Table 1.

Clinical and experimental evidence on the association between uric acid, cerebrovascular damage, and cognitive function.

Clinical Data—Cerebrovascular Outcomes
First Author (Year)	Study Design	Population	Results
Seminog, O. (2013) [36]	Prospective data from UK registries	202,033 patients	The relative risk for all strokes was 1.71 (1.68, 1.75), ischemic stroke 1.68 (1.64, 1.73), hemorrhagic stroke 1.69 (1.61, 1.77), and stroke of an unspecified type 2.00 (1.95, 2.06).
Keenan, T. (2016) [41]	Mendelian randomization	82,091patients	Results were in contrast with previous prospective studies. Serum urate levels, increased by 1 standard deviation due to the genetic score, were not associated with type 2 diabetes mellitus, chronic heart disease, ischemic stroke, or heart failure.
Singh, J.A. (2017) [38]	Retrospective registry cohort study	1,338,501 patients	Compared with diabetes mellitus (DM) only, gout was associated with a similar risk of stroke (HR 1.02, 95% CI 0.95–1.10). Compared with patients with DM only, patients with both gout and DM had higher HRs for incident stroke (HR 1.42, 95% CI 1.29–1.56).
Yen, F.S. (2020) [39]	Retrospective database propensitive score matching cohort study	5218 patients	Incidence rates of hospitalized stroke were 0.6 and 1.0 per 100 person-years for urate-lowering therapy (ULT) users and nonusers, respectively, after adjusting for age, sex, residence, comorbidities, and medications. ULT users showed lower adjusted hazard ratios for hospitalized stroke (aHR: 0.52, p < 0.001). The effect of uricosuric agents on the decrease in hospitalized stroke risk indicated a dose–response relationship.
Kang, H.S. (2023) [40]	Retrospective database propensitive score matching cohort study	44,960 patients	In patients with gout, the incidences of stroke were slightly higher than those in controls (9.84 vs. 8.41 per 1000 person-years). After adjustment, the gout group had an 11% (95% confidence interval [CI] = 1.04–1.19) higher likelihood of experiencing stroke than the control group.
Clinical Data—Cognitive Outcomes
Schretlen, D.J. (2007) [55]	Cross-sectional data	96 patients	The multivariate-adjusted odds of poor verbal memory aOR 5.02 (1.24 to 20.30) and working memory aOR 4.25 (1.44 to 12.57) were higher in patients with mildly elevated (but normal) serum UA.
Ruggiero, C. 2009 [56]	Cross-sectional study	1016 patients	Demented persons had higher (uric acid) UA levels (p = 0.001), and the prevalence of persons affected by dementia increased across UA tertiles (p < 0.0001). Persons belonging to the highest UA tertile had a threefold (OR = 3.32; 95% CI: 1.06–10.42) higher probability of suffering from dementia syndrome.
Cicero, A.F.G. (2015) [18]	Cross-sectional data	288 patients	The only factors associated with the mini-mental state examination score were age (B = −0.058, 95% CI −0.108, −0.009, p = 0.022), LDL-C (B = −0.639, 95% CI −0.912, −0.411, p = 0.034) and SUA (B = −0.527, 95% CI −0.709, −0.344, p = 0.022).
MacIsaac, R.L. (2016) [101]	Prospective case–control study	4064 patients	Allopurinol use was associated with a significantly lower risk of stroke aHR 0.50, 0.32–0.80. In exposed patients, high-dose (≥300 mg) was associated with a significantly lower risk of stroke aHR 0.58, 0.36–0.94.
Engel, B. 2018 [86]	Cross-sectional study	137,640 patients	Patients with a hyperuricemia diagnosis had a slightly reduced risk for dementia (aOR 0.94, 0.89–0.98). The risk reduction was more pronounced for patients treated with anti-hyperuricemic drugs (aOR 0.89, 0.85–0.94, for regular treatment).
Sing, J.A. (2018) [89]	Database cohort study	1,710,000 patients	Gout was independently associated with a significantly higher hazard ratio of incident dementia, with an HR of 1.15 (95% CI, 1.12, 1.18); sensitivity analyses confirmed the main findings. Compared to age 65 to < 75 years, age 75 to <85 and ≥85 years were associated with 3.5 and 7.8-fold higher hazards of dementia.
Chuang, T.J. 2020 [87]	Retrospective case–control study	3242 patients	Benzbromarone decreased the risk of dementia (aOR, 0.81, 0.68–0.97), and its use for ≥180 days showed a significantly lower risk of dementia (aOR, 0.72, 0.58–0.89).
Min, K.H. (2021) [88]	Database cohort study	125,768 patients	Gout was independently associated with a significantly lower hazard ratio of incident dementia, aHR 0.63, 0.60–0.66. Moreover, febuxostat use significantly decreased incident dementia.
Pan, S.Y. (2021) [78]	Meta-analysis	2,155,959 patients	Gout and hyperuricemia did not increase the risk of dementia, with a pooled HR of 0.94 (95% CI 0.69 to 1.28), but might decrease the risk of Alzheimer’s disease (AD), with a pooled HR of 0.78 (95% CI 0.64 to 0.95).
Topiwala, A. (2023) [43]	Prospective data (UK Biobank)	303,149 patients	Gout is associated with a higher incidence of dementia (average over study HR = 1.60 [1.38–1.85]). The risk was time-varying, highest in the first 3 years after gout diagnosis (HR = 7.40 [4.95–11.07]) and then decreasing. Risks were higher for vascular dementia (average HR = 2.41 [1.93–3.02]) compared to all-cause dementia but not for Alzheimer’s disease (average HR = 1.62 [1.30–2.02]). Amongst asymptomatic individuals, in the linear model, there was an inverse association between urate and dementia incidence (HR = 0.85, 95% CI: 0.80–0.89).
Yao, Y. (2024) [77]	Meta-analysis	2,928,152 patients	Hyperuricemia (or gout) did not reduce the overall risk of dementia (OR/HR = 0.92, 95% CI: 0.81–1.05) and vascular dementia (OR/HR = 0.74, 95% CI: 0.53–1.05), but may have a protective effect against Alzheimer’s disease (OR/HR = 0.82, 95% CI: 0.70–0.96).
In Vivo Study
First Author (Year)	Study Design	Population	Results
Bowman, G.L. (2010) [31]	Prospective study	32 patients	Cerebrospinal fluid (CSF) and plasma uric acid (UA) were positively correlated (r = 0.669, p = 0.001), and blood–brain barrier impairment was associated with higher CSF levels of UA (p = 0.028). Neither plasma nor CSF UA reached a significant association with rates of cognitive decline over 1 year.
Kaddurah-Daouk, R. (2013) [100]	Cross-sectional data	124 patients	At metabolic analyses, Alzheimer’s Disease (AD) subjects had elevated methionine (MET), 5-hydroxyindoleacetic acid (5-HIAA), vanillylmandelic acid, xanthosine, and glutathione versus controls. Mild cognitive impairment (MCI) subjects had elevated 5-HIAA, MET, hypoxanthine, and other metabolites versus controls. Metabolite ratios revealed changes within tryptophan, MET, and purine pathways. Initial pathway analyses identified steps in several pathways that appear altered in AD and MCI. A partial correlation network showed total tau most directly related to norepinephrine and purine pathways; amyloid-β (Ab42) was related directly to an unidentified metabolite and indirectly to 5-HIAA and MET.
Topiwala, A. (2023) [43]	Cross-sectional data (UK Biobank)	33,367 patients	From magnetic resonance imaging analyses, there were highly significant differences in regional grey matter volumes, particularly of mid- and hindbrain structures, such as cerebellum (beta = −9.91 × 10−4, T = −9.26, p = 2.25 × 10−20), pons (beta = −5.63 × 10−4, T = −6.23, p = 4.95 × 10−10) and midbrain (beta = −4.00 × 10−4, T = −5.15, p = 2.67 × 10−07) in gout and high urate. In addition, they had higher iron deposition (lower T2* and higher magnetic susceptibility) of several basal ganglia structures, including bilateral putamen (beta = 9.50 × 10−4, T = 9.25, p = 2.38 × 10−20) and caudate (7.62 × 10−4, T = 7.12, p = 1.13 × 10−12). Data were confirmed by genetic analyses for single-nucleotide polymorphisms associated with both elevated uric acid and gout.
Deng, F. (2024) [15]	Cross-sectional data	346 patients	The uric acid to HDL-C ratio (UHR) was found to be independently associated with plaque rupture, erosion, and thrombus. Furthermore, ROC analysis suggested that the UHR had a better predictive value than low-density lipoprotein cholesterol.
In vitro and Experimental Studies
First Author (Year)	Experimental Study Design		Results
Santos, M.J. (2005) [69]	Primary Rat Hippocampal Neuron Cultures		Pretreatment with Wy-14.463, a peroxisome proliferator, prevents neuronal cell death and neuritic network loss induced by the Aβ peptide by increasing both the number of peroxisomes and the catalase activity.
Tomioka, N.H. (2013) [70]	Mouse Ependymal Cells		Urate transporter 1 (URAT1) was distributed throughout the ventricular walls of the lateral ventricle, dorsal third ventricle, ventral third ventricle, aqueduct, and fourth ventricle, but not in the non-ciliated tanycytes in the lower part of the ventral third ventricle. Antibody specificity was confirmed by the lack of immunostaining in brain tissue from URAT1 knockout mice.
Desideri, G. (2017) [68]	Human neuroblastoma Cells		The incubation of the cells model (SHSY5Y neuroblastoma cells incubated with amyloid β to reproduce an in vitro model of Alzheimer’s disease) with uric acid significantly reduced cell viability and potentiated the proapoptotic effect of amyloid β.
Burrage, E.N. (2023) [90]	Mouse		Blocking xanthine oxidase using febuxostat prevented the unpredictable chronic mild stress (UCMS)-induced impaired middle cerebral artery response, while free radical production and hydrogen peroxide levels were like controls in the liver and brain of UCMS mice treated with febuxostat. Further, UCMS + Feb mice did not have a significant reduction in working memory.
Zhang, C. (2023) [102]	Mouse		The authors found 15 long noncoding RNAs (lncRNAs) related to maintaining the blood–brain barrier (BBB). This study demonstrated that febuxostat protected the brain after intracerebral hemorrhage (ICH). Fifteen lncRNAs were regulated and were associated with the effects of febuxostat on BBB integrity after ICH.