Association between the serum uric acid/serum creatinine ratio and cognitive function in older adults: NHANES in the United States – Nature.com

With rising international life expectancy, cognitive impairment has the potential to grow to be a significant well being problem for older adults. Nevertheless, with out preventive measures to delay cognitive impairment, the development of the situation will worsen, ultimately resulting in the event of Alzheimer’s illness (AD)¹. It has been reported that in the US alone, there have been roughly 6.2 million AD sufferers in 2021, and it’s projected to achieve 13.8 million by 2026². Because the development from cognitive impairment to AD is steady and irreversible, and there are at the moment no efficient therapies out there³, it’s essential to establish and mitigate modifiable components as early as potential.

Serum uric acid (SUA) is the tip product of purine and uric acid(UA) metabolism⁴, serving as each an indicator of renal perform and an efficient antioxidant within the human physique^5,6. SUA ranges rely upon the stability between dietary purine consumption, xanthine oxidase exercise, and renal excretion of UA⁷. Disruption of this stability can result in hyperuricemia or hypouricemia. Analysis has indicated that SUA might have a protecting impact on cognitive impairment⁸. Serum creatinine (SCR) is a byproduct of muscle metabolism and a typical biomarker used to evaluate renal perform⁹. Nevertheless, 90% of serum uric acid is filtered and reabsorbed by the kidneys^10,11. Due to this fact, it’s obligatory to contemplate the affect of renal perform when assessing the correlation between SUA and cognitive impairment. Latest research have proven that the serum uric acid/serum creatinine ratio (SUA/SCR) as a novel biomarker believed to higher replicate endogenous UA ranges¹². It has been reported that the SUA/SCR ratio is related to the development and prognosis of persistent kidney illness, metabolic syndrome, and respiratory system illnesses^13,14,15. Nevertheless, the connection between the SUA/SCR ratio and cognitive impairment has not been broadly explored.

Widespread strategies for assessing cognitive perform embrace psychological assessments, questionnaires, imaging examinations, and cerebrospinal fluid evaluation^16,17. In comparison with different testing strategies, serum biomarkers provide benefits when it comes to objectivity and accessibility, making them extra appropriate for the early identification of cognitive impairment. Equally, there’s a lack of focused early interventions for cognitive impairment. Due to this fact, based mostly on the present scenario, this examine goals to pick contributors aged 60 and above from the Nationwide Well being and Vitamin Examination Survey (NHANES) to analyze the potential affiliation between SUA/SCR and cognitive impairment.

Information sources and examine inhabitants

NHANES is a analysis program to evaluate the well being and dietary standing of adults and kids in America. This examine utilized knowledge from the 2001–2002 and 2011–2014 NHANES cycles for evaluation. Previous to knowledge assortment, all analysis procedures had been approved by the Ethics Assessment Board of the Nationwide Heart for Well being Statistics. Knowledgeable consent was obtained from all contributors, and the examine adopted the guiding ideas of the Declaration of Helsinki.

Within the 2001–2002 and 2011–2014 NHANES knowledge, a complete of 37,519 contributors had been included. Contributors below the age of 60, these missing knowledge on the Digit Image Substitution Take a look at (DSST), SUA/SCR, schooling stage, marital standing, smoking, alcohol consumption, blood strain, and ldl cholesterol had been excluded. Lastly, our examine included knowledge from 3874 contributors Fig. 1.

Examine variables

Cognitive impairment

The DSST is a take a look at that requires contributors to precisely encode a collection of symbols inside 120 s. This take a look at assesses the contributors’ response pace, consideration, spatial notion, associative studying, and reminiscence, making it a delicate indicator of cognitive perform¹⁸. As there is no such thing as a established DSST rating threshold to outline cognitive impairment, we outlined cognitive impairment (DSST < 33) utilizing the bottom unweighted quartile of DSST scores among the many examine contributors, in line with earlier analysis strategies¹⁹.

SUA/SCR

The SCR focus was measured utilizing the timed endpoint methodology with the DxC800. The DxC800 makes use of the Jaffe price methodology (kinetic alkaline picrate) within the modular chemistry part to find out the focus of SUA.

Covariates

The variables included age, gender, race, marital standing, BMI, schooling stage, hypertension, hyperglycemia, hypercholesterolemia, alcohol consumption, and smoking standing. Race was categorized as Mexican American, non-Hispanic White, non-Hispanic Black, different Hispanic, and different race. Marital standing was divided into married/cohabiting, widowed/divorced/separated, and by no means married. BMI was categorized as < 25 kg/m², 25–30 kg/m², and > 30 kg/m². Alcohol consumption was outlined as consuming at the very least 12 alcoholic drinks per 12 months, and smoking is outlined as smoking at the very least 100 cigarettes over a lifetime²⁰. Hypertension and hypercholesterolemia had been outlined as being knowledgeable by a healthcare skilled, whereas diabetes was outlined as being knowledgeable by a healthcare skilled or having a glycated hemoglobin (HbA1c) stage ≥ 6.5 mmol/L or fasting blood glucose ≥ 7.0 mmol/L.

Statistical evaluation

We chosen “wtmec2yr” because the weighting variable for the years 2001–2002 and 2011–2014. That is in line with earlier analysis strategies²¹. We carried out weighted t assessments or chi-square assessments to research the info of steady and categorical variables for the fundamental traits. Steady variables are offered because the imply ± customary error, whereas categorical variables are offered as 95% confidence intervals. To evaluate the affiliation between SUA/SCR and cognitive impairment, we employed weighted logistic regression evaluation. In Non-adjusted Mannequin, no adjustment for confounding components was made. In Partially adjusted mannequin, we included changes for age and race. In Full adjusted mannequin, we included age, gender, race, schooling, marital standing, smoking standing, alcohol consumption, BMI, hypertension, hypercholesterolemia, and diabetes for adjustment. Moreover, after adjusting for all covariates, we employed a generalized additive mannequin (GAM) and {smooth} curve becoming to look at non-linear correlations. Within the presence of non-linear correlations, a segmented regression mannequin was used to estimate threshold results. The recursive experimental method was utilized to establish the best-fitting mannequin with the utmost probability worth and decide the inflection level²². Lastly, we carried out subgroup evaluation utilizing a stratified multivariable logistic regression mannequin to evaluate the correlation between SUA/SCR and cognitive perform. The stratification variables included gender, age, BMI, smoking standing, alcohol consumption, hypertension, hypercholesterolemia, and diabetes. These stratification variables had been additionally thought-about potential impact modifiers. The interplay phrases had been evaluated utilizing probability ratio assessments to evaluate their heterogeneity. All knowledge had been analyzed utilizing R (model 4.2.0) and SPSS (model 27).

Institutional overview board assertion

The NHANES survey protocol was permitted by the CDC’s Nationwide Heart for Well being Statistics Institutional Analysis Ethics Assessment Board.

Baseline traits of the examine inhabitants

A complete of 3874 people participated on this examine, with 1900 males and 1974 females. The examine inhabitants was divided into two teams based mostly on the bottom quartile rating of DSST: people with DSST < 33 had been categorized as having cognitive impairment, whereas these with DSST ≥ 33 had been categorized as having noncognitive impairment. Noncognitive impairment was extra prevalent among the many Non-Hispanic White inhabitants, people with larger schooling ranges, and people with out hypertension. Then again, cognitive impairment was extra generally noticed amongst females, older people, and those that reported alcohol consumption (P < 0.05). Curiously, the SUA/SCR ratio was considerably decrease within the cognitive impairment group (P < 0.05). Desk 1

Affiliation between SUA/SCR and cognitive impairment

To additional examine the connection between SUA/SCR and cognitive perform, we employed a weighted logistic regression mannequin to research their affiliation. When adjusting for covariates, the fourth quartile of SUA/SCR confirmed a 43% discount in cognitive impairment danger in comparison with the primary quartile (OR 0.57; 95% CI 0.46, 0.71). After adjusting for some covariates, age, and race, we noticed the identical pattern. After adjusting for all covariates, Q1, Q2, Q3, and This fall had been 1.00, 0.65 (0.49, 0.86), 0.60 (0.40, 0.90), and 0.55 (0.39, 0.77), respectively. In comparison with the primary quartile, contributors within the fourth quartile had a forty five% diminished danger of cognitive impairment (OR 0.55; 95% CI 0.39, 0.77), P for pattern = 0.003. Desk 2

Utilizing a generalized additive mannequin, we explored whether or not there was a linear relationship between SUA/SCR and cognitive impairment

To validate the reliability and stability of the logistic regression evaluation outcomes, we carried out an evaluation utilizing a generalized additive mannequin whereas adjusting for all covariates. We noticed a nonlinear affiliation between SUA/SCR and cognitive impairment. Moreover, by way of threshold results, we recognized a turning level at 4.13. On the left facet of the turning level, the impact measurement was 0.611 (95% CI 0.487, 0.767), and on the fitting facet of the turning level, the impact measurement was 0.930 (95% CI 0.868, 0.997). A log probability ratio < 0.001. The above outcomes indicated {that a} nonlinear relationship between SUA/SCR and cognitive impairment Fig. 2 and Desk 3

The affiliation between SUA/SCR and cognitive impairment. The crimson line represents the smoothed curve match between the variables, whereas the blue line represents the fitted 95% confidence interval.

Full measurement picture

Subgroup evaluation outcomes of the affiliation between SUA/SCR and cognitive impairment

Additional subgroup evaluation revealed that SUA/SCR was considerably related to cognitive impairment (P < 0.05) within the subgroups stratified by age, smoking standing, consuming standing, hypertension, hypercholesterolemia, and diabetes. The correlation between SUA/SCR and cognitive impairment within the inhabitants with BMI < 25 and within the male inhabitants was not statistically important (P > 0.05). This lack of significance could also be attributed to the comparatively small proportion of people in these two classes. The interplay evaluation indicated no statistically important variations within the relationship between SUA/SCR and cognitive impairment amongst totally different subgroups, suggesting that gender, age, BMI, smoking standing, consuming standing, hypertension, hypercholesterolemia, and diabetes didn’t considerably have an effect on this adverse correlation (P > 0.05) Fig. 3.

Subgroup evaluation of the affiliation between SUA/SCR and cognitive impairment.

Full measurement picture

To the very best of our information, our examine is the primary investigation of the connection between SUA/SCR and cognitive impairment amongst older adults in NHANES dataset. On this cross-sectional examine, after adjusting for demographic, examination, and private knowledge of contributors from the NHANES database in 2001–2002 and 2011–2014, we discovered a major improve within the danger of cognitive impairment related to a lower within the SUA/SCR ratio. Moreover, by way of {smooth} curve becoming, we found a nonlinear relationship between SUA/SCR and cognitive impairment. The edge results evaluation revealed a turning level at 4.13, and when SUA/SCR was under or above 4.13, each had been impartial danger components for cognitive impairment. The subgroup evaluation outcomes indicated that, apart from the subgroup of BMI < 25 and males, the affiliation between SUA/SCR and cognitive impairment was statistically important within the remaining subgroups. The shortage of significance in these two subgroups could also be attributed to the comparatively small proportion of people. The outcomes of the interplay evaluation counsel that this affiliation is constant throughout totally different populations. Our analysis findings counsel that SUA/SCR displays a sure diploma of stability in sufferers with cognitive impairment. Sooner or later, SUA/SCR might function an efficient indicator for assessing cognitive impairment.

Cognitive impairment initially manifests as reminiscence loss, decreased government perform, language deficits, or impairments in visual-spatial talents^23,24. The particular mechanisms underlying cognitive impairment stay incompletely understood, and efficient therapies are at the moment missing^25,26. Moreover, the incidence of cognitive impairment enormously diminishes the standard of life for people affected, and with out efficient intervention, it poses an rising financial burden on nations, households, and people²⁷. Due to this fact, early detection and intervention to change contributing components are of paramount significance.

As the tip product of purine metabolism, UA maintains a gentle stability by way of the mixed results of endogenous manufacturing, exogenous provide, excretion, and reabsorption. Lately, many research have centered on the connection between uric acid and the event and prognosis of cognitive dysfunction. Nevertheless, whether or not UA is a protecting or danger issue for cognitive perform stays controversial. A meta-analysis in 2023 demonstrated no important affiliation between SUA ranges and the chance of cognitive impairment²⁸. In distinction, some research assist the protecting position of SUA in opposition to cognitive impairment. Barbara Iazzolino et al. discovered that top SUA considerably prevented cognitive impairment in amyotrophic lateral sclerosis²⁹. A retrospective examine emphasised the neuroprotective impact of excessive UA ranges (> 237 mmol/L), probably attributed to uric acid’s antioxidant properties³⁰. Zelin Yuan et al. cross-sectional examine on 6509 contributors revealed an affiliation between decrease SUA and poorer cognitive perform in females³¹. A potential examine discovered that low plasma UA ranges had potential dangerous results on cognition³². Since 90% of UA within the serum is filtered and reabsorbed by the kidneys, UA ranges within the blood are strongly influenced by renal perform. Research have proven that the impact of UA on cognitive impairment is determined by renal perform^10,11. Due to this fact, assessing the connection between SUA/SCR and cognitive impairment necessitates contemplating the affect of renal perform. Analysis has discovered that SUA/SCR serves as a high-quality biomarker reflecting endogenous UA ranges^33,34.

On this examine, we discovered that people with decrease SUA/SCR ratios had the next danger of cognitive impairment. In a latest potential examine involving 508 sufferers with Parkinson’s illness (PD), an investigation and evaluation of cognitive impairment in PD sufferers revealed {that a} lower within the UA to creatinine ratio was related to elevated accumulation of total-tau and phosphorylated-tau in cerebrospinal fluid. The examine concluded {that a} lower within the UA to creatinine ratio predicts the worsening of cognitive perform in PD sufferers over time³⁵. This discovering is in line with our analysis outcomes. In our examine, we noticed a nonlinear adverse correlation between SUA/SCR and the chance of cognitive impairment, the place decrease SUA/SCR ratios had been related to an elevated danger of upper cognitive impairment. Moreover, the brink results evaluation confirmed important statistical significance on either side of the turning level. Equally, in our interplay evaluation, we discovered that the connection between SUA/SCR and cognitive impairment was not considerably influenced by the covariates we included. This implies that SUA/SCR might have promising prospects in predicting cognitive impairment.

The precise mechanism by which the SUA/SCR ratio is concerned within the growth and prognosis of cognitive impairment stays unclear. Analysis has discovered that UA, an antioxidant, is produced throughout hypoxia^36,37. Nevertheless, oxidative stress in neurons is without doubt one of the major mechanisms influencing cognitive impairment³⁸. Preclinical research have proven that UA, as a pure antioxidant, can alleviate behavioral and cognitive impairments in MPTP-induced PD mice by activating the Nrf2-ARE pathway, thereby appearing as a neuroprotectant by regulating neuroinflammation and oxidative stress³⁹. Due to this fact, we speculate that the antioxidant motion of SUA could also be one of many protecting mechanisms defending in opposition to cognitive impairment, and decrease uric acid ranges might make sufferers extra prone to cognitive impairment when renal perform is analogous.

Our examine has a number of benefits in comparison with earlier articles. First, we had a big pattern measurement and utilized weighted knowledge evaluation. Second, the smoothed fitted curves constructed based mostly on a completely adjusted mannequin helped us establish potential linear relationships. Lastly, contemplating the potential affect of covariates on the outcomes, our subgroup evaluation might assist to confirm the steadiness of the outcomes. Nevertheless, our examine additionally has sure limitations. As an illustration, the NHANES database is a cross-sectional survey, so we will solely analyze the correlation between the SUA/SCR and cognitive impairment, and can’t examine the causal relationship amongst them. Due to this fact, potential research are wanted to confirm these causal relationships, which can be a spotlight of our future analysis. Moreover, regardless of our efforts to incorporate as many covariates as potential, we can’t fully remove the interference of different potential confounding components.

In conclusion, our examine findings counsel a adverse correlation between the SUA/SCR ratio and the chance of cognitive impairment amongst older adults aged 60 and above in the US. Additional potential research are wanted sooner or later to confirm the potential mechanisms underlying this relationship.

All contributors supplied written knowledgeable consent previous to enrollment.