Elsevier

Cortex

Volume 132, November 2020, Pages 29-40
Cortex

Research Report
The functional and structural connectomes of telomere length and their association with cognition in mild cognitive impairment

https://doi.org/10.1016/j.cortex.2020.08.006Get rights and content

Abstract

Previous findings on the relationship between telomere length and cognition have inconclusive, despite the relatively consistent telomere-shortening associated atrophy in the subcortical regions. Perhaps, there could be other more important telomere-associated factors in the brain, such as functional connectivity (FC) and structural connectivity (SC) that modulate cognition. The current study examined the relationship between telomere length, connectivity, and cognition. Telomere length measurements, neurocognitive scores, diffusion tensor and resting-state functional magnetic resonance imaging scans were collected from 82 older adults with mild cognitive impairment. SC and FC matrices were derived from these scans and, in various combinations, entered into connectome-based predictive models to predict telomere length. The telomere-associated features were then used to predict memory and executive functions. Leave-one-out cross-validation was performed. Predictive accuracy was assessed via the correlation between predicted and observed scores (rpredicted-observed). Correlation analyses were carried out between cognition and telomere length. Telomere length was significantly and negatively correlated with executive functions (EF), after controlling for demographical confounds. Telomere length was best predicted by negative SC and positive FC features (rpredicted-observed = .57; p < .001). The telomere-associated negative SC features significantly predicted EF scores (rpredicted-observed = −.26; p = .015). Telomere-shortening was associated with better EF and alterations in both FC and SC. This enhanced EF can be partly attributed to the telomere-associated changes in SC. Given that telomere is known to be a nonspecific marker of health, our findings illustrated a potential clinical use of telomere length to predict individualized health-related information from FC and SC features.

Introduction

Telomeres, the TTAGGG tandem repeat sequence, are nucleoprotein structures that protect the ends of eukaryotic chromosomes (Turner, Vasu, & Griffin, 2019; Zhang et al., 2016). Each end of the chromosome maintains genomic stability by providing protection from degradation and end-to-end chromosomal fusions (Giardini, Segatto, da Silva, Nunes, & Cano, 2014). Several protein complexes associated with telomeres, maintain equilibrium between telomere length and telomere homeostasis (Tomita, 2018). These six complex protein subunits forming telomere - binding protein are arranged in a T-loop structure, called as telosome or shelterin complex communicate with variety of cell signaling mechanisms to maintain telomere activity (Chen, Liu, & Songyang, 2007; Menendez et al., 2015; Xin, Liu, & Songyang, 2008). Moreover, during the process of biological aging, exposure to oxidative and inflammatory stress factors are highly elevated leading to telomere attrition which remained as a major determinant, for lowering replication machinery (Bekaert, De Meyer, & Van Oostveldt, 2005; Ilmonen, Kotrschal, & Penn, 2008; Zhang et al., 2016). In some instances, telomere shortening is caused by cellular senescence resulting in cell cycle arrest indicating Hayflick limit (Liu, Wang, Wang, & Liu, 2019; Shay & Wright, 2000). During each cell division, the telomere repeats are lost due to insufficient DNA polymerase activity at both the ends of the chromosomes. Telomerase, a reverse transcriptase (TERT), helps telomere to maintain its length, by adding 3' telomeric G-rich overhangs to protect the telomeric repeats (Giardini et al., 2014). The loss of repeats ends triggers in apoptosis and cellular senescence as a result of aging (Cleal, Norris, & Baird, 2018; Victorelli & Passos, 2017; Zhang et al., 2016). In this regard, telomere length is thought to be a biological age predictor of cellular aging and neurodegeneration (Fasching, 2018), wherein telomere shortening is associated with greater neurodegeneration and correspondingly, worse neurocognition.

Indeed, in terms of neurodegeneration, the empirical findings have been consistent with such predictions. Studies that looked at the relationship between telomere length and gray matter atrophy found shorter telomeres associated with gray matter atrophy, mostly in the subcortical/limbic regions (Grodstein et al., 2008; Jacobs, Epel, Lin, Blackburn, & Rasgon, 2014; King et al., 2014; Powell, Dima, Frangou, & Breen, 2018; Wikgren et al., 2013). However, in terms of neurocognition, the accumulated evidence is less consistent. While most studies showed that telomere shortening was associated with worse cognitive functioning (Devore, Prescott, De Vivo, & Grodstein, 2011; Hägg et al., 2017; Leibel et al., 2020; Ma et al., 2013, 2019; Martin-Ruiz et al., 2006; Valdes et al., 2010; Yaffe et al., 2011), other studies reported the reverse associations (Harris et al., 2006; Lee, Kim, & Lee, 2017; Liu et al., 2016; Mahoney et al., 2019; Wikgren et al., 2012). Several other studies also reported null associations between telomere length and cognition (Bendix et al., 2011; Brown, Zhang, Mitchell, & Ailshire, 2018; Harris et al., 2016; Insel, Merkle, Hsiao, Vidrine, & Montgomery, 2011; Mather et al., 2010; Zhan et al., 2018). The fact that shorter telomeres were not always associated with worse cognition, despite the likely subcortical atrophy, suggests there might be other unstudied telomere-associated factors in the brain that modulate cognition. Under certain circumstances, these factors might protect against cognitive impairment or even enhance cognitive function.

In this regard, we posit that brain connectivity, both structural and functional, to be one such factor. As a result of certain neurological insults, some connections between large scale networks would be affected. The brain would reorganize itself by exploiting alternative routes between networks to maintain connectivity across networks (Kelly & Castellanos, 2014). It is possible that telomere shortening may facilitate such reorganization in order to compensate for hubs that has degenerated in the brain, and so as to maintain normal cognitive functioning. Thus far, one study has showed that telomere length was positively associated with increased functional connectivity (FC) between the inferior occipital gyrus and ventral prefrontal cortex during an affect recognition task (Powell, De Jong, Breen, Lewis, & Dima, 2019), alluding to a telomere-associated reorganization of FC. Another study (Staffaroni et al., 2018) showed that telomere shortening was longitudinally associated with compromised white matter (WM) microstructural integrity in a bilateral fornix region-of-interest, hinting to the disrupted structural connections within the limbic region. Apart from these studies, the functional and structural connectomes associated with telomere length remain largely unexplored.

To this end, the goal of the current study is threefold. First, we examined the associations between telomere length and cognition—as broadly divided into executive functions (EF) and memory. Second, we identified patterns of FC and structural connectivity (SC) which are associated with telomere length; the current study is the first to examine whole-brain structural connectivity patterns associated with telomere length. Third, we examined if cognition is modulated by these patterns of connectivity. In relation to the latter two goals, we took advantage of the connectome-based predictive modelling (CPM) (Shen et al., 2017) approach to model the relationships between FC/SC, telomere and cognition. CPM involves building a generalizable model using brain connectivity data to predict scores in novel subjects and measures. When applied in the current context, it identified models of connectomes that were highly predictive of telomere length in novel subjects and assessed if such models could predict cognition as well.

Section snippets

Material and methods

The study procedure and analyses were not pre-registered before the research being conducted. We report how we determined our sample size, all data exclusions, all inclusion/exclusion criteria, whether inclusion/exclusion criteria were established prior to data analysis, all manipulations, and all measures in the study. As this is first study that attempted to correlate telomere length with, SC and resting state FC edges, we did not have an a priori effect size estimate to guide our sample size

Correlations between telomere length and cognition

Among the full sample of participants with valid telomere measurements (N = 109), telomere length was not significantly associated with memory (r = −.052; p = .594) or EF (r = −.182; p = .058). However, given that telomere and cognition are both likely to be confounded by age, sex and education levels, we carried out partial correlation analyses, controlling for these demographic variables. These partial correlation analyses revealed a significant association between telomere length and EF

Discussion

The current study set out to investigate the relationship between telomere length, cognition and brain connectivity. We observed a significant negative association between EF and telomere length after controlling for demographic variables. Our CPM analyses identified several FC and SC edges that contributed complementarily in the individualized prediction of telomere length. Finally, we showed that some of these SC changes can partially explain the association between EF and telomere length. We

CRediT author statement

Yu Junhong: Writing - Original Draft, Conceptualization, Methodology, Software, Formal analysis, Visualization Madhu Mathi Kanchi: Writing - Review & Editing, Investigation Iris Rawtaer: Writing - Review & Editing, Lei Feng: Writing - Review & Editing, Alan Prem Kumar: Writing - Review & Editing, Resources Kua-Ee Heok: Resources, Writing - Review & Editing, Project administration, Funding acquisition Rathi Mahendran: Resources, Writing - Review & Editing, Project administration, Funding

Data and code availability

The conditions of our ethics approval do not permit public archiving of the data supporting this study. Interested researchers seeking access to the anonymized data should contact the corresponding authors and complete a formal data sharing agreement. Access will be granted in accordance with ethical procedures governing the reuse of data.

The MATLAB code used for the analyses and the R code used for generating the figures are available at https://osf.io/zxfeq/

Declaration of competing interest

The authors declare that they have no conflict of interest.

Acknowledgements

This work was supported by Research Donations from Kwan Imm Thong Hood Cho Temple and Lee Kim Tah Holdings Pte Ltd, under the Mind Science Centre, Department of Psychological Medicine, National University of Singapore. Alan Prem Kumar is supported by a grant from the National Medical Research Council of Singapore. Alan Prem Kumar is also supported by the National Medical Research Council of Singapore and the Singapore Ministry of Education under its Research Centres of Excellence initiative to

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