Sleep complaints are common in older adults, and it is estimated that around 40% to 70% of older adults have chronic sleep issues. However, long-term sleep problems could hamper cognitive functions, especially memory, and increase the risk of neurocognitive disorders (e.g., Alzheimer's disease) in older adults. Understanding the neurophysiological mechanism underpinning sleep-related memory declines in older adults is crucial for developing effective treatments and promoting healthy aging. Our recent study published in Molecular Psychiatry sheds light on the interplay between sleep quality, the glymphatic system, and human brain networks and its influence on memory functions.

The Glymphatic System: A Waste Clearance Pathway of the Human Brain

The glymphatic (glial-lymphatic) system is a newly discovered fluid transport pathway that plays an important role in clearing waste from the brain. It involves the flow of cerebrospinal fluid (CSF) transferring along the perivascular space into the brain interstitium (Iliff et al., 2012). It plays a vital role in determining brain health, particularly in aging populations. Yet, sleep quality is a key influencing factor for glymphatic functioning. By investigating this system, we aimed to reveal how sleep quality affects brain health through glymphatic functioning.

Human Brain Network

The human brain is a complex network of interconnected brain regions (Bullmore & Sporns, 2009). The connection within the brain network can be either functional connectivity (FC; i.e., temporal correlation between regional time series) or structural connectivity (SC; i.e., white matter connection between brain regions). Previous studies suggested that the FC, SC, and their relationship (SC-FC coupling) are sensitive biomarkers of memory functions and pathology of a broad range of neuropsychological diseases (Pievani et al., 2014). Therefore, taking the brain network as an indicator of brain health, we suspect that a change in glymphatic functioning may affect memory functions through the underlying brain networks.

The Study’s Approach

In this study, we analyzed multimodal MRI data [i.e., resting-state functional magnetic resonance imaging (R-fMRI) and diffusion MRI] and sleep measurements [i.e., Pittsburgh Sleep Quality Index (PSQI) and polysomnographic (PSG) recordings] from a group of community-dwelling older adults. We employed the Diffusion Tensor Image Analysis along the Perivascular Space (DTI-ALPS) (Taoka et al., 2017) as a proxy for the functioning of the glymphatic system. Then we examined the association between DTI-ALPS and multimodal brain networks and tested whether DTI-ALPS can mediate the relationship between sleep and brain networks. Last but not least, we tested whether the sleep-related brain-glymphatic relationship could underlie individual memory function.

Key Findings

·         Glymphatic Functioning and Sleep Quality: Our study found a negative association between DTI-ALPS and subjective (i.e., PSQI) and objective sleep quality measures [i.e., apnea-hypopnea index (AHI)]. Higher PSQI and AHI indicate worse sleep quality, suggesting poor sleep quality is associated with poor glymphatic functioning.

·         Neural Correlates of Glymphatic Functioning: The DTI-ALPS correlated with both SC and FC, involving a broad range of brain regions, such as parahippocampal gyrus, precuneus, and orbital frontal gyrus. Moreover, we found a negative correlation between DTI-ALPS and SC-FC coupling of rich-club connections, which are the backbone of the human brain network.

·         Mediation Effect of Glymphatic Functioning: The DTI-ALPS significantly mediated the association between sleep quality (PSQI or AHI) and rich-club SC-FC coupling, where a poorer sleep quality was associated with poorer glymphatic functioning, and in turn, led to less flexible brain communication (i.e., higher rich-club SC-FC coupling).

·         Moderated Mediation Model of Memory Function: The rich-club SC-FC coupling further mediated the association between DTI-ALPS and the memory score of the Everyday Cognition Questionnaire (ECog). However, this relationship was moderated by sleep quality, where the mediating effect was only observed in good sleepers (PSQI ≤ 5) but not in poor sleepers.

Implications and Conclusions

By using the DTI-ALPS, our study was able to non-invasively evaluate glymphatic functioning and examine its relationship with sleep and the human brain network. Although emerging evidence has reported the relationship between glymphatic functioning and brain health, to our knowledge, there still lacks evidence on communication within the human brain. From the perspective of network neuroscience, our findings provide novel insights that the glymphatic system is protective of neural interaction in the human brain, which can also be the missing link between glymphatic functioning and the pathologies of neurodegenerative diseases (e.g., Alzheimer's disease). With regard to the effect of sleep quality, our finding reveals that poor sleep quality in older adults may gradually impair normal brain function (i.e., SC-FC coupling) by deactivating the restorative glymphatic system. The disrupted brain-glymphatic relationship failed to support memory function in poor sleepers. With the imperative role of the glymphatic system in protecting against cognitive decline, future studies should develop efficient treatments in promoting glymphatic functioning, such as voluntary exercise (He et al., 2017) and polyunsaturated fatty acid supplements (Liu et al., 2020). Overall, our study adds to existing evidence that sleep quality is crucial for promoting cognitive health through the underpinned neural relationships and the interplay between the glymphatic system and multimodal brain networks.

Please refer to the paper for a comprehensive overview of the findings:

Ma, J., Chen, M., Liu, G. H., Gao, M., Chen, N. H., Toh, C. H., ... , Fang, J. T.*, Lee, S. H.* & Lee, T. M. C.* (2024). Effects of sleep on the glymphatic functioning and multimodal human brain network affecting memory in older adults. Mol Psychiatry. https://doi.org/10.1038/s41380-024-02778-0

Reference

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Bullmore E, Sporns O. Complex brain networks: graph theoretical analysis of structural and functional systems. Nat Rev Neurosci 2009; 10(3): 186-198.

Pievani M, Filippini N, van den Heuvel MP, Cappa SF, Frisoni GB. Brain connectivity in neurodegenerative diseases--from phenotype to proteinopathy. Nat Rev Neurol 2014; 10(11): 620-633.

Taoka T, Masutani Y, Kawai H, Nakane T, Matsuoka K, Yasuno F et al. Evaluation of glymphatic system activity with the diffusion MR technique: diffusion tensor image analysis along the perivascular space (DTI-ALPS) in Alzheimer's disease cases. Jpn J Radiol 2017; 35(4): 172-178.

He XF, Liu DX, Zhang Q, Liang FY, Dai GY, Zeng JS et al. Voluntary Exercise Promotes Glymphatic Clearance of Amyloid Beta and Reduces the Activation of Astrocytes and Microglia in Aged Mice. Front Mol Neurosci 2017; 10: 144.

Liu X, Hao J, Yao E, Cao J, Zheng X, Yao D et al. Polyunsaturated fatty acid supplement alleviates depression-incident cognitive dysfunction by protecting the cerebrovascular and glymphatic systems. Brain Behav Immun 2020; 89: 357-370.