4213
Functional Connectivity Mediates the Impact of Iron Content on Cognition in Women with Suspected Coronary Microvascular Dysfunction
Arzu C Has Silemek1,2, Jeffrey Wertheimer3, Janet Wei 4, Oana Dumitrascu5, Sarah Kremen1, Yibin Xie2, Debiao Li2, Michael D Nelson6, Zaldy S Tan7, Noel Bairey Merz4, Pascal Sati1,2, and Wei Gao2
1Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, United States, 2Department of Biomedical Sciences and Imaging, Biomedical Imaging Research Institute (BIRI), Cedars-Sinai Medical Center, Los Angeles, CA, United States, 3Department of Physical Medicine and Rehabilitation, Cedars-Sinai Medical Center, Los Angeles, CA, United States, 4Barbra Streisand Women's Heart Center, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States, 5Department of Neurology, Mayo Clinic College of Medicine and Science, Scottsdale, AZ, United States, 6Department of Kinesiology, The University of Texas at Arlington, Arlington, TX, United States, 7Departments of Neurology and Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, United States
1Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, United States, 2Department of Biomedical Sciences and Imaging, Biomedical Imaging Research Institute (BIRI), Cedars-Sinai Medical Center, Los Angeles, CA, United States, 3Department of Physical Medicine and Rehabilitation, Cedars-Sinai Medical Center, Los Angeles, CA, United States, 4Barbra Streisand Women's Heart Center, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States, 5Department of Neurology, Mayo Clinic College of Medicine and Science, Scottsdale, AZ, United States, 6Department of Kinesiology, The University of Texas at Arlington, Arlington, TX, United States, 7Departments of Neurology and Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, United States
Synopsis
Keywords: Aging, Heart, Brain, Iron, Cognition, fMRI, women with INOCA, high resolution QSM Aging, Dementia
Motivation: Women with ischemia and non-obstructive coronary arteries (INOCA) may experience cognitive decline due to non-heme iron accumulation causing oxidative stress and cell death, but underlying mechanism is still unknown.
Goal(s): This study aims to understand how iron affects brain function and cognitive performance in women with suspected INOCA.
Approach: By combining high-resolution Quantitative Susceptibility Mapping and resting-state fMRI, the research focused on thalamic iron and its association with brain connectivity and cognitive metrics.
Results: Results indicated that thalamic iron impacts cognitive outcomes, particularly executive functions and processing speed, in women with suspected INOCA, with these effects partly mediated by changes in functional connectivity.
Impact: This study's insights into iron's cognitive effects may guide early interventions, influence therapeutic strategies for INOCA patients, and prompt further research into the systemic impact of iron on brain connectivity and cognitive health.
Background and Aim
Women with suspected ischemia without obstructive coronary arteries (INOCA) can face cognitive decline due to cerebral small vessel disease1. A probable cause is the accumulation of non-heme iron, leading to changes in brain function2-5 from oxidative stress and cell death6. However, its underlying mechanism is still unknown. Therefore, combining high resolution quantitative susceptibility mapping (QSM) approach with resting-state fMRI (rs-fMRI) has the potential of elucidating the role of iron deposition on the brain’s functional organization and its effect on cognition during normal and pathological aging.In this study, we hypothesize significant associations among thalamus iron content, thalamic/whole brain functional connectivity pattern, and cognitive performances, based on which formal mediation analysis7 would reveal significant effect of functional connectivity variables between the other two. We specifically focus on the thalamus given its central role in relaying peripheral signals to different parts of the cortices and its close involvement in cognition8, 9. To test our hypothesis, we quantified the iron content within the thalamus, computed whole brain graph theoretical functional connectivity, and assessed cognition in women with suspected INOCA10.
Material and Methods
Twenty-seven women with suspected INOCA [Age; mean (sd) = 53.3 (9.8)] from the Women’s Ischemia Syndrome Evaluation (NCT03876223) study underwent brain 3T-MRI (Siemens, Vida). Structural imaging included submillimeter sagittal T2* 3-dimensional echo-planar-imaging (T2*-3D-EPI)11, 12, FLAIR and T1-MPRAGE sequences (parameters in Table-1). Rs-fMRI was collected instructing subjects to keep eyes open (Table-1).Cognitive functions were assessed using National Institutes of Health Toolbox – Cognition Battery (NIHTB-CB)13.
QSM was quantified using submillimeter T2*-3D-EPI via TGV-based method14. Thalamus parcellation was automated from T1-MPRAGE aligned with T2*-3D-EPI using ANTs15 and Freesurfer16. QSM images were normalized subtracting cerebrospinal fluid to estimate iron deposition in the thalamus.
For the functional connectivity, preprocessing involved skull stripping, segmentation, motion and slice timing correction, bandpass filtering, spatial smoothing, and rs-fMRI image registration to MNI using ANTs15, FSL17 and AFNI18. Then, global signal regression was applied. Functional connectivity was then assessed within the correlations of 78-regions in the AAL-atlas (p<0.01).
Functional integrity was determined through a graph theoretical method19, deriving measures like nodal degree, local efficiency, and betweenness centrality across 78-regions via RStudio's igraph package.
The relationship between QSM values and rs-fMRI was determined through linear regression analysis in RStudio, adjusting for age and comorbid.
Mediation analysis was conducted using Python Statsmodels.
Results
The cognitive outcomes yielded negative median z-scores in processing speed, executive function and working memory in women with suspected INOCA (Figure-1).The effect of increased thalamus iron content was seen in functional connectivity determined by different graph theoretical metrics: a lower nodal degree in left orbitofrontal gyrus (p = 0.027, r² = 0.19, default-mode-network) and right precuneus (p=0.03, r²=0.38, default-mode-network) (Figure-2A), a lower local efficiency in the left thalamus (p=0.041, r²=0.19) (Figure-2B), and a higher nodal degree in bilateral calcarine (right/left: p=0.003/0.011, r²=0.27/0.22, visual-network) and right cuneus (p=0.006, r²=0.28, visual-network), right rectus (p=0.033, r²=0.22, limbic-network) and left superior orbitofrontal gyrus (p=0.013, r²=0.21, limbic-network) (Figure-2A) as well as a higher betweenness centrality in right calcarine (p=0.005, r²=0.28, visual-network) (Figure-2C).
Then, we found a direct effect of elevated thalamic iron deposition on the lower cognitive performance in the processing speed domain (p=0.036, coefficient=-985.11) (Figure-3C) in women with suspected INOCA. This effect was mediated by the functional connectivity in the right calcarine (indirect effect: p=0.03, coefficient=638.63) (Figure-3C). Functional connectivity carried indirect effect of the iron deposition on the domains of language and executive function via its association in local degree in left calcarine (indirect effect: p=0.036, coefficient=-1196.79) (Figure-3A), and local efficiency in thalamus (indirect effect: p=0.044, coefficient=227.81) (Figure-3B).
Discussion
Consistent with our hypotheses and other studies20, findings in this study showed that thalamic iron levels are associated with cognitive performances, particularly executive function, and processing speed domains, functions known to have high sensitivity and relations to compromised neural networks21. Moreover, thalamic iron levels are also significantly correlated with functional connectivity within and outside the thalamus, especially in occipital and frontal/parietal areas that are crucial for cognition. Formal mediation analysis further showed significant mediating role of the brain’s functional connectivity between iron deposition and cognitive performances. If validated, these findings open a new window in the search of the complex brain mechanisms underlying normal and abnormal aging.Conclusions
In this study, we demonstrated the effect of the iron deposition in the thalamus on the cognitive outcomes in women with suspected INOCA, and this impact is partially mediated by alterations in functional connectivity within specific brain regions.Future research with a larger cohort is necessary to validate and expand upon these findings.
Acknowledgements
The women’s ischemia syndrome evaluation (WISE) Pre- Heart Failure With Preserved Ejection Fraction (Pre-HFpEF) (NCT03876223) study funded undergrant number R01-HL-146148-01.References
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Figures
Table 1. Sequences parameters involved in the MRI protocol in 3T.
Figure 1. Figure indicates the effect of the cognitive data presented by Z-scores in women with suspected ischemia but no obstructive coronary artery disease. Z-scores were calculated as: (Performance – Mean / Standard deviation). Diamonds represent the outliers. Abbreviations: Age Std. = age corrected standard score.
Figure 2. The scatter plots illustrate the association between iron deposition in thalamus and functional connectivity determined by local degree (A), local efficiency (B) and betweenness centrality (C) in women with suspected ischemia but no obstructive coronary artery disease. Color code of boxes indicates each network. DMN = Default mode Network.
Figure 3. Figure indicates the effect of iron deposition in thalamus on cognitive decline mediated by functional connectivity (FC) determined via local degree (A), efficiency (B) and betweenness (C). Blue arrow indicates the effect of the iron deposition on FC. Green arrow shows the effect of FC on the cognitive function. Red arrow shows the direct effect of the iron deposition on the cognitive function controlling for functional connectivity. Yellow box involves the mediation results (ACME = the average causal mediation effect).
DOI: https://doi.org/10.58530/2024/4213