Association of Gout with Brain Reserve and Vulnerability to Neurodegenerative Disease

Abstract

Objective To assess the associations between gout, brain structure, and neurodegenerative disease incidence. Methods Using observational and Mendelian randomization analyses we investigated causal relationships between gout and brain health. Exposures included gout diagnosis (from self-report, linked health records and death records) and genetically proxied gout and serum urate. Outcomes were neuroimaging markers of brain structure and neurodegenerative disease incidence (ascertained through self-report, health records and death reports). Cox proportional hazards models were used to examine time to neurodegenerative disease diagnosis. Results 11,735 UK Biobank participants (mean age 55.5 (s.d. 8.0) years and 50.5% female) had a diagnosis of gout (n=1165 in MRI subset). Dementia was ascertained in 3126 individuals over a mean follow-up time of 12.4 (s.d. 1.9) years. Gout patients had smaller global and regional brain volumes and higher brain iron markers. Genetic associations mirrored observational associations. Genetically proxied gout associated with lower global grey matter volume (beta= -0.05[-0.08 to -0.01]). Participants with gout had higher incidence of all-cause dementia (hazard ratio (HR)=1.60, 95% confidence interval (CI) [1.38-1.85]),Parkinsons disease (HR=1.43[1.15 to 1.79]), and probable essential tremor (HR=6.75[5.69 to 8.00]). Risks were strongly time dependent, whereby associations with incident dementia were highest in the first 3 years after gout diagnosis (HR=7.40[4.95 to 11.07]). Conclusions These findings suggest gout is causally related to several measures of brain structure. Lower brain reserve amongst gout patients may explain their higher vulnerability to multiple neurodegenerative diseases.

Bidirectional Mendelian randomization explores the causal relationship between arthritis and cerebral cortical volume

“…Black CN et al found that the severity and duration of symptoms of major depression or anxiety disorders were negatively correlated with uric acid levels [31] .Additionally, it has been reported that gout affects the volume of speci c brain regions as well. In a Mendelian randomization study of gout and brain volume, researchers found that genetically predicted gout was signi cantly associated with gray matter volume in the whole brain, and genetically predicted hyperuricemia was also signi cantly correlated with gray matter volume in several regions, including the cerebellum, midbrain, pons, and brainstem [32] . Compared with this previous study, our study provides a more detailed delineation of brain regions, further revealing the correlation between gout and the more subtle brain regions of the Left Frontal Operculum Cortex and Left Precentral Gyrus.Furthermore,Yang et al, in an imaging study using MRI technology to detect cortical volume in gout patients, found that the cortical thickness in the left upper frontal lobe region of gout patients was thinner than that of the healthy control group [33] .…”

Revealing brain cell-stratified causality through dissecting causal variants according to their cell-type-specific effects on gene expression

“…Though direct association between astrocyte and CAD has not been fully elucidated, the underlying mechanisms could be explained by the predominant function of astrocyte in controlling blood glucose and blood pressure 35 , of which the increase are regarded as major risk factors to develop CAD. As for gout, evidence from recent observational studies suggest the association between gout and brain structure 37 , however, the mechanism underlying how brain or which brain cell type affects gout is still unclear.…”

Iron metabolism and arthritis: Exploring connections and therapeutic avenues

“…[92] Patients with gout have smaller global and regional brain volumes and higher brain iron levels. [93] Elevated serum uric acid, which is involved in iron metabolism, has been increasingly recognized as a risk factor for gout. [94] Iron supplementation exacerbates joint inflammation in mice with acute GA. [95] Targeting iron metabolism to treat GA is also a promising approach.…”