Cognitive decline and dementia in chronic widespread pain: A longitudinal population-based study

Background: Despite preliminary research suggesting an impact of chronic pain on cognition, the direct effects of chronic widespread pain (CWP) on cognition and its underlying mechanisms remain unclear. This study aims to investigate the effects of CWP on dementia and cognitive performance and explore its potential neurobiological mechanisms. Methods: This was a population-based cohort study utilizing data from the UK Biobank, which enrolled 500,000 individuals aged 37 to 73 years from 2006 to 2010, with brain imaging scans initiated in 2014. CWP was defined based on participants' self-reported pain all over the body lasting for ≥3 months. The incidence of dementia and mild cognitive impairment was identified through inpatient records. Cognitive performances were assessed using eight tests: fluid intelligence, numeric memory, trail making (A and B), symbol digit substitution, paired associate learning, matrix pattern completion, and pairs matching. Systemic inflammatory markers were extracted from baseline blood samples. Data analysis was conducted from April 2024 to August 2024. Results: We analyzed 13 years of follow-up data from 188,594 participants to assess the relationship between CWP and cognitive outcomes, while exploring the mediating effects of brain structure and systemic inflammation. Individuals with CWP have an elevated risk of mild cognitive impairment (HR [95%CI]: 2.55[1.31 - 4.97]) and dementia (1.53 [1.13 - 2.0]). No evidence of a causal association was found between CWP and dementia (β = 1.50, P Adjusted = 0.076). Additionally, brain structural volumes (thalamus, insular cortex, prefrontal cortex, amygdala, precentral gyrus, and postcentral gyrus) and systemic inflammatory markers (lymphocytes, platelets, neutrophils, and leukocytes) may mediate the relationship between CWP and cognitive performance, as imprecision in timing of mediator assessment should lead to cautious interpretation. Conclusions: CWP is significantly associated with an elevated risk of cognitive impairment and dementia, mediated by alterations in brain structure and systemic inflammation.