Impact of social isolation on grey matter structure and cognitive functions: A population-based longitudinal neuroimaging study

Article activity feed

1. 

   Version published to 10.7554/elife.83660 on eLife

   Jun 20, 2023
2. 

   eLife

   Apr 1, 2023

   Author Response

   Reviewer #1 (Public Review):

   Lammer et al. examined the effects of social loneliness, and longitudinal change in social loneliness, on cognitive and brain aging. In a large sample longitudinal dataset, the authors found that both baseline loneliness and an increase in loneliness at follow-up were significantly associated with smaller hippocampal volume, reduced cortical thickness, and worse cognition in healthy older adults. In addition, those older adults with high loneliness at baseline showed even smaller hippocampal volume at follow-up. These results are interesting in identifying the importance of social support to cognitive and brain health in old age. With a longitudinal design, they were able to show that increased loneliness was related to reduced brain structural measures. Such results could help guide …

   Author Response

   Reviewer #1 (Public Review):

   Lammer et al. examined the effects of social loneliness, and longitudinal change in social loneliness, on cognitive and brain aging. In a large sample longitudinal dataset, the authors found that both baseline loneliness and an increase in loneliness at follow-up were significantly associated with smaller hippocampal volume, reduced cortical thickness, and worse cognition in healthy older adults. In addition, those older adults with high loneliness at baseline showed even smaller hippocampal volume at follow-up. These results are interesting in identifying the importance of social support to cognitive and brain health in old age. With a longitudinal design, they were able to show that increased loneliness was related to reduced brain structural measures. Such results could help guide clinicians and policymakers in designing social support systems that would benefit the growing aging population.

   The strength of the current study lies in the large sample size and longitudinal follow-up design. The multilevel models used to separate within and between subject effects are well constructed. Combining neuroimaging data with behavioral changes provided further evidence that social loneliness may be related to accelerated brain aging. Stringent FDR correction, Bayes factor comparison, and the additional analyses for sensitivity showed the robustness and credibility of the results.

   Thank you for a thorough and overall positive evaluation of our manuscript and the constructive feedback. We considered all of your comments valuable, please see point-by-point responses below for more details.

   Weaknesses of the study were related to the interpretation and discussion of their findings.

   1a) Social loneliness is a relatively little-studied factor in cognitive ageing, and the authors should consider expanding the discussion, with some additional analyses, as to how their results could be used by clinicians and older adults to monitor social behaviors.

   We agree with the reviewer and are thankful for these suggestions. We have run additional analyses following the clinical cut-off of the questionnaire on social isolation and added those and their interpretations to the results and discussion section. Please see below response to questions 2a) and 3a) as well as to those in section b) to this reviewer how we implemented the reviewer’s advice in detail.

   2a) The authors examined the interaction between baseline and age change to see if higher baseline loneliness was associated with accelerated decline. The interaction was significant, but the authors did not further explore the interaction effect, which may have clinical significance. The authors should consider identifying a cut-off point in LSNS that suggests persons scoring less than this score on the LSNS may be at greater risk of accelerated brain decline than others. Such a cut-off point is important for clinicians, as well as for future researchers to compare their results.

   2a) Thanks to your recommendation, we decided to explore differences between handling LSNS as a categorical (using the standard threshold of 12) and continuous variable and recalculated all LMEs on HCV and cognitive functions with LSNS coded dichotomously. We found the results to be similarly good in detecting adverse effects of social isolation (see new Tables S16-18). The interaction of categorical LSNS with change in age on HCV tends towards showing an effect but does not reach significance even before FDR-correction.

   As cut-off points are central to clinical work, we are convinced that this expansion improved our study greatly, contributed to its benefit to our readers and we are thus very grateful for this valuable question.

   Our analyses indicate that the cut-off can be employed in clinical settings to detect social isolation that might harm patients’ brain health.

   However, this does not answer another important question, namely which public health strategy is most suitable to target social isolation for preventive purposes. Should it focus on the most isolated individuals (i.e. those categorised as socially isolated) or pursue a population strategy (Rose et al., 2008)? This actually is the topic of ongoing research in our group and we hope to answer it in future work. For now, we ran additional models testing an interaction effect of dichotomous LSNS with continuous LSNS. Finding evidence for such an interaction effect would suggest that having less social contact has stronger negative effects for those that are categorised as socially isolated. Roughly speaking, is it worse to have one instead of two reliable friends than it is to have four instead of five? If this were the case, this would point public health towards a high-risk rather than population strategy. We did not find any evidence for such an interaction effect and thus can not say that we have found that more social contact ceases to be beneficial beyond the threshold score of 12. In addition to the new results, we have expanded on this in the discussion section where it now reads: „We showed that the established LSNS cut-off can be employed by clinicians to identify subjects likely to suffer adverse effects due to social isolation. However, the absence of evidence for more pronounced negative effects of less social contact amongst those that are deemed socially isolated by the cut-off renders a public health strategy focused on high-risk individuals questionable.”

   3a) Although it was not directly tested in the paper, LSNS scores did not seem to change with increasing age (Table 1). This general stability of LSNS scores in older adults should be discussed further. The authors should consider how their relatively healthy and high SES sample may be less vulnerable to loss of family or friends in old age, making this sample sub-optimal for the question they have. The significance of the subject effect suggests that some individuals still experience a loss of social connectedness. The authors may want to elaborate on this and give some explanations of such subject differences in the ageing effect on social loneliness. Although stress was not a significant mediating factor, is it related to baseline loneliness or changes in loneliness in the current sample?

   Concerning the link between change in age and LSNS we indeed found a statistically significant effect of age change on higher social isolation in an ancillary LME. However, as the reviewer noticed, the per year effect is very small, meaning that it would need getting more than 20 years older to score one point higher on the LSNS sum score (see new Table S2, see also answer below to questions 4a and 3b). We therefore tend to agree that in our sample, higher age does not affect social isolation substantially.

   Furthermore, we very much appreciated your recommendation to further discuss how our relatively high SES-sample might be less vulnerable to loss of social contact during the aging process. As a foundation for this discussion, we investigated the link between SES and LSNS using an LME and found the association to be highly significant (see new Table S2). Furthermore, we added a table showing which percentage of our participants fell into the SES quintiles that would be observed in a fully representative German sample to help our readers to interpret our findings (see new Table S3). Following your advice, we have added a comment highlighting how the relatively high SES of our sample might have contributed to this in the limitations section: “As we found higher SES to be associated with lower LSNS scores, this relatively high SES sample might have led to underestimation of the detrimental effects of social isolation and increases in social isolation in the aging process.”

   Regarding the importance of chronic stress to social isolation, we did not only find no mediating effect of stress, we also did not find a significant simple association between TICS and LSNS scores (see new Table S2). We are hesitant to attribute this finding to the incorrectness of the stress-buffering hypothesis as the missingness in stress data makes all interpretations of analyses involving TICS scores problematic. We have expanded on this in the discussion section and added emphasis to the importance of also pursuing other mechanistic theories in our discussion, where it reads: “we could not find evidence that social isolation affected hippocampal volume through higher chronic stress measured with questionnaires, a hypothesis put forward by the stress buffering theory (Kawachi & Berkman, 2001). These latter analyses suffered from small sample sizes and a limited number of timepoints. Nonetheless, the lack of any significant link between chronic stress and social isolation (see Table S2) is hard to align with the stress-buffering hypothesis in spite of the missingness in the TICS.”.

   4a) The presentation of longitudinal data (Figure 1) lacks dimensionality. The scatter plots presented here are more suitable for cross-sectional studies and could cause confusion regarding the interpretation of the results. The authors should consider individual growth curves or spaghetti plots in visualizing change within subjects.

   We are grateful for your advice to visualise individual developments in social isolation and outcome measures over time in spaghetti plots and have done so to give our readers insight into these developments (see new Fig. S1). As you had assumed, there is no unequivocal pattern of increasing social isolation over time (see also answer to 3a). In addition, we decided to stick with presenting results of the statistical modeling of linear mixed effect using scatterplots in Figure 1, as this is regarded the most appropriate visualization of the tested effectors. Please see also response to 5b.

   Reviewer #2 (Public Review):

   The paper by Laurenz Lammer and colleagues used cohort data to investigate the cross-sectional and longitudinal association between loneliness and brain structure and cognitive function. The main finding was that baseline social isolation and change in social isolation were associated with smaller hippocampus volumes, reduced cortical thickness, and poorer cognitive function. Given that more and more people feel lonely nowadays (e.g., due to the pandemic), the study by Lammer and colleagues addresses a highly relevant health concern of our time.

   Significant strengths of the study:

   • large cohort;

   • the cross-sectional and longitudinal analyses confirmed the findings;

   • the study was preregistered;

   • the study included men and women;

   • analyses were sound and controlled for essential confounders.

   Thank you for your time to thoroughly review the manuscript and for the encouraging comments. Please see below how we implemented your advice.

   The major weaknesses of the study:

   1a) it is unclear whether loneliness causally contributes to brain structure and cognitive function;

   Indeed, based on structural equation analyses of the available data from this cohort, we could not find strong evidence for neither causality (social isolation causes brain/cognitive decline) nor reverse causality (brain/cognitive decline causes social isolation). This could be due to a lack of power to detect such effects due to the drop in sample size for these analyses. Overall, regarding these two competing hypotheses, we see some minor indication of support for causality of social isolation in our data due to the presence of robust and significant associations in our very healthy sample, the absence of clear increases in effect size when including cognitively less healthy participants and the absence of clear decreases in effect sizes when only including participants with high MMST scores. Accordingly, we added this concluding synopsis to our paragraph on causality in our discussion: “Still, overall these results only add a modicum of corroboration to the case for a causal role of social isolation.” and pointed towards the key role of RCTs in understanding causality in this regard: ”Intervention studies will be the gold standard to provide evidence with regards to the causal role and effect size of social isolation.”

   2a) the factors that may cause loneliness are unclear.

   Thank you very much for encouraging us to shed some light on participant characteristics of potential relevance to social isolation. Starting from the impulse to look into marital status and employment, we also investigated links to socioeconomic status, migration background, age at baseline, change in age, gender, living alone and the number of persons living in the participants dwelling. We found all of these factors except for gender and migration background to be significantly linked to social isolation. Results are presented in Table S2 and briefly referred to in the results section: “In our sample, social isolation was positively correlated with not living alone, being married, the number of persons living in the participants’ dwelling, being gainfully employed, younger baseline age and less change in age and being married but no to gender or having a migration background. See Tables S1-2 for descriptive statistics and details of the associations. To contextualise the observed link to SES, a comparison of SES category frequencies in LIFE-Adult and a fully representative sample (Lampert et al., 2013) is provided in Table S3.” And added to the discussion: “Existing and future research on reasons for and the role of social isolation in health and disease should provide guidance for the urgently needed development and evaluation of tailored strategies against social isolation and its detrimental effects.”

   Read the original source
3. 

   eLife

   Mar 31, 2023

   eLife assessment

   This study provides an important demonstration that loneliness is associated with smaller hippocampal volume, reduced cortical thickness, and worse cognition in healthy older adults. This has theoretical or practical implications beyond a single subfield. The strength of evidence is solid given the cross-sectional and longitudinal design with a few weaknesses. With the analytical and interpretational part strengthened, this paper would be of interest to gerontologists, and dementia/cognitive aging researchers.

   Read the original source
4. 

   eLife

   Mar 31, 2023

   Reviewer #1 (Public Review):

   Lammer et al. examined the effects of social loneliness, and longitudinal change in social loneliness, on cognitive and brain aging. In a large sample longitudinal dataset, the authors found that both baseline loneliness and an increase in loneliness at follow-up were significantly associated with smaller hippocampal volume, reduced cortical thickness, and worse cognition in healthy older adults. In addition, those older adults with high loneliness at baseline showed even smaller hippocampal volume at follow-up. These results are interesting in identifying the importance of social support to cognitive and brain health in old age. With a longitudinal design, they were able to show that increased loneliness was related to reduced brain structural measures. Such results could help guide clinicians and …

   Reviewer #1 (Public Review):

   Lammer et al. examined the effects of social loneliness, and longitudinal change in social loneliness, on cognitive and brain aging. In a large sample longitudinal dataset, the authors found that both baseline loneliness and an increase in loneliness at follow-up were significantly associated with smaller hippocampal volume, reduced cortical thickness, and worse cognition in healthy older adults. In addition, those older adults with high loneliness at baseline showed even smaller hippocampal volume at follow-up. These results are interesting in identifying the importance of social support to cognitive and brain health in old age. With a longitudinal design, they were able to show that increased loneliness was related to reduced brain structural measures. Such results could help guide clinicians and policymakers in designing social support systems that would benefit the growing aging population.

   The strength of the current study lies in the large sample size and longitudinal follow-up design. The multilevel models used to separate within and between subject effects are well constructed. Combining neuroimaging data with behavioral changes provided further evidence that social loneliness may be related to accelerated brain aging. Stringent FDR correction, Bayes factor comparison, and the additional analyses for sensitivity showed the robustness and credibility of the results.

   Weaknesses of the study were related to the interpretation and discussion of their findings.

   Social loneliness is a relatively little-studied factor in cognitive ageing, and the authors should consider expanding the discussion, with some additional analyses, as to how their results could be used by clinicians and older adults to monitor social behaviors.

   The authors examined the interaction between baseline and age change to see if higher baseline loneliness was associated with accelerated decline. The interaction was significant, but the authors did not further explore the interaction effect, which may have clinical significance. The authors should consider identifying a cut-off point in LSNS that suggests persons scoring less than this score on the LSNS may be at greater risk of accelerated brain decline than others. Such a cut-off point is important for clinicians, as well as for future researchers to compare their results.

   Although it was not directly tested in the paper, LSNS scores did not seem to change with increasing age (Table 1). This general stability of LSNS scores in older adults should be discussed further. The authors should consider how their relatively healthy and high SES sample may be less vulnerable to loss of family or friends in old age, making this sample sub-optimal for the question they have. The significance of the subject effect suggests that some individuals still experience a loss of social connectedness. The authors may want to elaborate on this and give some explanations of such subject differences in the ageing effect on social loneliness. Although stress was not a significant mediating factor, is it related to baseline loneliness or changes in loneliness in the current sample?

   The presentation of longitudinal data (Figure 1) lacks dimensionality. The scatter plots presented here are more suitable for cross-sectional studies and could cause confusion regarding the interpretation of the results. The authors should consider individual growth curves or spaghetti plots in visualizing change within subjects.

   Read the original source
5. 

   eLife

   Mar 31, 2023

   Reviewer #2 (Public Review):

   The paper by Laurenz Lammer and colleagues used cohort data to investigate the cross-sectional and longitudinal association between loneliness and brain structure and cognitive function. The main finding was that baseline social isolation and change in social isolation were associated with smaller hippocampus volumes, reduced cortical thickness, and poorer cognitive function. Given that more and more people feel lonely nowadays (e.g., due to the pandemic), the study by Lammer and colleagues addresses a highly relevant health concern of our time.

   Significant strengths of the study:

   - large cohort;
   - the cross-sectional and longitudinal analyses confirmed the findings;
   - the study was preregistered;
   - the study included men and women;
   - analyses were sound and controlled for essential confounders.

   The major …

   Reviewer #2 (Public Review):

   The paper by Laurenz Lammer and colleagues used cohort data to investigate the cross-sectional and longitudinal association between loneliness and brain structure and cognitive function. The main finding was that baseline social isolation and change in social isolation were associated with smaller hippocampus volumes, reduced cortical thickness, and poorer cognitive function. Given that more and more people feel lonely nowadays (e.g., due to the pandemic), the study by Lammer and colleagues addresses a highly relevant health concern of our time.

   Significant strengths of the study:

   - large cohort;
   - the cross-sectional and longitudinal analyses confirmed the findings;
   - the study was preregistered;
   - the study included men and women;
   - analyses were sound and controlled for essential confounders.

   The major weaknesses of the study:

   - it is unclear whether loneliness causally contributes to brain structure and cognitive function;
   - the factors that may cause loneliness are unclear.

   Read the original source
6. 

   Version published to 10.1101/2021.12.14.21267787v2 on medRxiv

   Sep 23, 2022
7. 

   Version published to 10.1101/2021.12.14.21267787v1 on medRxiv

   Dec 16, 2021