645-657Article in journal (Refereed) Published
Abstract [en]

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.

National Category
Psychology Neurosciences
Research subject
Social Sciences, Psychology
Identifiers
urn:nbn:se:lnu:diva-59565 (URN)10.3233/JAD-160593 (DOI)000389695700018 ()27716670 (PubMedID)
Projects
SAGE
Funder
The Kamprad Family Foundation
Available from: 2017-01-02 Created: 2017-01-02 Last updated: 2018-01-13Bibliographically approved
2. Association between mid-life marital status and cognitive function in later life: population based cohort study
Open this publication in new window or tab >>Association between mid-life marital status and cognitive function in later life: population based cohort study
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2009 (English)In: BMJ. British Medical Journal, E-ISSN 1756-1833, Vol. 339, no July, p. Article number: b2462-Article in journal (Refereed) Published
Abstract [en]

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.

Keyword
Dementia, Alzheimer's disease, mild cognitive impairment, marital status
National Category
Neurology Public Health, Global Health, Social Medicine and Epidemiology Psychology (excluding Applied Psychology)
Research subject
Social Sciences, Psychology
Identifiers
urn:nbn:se:vxu:diva-5563 (URN)10.1136/bmj.b2462 (DOI)000267678700006 ()
Available from: 2009-11-09 Created: 2009-07-03 Last updated: 2017-12-13Bibliographically approved
3. Feelings of Hopelessness in Midlife and Cognitive Health in Later Life: A Prospective Population-Based Cohort Study.
Open this publication in new window or tab >>Feelings of Hopelessness in Midlife and Cognitive Health in Later Life: A Prospective Population-Based Cohort Study.
2015 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 10, p. 1-16, article id e0140261Article in journal (Refereed) Published
Abstract [en]

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.

National Category
Gerontology, specialising in Medical and Health Sciences
Research subject
Social Sciences, Psychology
Identifiers
urn:nbn:se:lnu:diva-51884 (URN)10.1371/journal.pone.0140261 (DOI)26460971 (PubMedID)
Note

Correction published in:Håkansson K, Soininen H, Winblad B, Kivipelto M (2015) Correction: Feelings of Hopelessness in Midlife and Cognitive Health in Later Life: A Prospective Population-Based Cohort Study. PLoS ONE 10(11): e0142465. doi:10.1371/journal.pone.0142465

Available from: 2016-04-01 Created: 2016-04-01 Last updated: 2018-01-10Bibliographically approved

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