Chronic musculoskeletal pain (CMP) impacts over 40% of the global population, posing significant health and socio-economic challenges. Beyond the persistent pain, accelerated cognitive decline and increased dementia risk are emerging as daunting hurdles for those affected. However, effective preventative measures are scarce, largely due to a limited understanding of the neural mechanisms involved.
In the aging process, every system in the body shows signs of decline, with accelerated brain aging being a critical factor in cognitive impairment and dementia. Research led by Yi-Teng Tu from the Institute of Psychology, Chinese Academy of Sciences (Zhao et al., PNAS, 2023) revealed that chronic pain patients exhibit accelerated aging in the hippocampus, which mediates cognitive function deterioration. However, the high heterogeneity and complex mechanisms of chronic pain mean that the patterns and mechanisms of brain aging in different types of chronic pain patients remain unclear.
Therefore, Yi-Teng Tu's research team utilized longitudinal and cross-sectional data from over 9,000 individuals to characterize brain aging features in various CMP groups (including pain in the shoulders, neck, lower back, hips, and knees) and decoded the underlying genetic and molecular mechanisms. These findings have been published online in Nature Mental Health, under the title "Morphological and genetic decoding show heterogeneous patterns of brain aging in chronic musculoskeletal pain."
Figure 1. Research Framework Diagram
Drawing on structural MRI data from over 6,000 healthy individuals in the UK Biobank database, this study has developed a model for predicting brain age, utilizing it to assess brain aging patterns in Chronic Musculoskeletal Pain (CMP). Among various types of CMP, only those individuals with Knee Osteoarthritis (KOA) showed signs of accelerated brain aging, a finding that was validated in an independent dataset. Further analysis indicated that brain regions responsible for cognitive functions, such as the hippocampus, are significant contributors to the accelerated brain aging observed. By conducting a 5-year follow-up with KOA patients, the study reveals the critical value of accelerated brain aging in predicting memory impairment and the risk of dementia in individuals with knee osteoarthritis.
Figure 2: CMP Brain Accelerated Aging Patterns and Brain Volume Changes Related to Accelerated Aging
To further elucidate the molecular and biological foundations behind the accelerated aging of the brain in KOA, this study combined spatial patterns of brain aging with the human brain transcriptome atlas. It was discovered that the expression characteristics of the SLC39A8 gene, along with glial cells and neurodevelopmental pathways, are key factors in the accelerated aging process of the KOA brain.
图3. 富集分析揭示与KOA神经影像表型高度相关的基因
研究结果多尺度揭示了KOA患者的大脑加速老化现象和机制，为人们理解CMP与大脑老化之间的关系提供了新的视角。这一发现不仅为未来在临床诊疗中更好地理解和预测CMP患者的认知衰退提供了理论基础，也强调了早期干预的重要性，以减缓CMP患者的大脑老化进程，保持其认知功能。
该研究得到了科技部科技创新2030“脑科学与类脑研究”青年科学家项目、国家自然科学基金、中国科学院心理研究所科学基金和中国科协青年人才托举工程项目的资助。
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