Background & Aims

Chronic musculoskeletal pain (CMP), a prevalent and heterogeneous condition characterized by persistent pain in the muscles, joints, or other body parts, is a leading cause of disability worldwide and significantly affects a patient’s brain. Apart from experiencing pain, older adults with CMP also have an accelerated cognitive decline and higher dementia risk with limited understanding. A multiscale study to disentangle pathological brain aging from normal brain aging may reveal the underlying mechanisms.
In this study, our objective is to investigate which type of CMP demonstrates accelerated brain aging and determine whether this acceleration correlates with future cognitive decline and dementia risk. Additionally, we aim to explore whether this acceleration has a genetic basis.

Methods

We trained and validated a brain age model using a training set and a hold-out set consisting of healthy individuals from UKB, respectively. Then, we applied the brain age model to six CMP cohorts from UKB (Dataset 1) to estimate their distinct patterns of brain aging. Following the identification of the CMP cohort that showed brain aging acceleration, we validated the findings based on the same type of CMP cohort (i.e., knee osteoarthritis [KOA] cohort in this study) and healthy control (HC) from a locally collected dataset (Dataset 2). Furthermore, we investigated the associations of brain aging acceleration with the global cognitive function, memory function, and pain characteristics in the KOA patients. We also investigated the associations of their brain aging acceleration at baseline with cognitive and memory decline, as well as dementia risk during a 5-year follow-up. Finally, we examined the molecular genetic basis of brain aging acceleration.

Results

Our study unveiled an accelerated brain aging pattern in knee osteoarthritis (KOA) cohorts, signified by a significantly increased PAD in comparison to healthy controls (HC). This PAD increase in KOA was subsequently validated in an independent dataset (N = 192), suggesting a replicable accelerated brain aging pattern in KOA. This acceleration predicted memory decline and dementia incidents in a 5-year follow-up. The gene SLC39A8 showed pleiotropy between brain aging accelerations and KOA and exhibited spatially transcriptional associations with the regional contributions to brain aging accelerations in KOA. Imaging-transcriptomic analyses demonstrated that the genes exhibiting spatially strong transcriptional associations with the regional contributions to brain aging accelerations in KOA were highly expressed in microglial cells and astrocytes, and mainly enriched in synaptic structure and neurodevelopment.

Conclusions

In conclusion, we identified specific accelerated brain aging in individuals with KOA contrasting several common types of CMP across two independent datasets. This acceleration was primarily driven by the brain structures for cognitive processing and related to longitudinal memory decline and dementia risk. Furthermore, we demonstrated that SLC39A8 – a gene highly expressed in glial cells – might be a key genetic underpinning of this acceleration. Gene markers of Mic and Ast and those involved in synaptic structure and neurodevelopment were particularly strong transcriptional associates of the regional contributions to this acceleration. Together, we demonstrated the heterogeneity of brain aging in CMP and identified a distinct heritable accelerated brain aging pattern linking KOA to dementia by providing an integrative biological profile that connects specific genes, molecular processes, and cell classes with morphological alterations.

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Presenting Author

Lei Zhao

Poster Authors

Lei Zhao

PhD candidate

Institute of Psychology, Chinese Academy of Sciences

Lead Author

E-mail

Topics

  • Genetics