The role of kidney function in the association between pro- inflammatory diet and cognitive impairment: NHANES from 2011 - 2014

doi:10.21203/rs.3.rs-3402224/v1

Aims: It has been well known that the higher inflammation levels are associated with the higher risk of cognitive impairment. Therefore, a high pro-inflammation diet may increase the risk of cognitive impairment by inducing the body’s inflammation process. At the same time, chronic kidney disease (CKD) is also a common risk factor of the cognitive impairment, in this article, we try to investigate if the kidney function or CKD plays a mediating role between pro-inflammation diet and cognitive impairment.

Methods and results: Data for this study were acquired from NHANES database, and 3124 participants were enrolled based on the dietary inflammation index (DII) and some essential cognitive tests such as the AF, CERAD-WL, CERAD-DR, and DSST. Subgroup analysis, trend analysis, and logistic regression were used to evaluate the correlation between DII and cognitive impairment. The study found that mean DII score was higher in those with cognitive impairment than those with normal cognition, the logistic regression revealed that high DII was associated with the cognitive impairment, and the proportion of individuals with cognitive impairment increased gradually as the DII level increased (p. trend < 0.001). Further mediation analysis was performed to investigate whether CKD mediates the association between cognitive impairment and pro-inflammatory diets, and revealed that the influence of DII on cognitive impairment was partially due to the indirection effect through kidney function, the indirection effect was -0.015(29.9% of the total effect value)

Conclusion: Pro-inflammatory diet (high DII) is associated with cognitive impairment, and this association is partially mediated by CKD.

pro-inflammation diet

cognitive impairment

dietary Inflammation Index

mediation analysis

kidney function

Cognitive impairment refers to a deficit in one or more cognitive domains, including memory, learning, attention, and decision-making. Cognitive impairment mainly includes mild cognitive impairment and dementia. Individuals with advanced dementia experience significant limitations in performing daily activities independently, as well as in their social and occupational function. In 2018, it was estimated that there were about 50 million people around the world suffered from dementia, and this number will exceed 110 million by 2050.^{[1, 2]} Cognitive impairment imposes a significant economic burden on both families and societies. In 2015, the global cost of dementia was estimated to be $818 billion, and this figure is projected to reach nearly $4 trillion by 2050.^[2] Currently, there are no early interventions for cognitive impairment. Cholinesterase inhibitors, which are the preferred treatment currently, offer only limited cognitive benefits in the short term. However, the clinical utility is still a controversial topic due to the potential risk of adverse events observed in clinical trials. ^{[3, 4]} In another way, researchers can be dedicated to identifying modifiable risk factors associated with cognitive impairment so that we can prevent or delay the cognitive impairment.

Some recent studies have shown that a pro-inflammatory dietary pattern increases the risk of cognitive impairment,^[5] and the mechanism is thought to be related to the induction of systemic inflammation.^[6–8]These reports suggested that dietary components and dietary patterns might have an effect on body’s inflammatory status. Dietary patterns that are abundant in anti-inflammatory properties, such as the Mediterranean diet, have been found to be associated with reduced levels of inflammation. However, diets that resemble the Western style and consist of refined grains, high-fat dairy products, and red meat have been found to be associated with elevated levels of fibrinogen, IL-6, and CRP.^[9] Systemic inflammation can disrupt the blood-brain barrier, leading to brain inflammation, synaptic remodeling, and neurodegeneration in core regions associated with cognition. This can ultimately result in cognitive impairment.^{[10, 11]} The interaction between systemic inflammation and neuroinflammation can lead to the abnormal activation of glial cells. This activation results in the release of neurotoxins and the spread of tau protein deposits, which contribute to the development and advancement of cognitive impairment.^{[12, 13]}

A pro-inflammation diet is a modifiable factor that significantly contributes to the accelerated decline of kidney function and the development of chronic kidney disease (CKD), ^{[14, 15]} CKD is identified as an important risk factor for cognitive impairment. Cognitive impairment is common in individuals with CKD by complex and diverse mechanisms, including the induction of cerebrovascular disease, accumulation of neurotoxins, altered hemodynamics, and disturbances in lipid metabolism.^{[16, 17]} However, it is unclear whether CKD mediates the association between pro-inflammatory diet and cognitive impairment.

Thus, in this study, we investigate the relationship between a pro-inflammatory diet and cognitive impairment, specifically examining the mediating effect of CKD. We used the data from the National Health and Nutrition Examination Survey (NHANES) and employed the Dietary Inflammatory Index (DII) and mediation analysis, Our findings provide a new perspective for better understanding the correlation between pro-inflammatory diet and cognitive impairment.

Study Population

We use data from the National Health and Nutrition Examination Survey (NHANES), a nationally representative survey conducted by the National Center for Health Statistics (NCHS).covering the non-institutionalized civilians in the District of Columbia and fifty states in the United States, aiming to evaluate the nutritional and health status of the population through laboratory tests, physical examinations, and interviews.^[18] NHANES uses "stratified multistage probability sampling" to ensure the representativeness of the samples. Each survey cycle of NHANES is two years. This study was based on the NHANES data between 2011 and 2014. All data of NHANES is publicly available.

A total of 19931 participants with dietary information were initially enrolled in this study, leaving

3124 participants after excluding those under 20 years old and those lacking the date of cognitive function tests(n = 16807).

Dietary Inflammatory Index

For DII calculation in the NHANES participants, the 24-hour dietary recall interviews conducted at the mobile examination center (MEC) were applied, a tool that assesses the inflammatory potential of individual’s diet as soon as his or her dietary dates are available. The score reflects the overall effect of diet on the levels of six inflammatory markers (TNF-α, IL-1β, IL-10, IL-4, IL-6, and CRP). A higher DII indicates that a diet with more pro-inflammatory properties and a lower DII indicates that a diet with more anti-inflammatory properties.^[19]

The detailed calculation process of DII has been introduced in the article by Shivappa et al.^[20] Briefly, the intake of food parameter minus the mean daily reference intake and divided by the standard deviation, and a Z-score was obtained. Then, the Z-score was converted to a percentile value, which was doubled and then subtracted by "1" to obtain the centred percentile value. The "food parameter-specific DII score" was further calculated by multiplying the centred percentile value by the "overall food parameter-specific inflammatory effect score". Finally, the individual's "overall DII score" was given by summing all the "food parameter-specific DII score".

In the calculation of DII, 28 available food parameters were applied, including pro-inflammatory food parameters (total fat, saturated fat, protein, iron, energy, vitamin B12, cholesterol, and carbohydrate) and anti-inflammatory food parameters (caffeine, n-3 fatty acids, vitamin A, thiamin, riboflavin, vitamin D, vitamin E, vitamin C, vitamin B6, β-carotene, n-6 fatty acids, monounsaturated fatty acids, polyunsaturated fatty acids, folic acid, alcohol, fiber, selenium, niacin, zinc, and magnesium).^[20] DII was analyzed as a continuous variable, and all participants were categorized into quartiles according to DII, the range of DII scores for each quartile are: -4.65 to -0.07 (quartile 1), -0.07 to 0.99 (quartile 2), 0.99 to 2.29 (quartile 3), and 2.29 to 4.57 (quartile 4), respectively.

Cognitive Ability Tests

The Animal Fluency (AF) test,^[21] Consortium to Establish a Registry for Alzheimer’s Disease Word Learning (CERAD-WL) and Delayed Recall (CERAD-DR) tests,^[22] and Digit Symbol Substitution Test (DSST) ^[23] were applied for the assessment of cognitive function. In the AF test, participants had one minute to name as many animals as possible to evaluate categorical verbal fluency. Taking the number of animals named as the score, and the AF score < 14 was considered indicative of cognitive impairment.^[24]

The CERAD tests assess immediate and delayed learning ability for new verbal information(memory sub-domain) and consist of three consecutive learning (CERAD-WL) trials and a delayed recall (CERAD-DR) test. In each learning trial, participants ha to read 10 unrelated words aloud and then recalled them immediately. The score for each learning trial was the number of words correctly recalled. Each learning trial shuffled the order of the words. The final score was the sum of the scores from the three trials, with a maximum score of 30. The CREAD-DR test was implemented after all other cognitive function assessments were completed. A score < 17 on the CERAD-WL test or < 5 on the CERAD-DR test indicated cognitive impairment.^[25]

The DSST is widely used to evaluate sustained attention, processing speed, and working memory. In this test, participants were given a set of number-symbol pairs, and they have two minutes to match the symbols with corresponding numbers The score is the total number of correct symbols drown, with a maximum score of 133. A DSST score < 34 is used as a cut off value to identify potential cognitive impairment.^[26] In this study, participants meeting any of the above criteria were considered cognitive impairment.

Study Covariates

Covariates in this study included age, gender, race (non-Hispanic Black, non-Hispanic White, Mexican American, other-Hispanic, and other), body mass index (BMI, kg/m²), family poverty income ratio (PIR), smoking status, and a history of chronic diseases including dysglycemia (diabetes mellitus, impaired glucose tolerance, and impaired fasting glucose), cardiovascular disease (CVD), hyperlipidemia, stroke, hypertension, and chronic kidney disease (CKD). Age was included as a continuous variable. BMI was obtained by dividing weight by height squared. PIR was the ratio of household income to the U.S. federal poverty threshold, used to define an individual's economic level, with three grades: > 3.5 (high income), 1.3–3.5 (middle income), and < 1.3 (low income).^[27] The detailed measurement procedures for the study variables can be publicly obtained at www.cdc.gov/nchs/nhanes/.

Mediation Analysis

In the mediation analysis, DII score was used as the exposure variable and cognitive performance as the outcome variable. As a result, the study constructed three models to verify the mediating effect of kidney function on the relationship between DII and cognitive impairment. Three mediating effect models were CKD (yes or no), estimated glomerular filtration rate (eGFR, ml/min/1.73m²), and uric acid (umol/L), respectively. The definition of CKD was eGFR < 60 ml/min/1.73m², lasting for more than 3 months.^[28] The CKD Epidemiology Collaboration formula was applied for the calculation of eGFR.^[29] The "mediation" R package was used for the execution of the mediation analysis to calculate the indirect effects (average causal mediation effect, ACME), direct effects (average direct effect, ADE), and total effects (TE) of DII on cognitive performance.^[30] Bootstrapping was applied for significance testing.

Statistical Analysis

Statistical analysis was implemented by R software (version 3.6.1). The mean ± standard deviation (SD) was applied to report continuous data. Categorical variables were described as counts (n) with percentage (%). Comparison of mean values was conducted by t-test, and chi-squared test was applied for the comparison of categorical variables. Cuzick's test for trend was used to test the existence of a linear relationship trend between study variables and DII. Logistic regression models were applied to evaluate the association between risk of cognitive impairment and DII score. In this study, p-value ≤ 0.05 was taken as the threshold for statistical significance.

Association of DII and cognitive performance

The entire workflow of this study is shown in Fig. 1. The 3124 participantswere classified as either cognitively normal (n = 1342) or cognitively impaired(n = 1782) Table 1 summarizes the general characteristics of the participants based on their cognitive function. The DII scores differed significantly between the cognitively impaired and cognitively normal groups (p < 0.001, Table 1). Cognitively impaired individuals tended to be in the high-DII quartile (quartile 4 accounted for the highest proportion at 27.0%), while cognitively normal individuals tended to be in the low-DII quartile (quartile 1 accounted for the highest proportion at 29.3%). Trend analysis indicated that as the DII level increased from quartile one to four, there was a gradual upward trend in the proportion of participants with cognitive impairment (p.trend < 0 .001, Table 2).

Table 1

General characteristics of participants grouped by cognitive status.
	Cognitive impairment	cognitive normal	p.overall
	N = 1782	N = 1342
Age (years, mean ± SD)	71.2 ± 6.91	67.7 ± 6.21	<0.001
Gender (n, %)			<0.001
Female	840 (47.1%)	772 (57.5%)
Male	942 (52.9%)	570 (42.5%)
PIR (n, %)			<0.001
< 1.3	654 (40.4%)	240 (19.4%)
> 3.5	348 (21.5%)	525 (42.5%)
1.3 to < 3.5	617 (38.1%)	470 (38.1%)
Ethnicity (n, %)			<0.001
Mexican American	180 (10.1%)	104 (7.75%)
Non-Hispanic Black	509 (28.6%)	254 (18.9%)
Non-Hispanic White	679 (38.1%)	771 (57.5%)
Other Hispanic	231 (13.0%)	91 (6.78%)
Other	183 (10.3%)	122 (9.09%)
BMI (kg/m², mean ± SD)	28.7 ± 6.24	29.4 ± 6.44	0.006
DII Quartiles (n, %)			<0.001
Quartile 1	388 (21.8%)	393 (29.3%)
Quartile 2	462 (25.9%)	319 (23.8%)
Quartile 3	450 (25.3%)	331 (24.7%)
Quartile 4	482 (27.0%)	299 (22.3%)
DII Score (mean ± SD)	1.04 ± 1.72	0.76 ± 1.76	<0.001
Dysglycemia (n, %)			<0.001
DM	684 (38.4%)	375 (27.9%)
IFG	73 (4.10%)	56 (4.17%)
IGT	112 (6.29%)	65 (4.84%)
No	913 (51.2%)	846 (63.0%)
CKD (n, %)			<0.001
No	930 (55.7%)	942 (73.1%)
Yes	739 (44.3%)	346 (26.9%)
eGFR (ml/min/1.73m²)	71.2 ± 21.4	76.4 ± 17.5	<0.001
Uric acid (umol/L)	342 ± 90.8	335 ± 83.7	0.027
Stroke (n, %)			<0.001
No	1586 (89.2%)	1280 (95.5%)
Yes	192 (10.8%)	60 (4.48%)
CVD (n, %)			<0.001
No	1285 (72.2%)	1123 (83.7%)
Yes	496 (27.8%)	219 (16.3%)
Hypertension (n, %)			<0.001
No	427 (24.0%)	451 (33.6%)
Yes	1355 (76.0%)	891 (66.4%)
Hyperlipidemia (n, %)			0.134
No	355 (19.9%)	238 (17.7%)
Yes	1427 (80.1%)	1104 (82.3%)
Smoke (n, %)			0.133
No	1539 (86.4%)	1184 (88.3%)
Yes	242 (13.6%)	157 (11.7%)

Table 2

General characteristics of the DII quartiles.
	Quartile1	Quartile2	Quartile3	Quartile4	p.overall	p.trend
	N = 781	N = 781	N = 781	N = 781
Age (years, mean ± SD)	69.2 ± 6.77	70.3 ± 6.96	69.7 ± 6.88	69.7 ± 6.70	0.011	0.355
Gender (n, %)					<0.001	< 0.001
Female	319 (40.8%)	388 (49.7%)	442 (56.6%)	463 (59.3%)
Male	462 (59.2%)	393 (50.3%)	339 (43.4%)	318 (40.7%)
PIR (n, %)					<0.001	0.016
< 1.3	159 (22.2%)	219 (31.9%)	240 (32.6%)	276 (38.7%)
> 3.5	310 (43.2%)	203 (29.5%)	207 (28.1%)	153 (21.4%)
1.3 to < 3.5	248 (34.6%)	265 (38.6%)	289 (39.3%)	285 (39.9%)
Ethnicity (n, %)					<0.001	0.082
Mexican American	80 (10.2%)	79 (10.1%)	64 (8.19%)	61 (7.81%)
Non-Hispanic Black	145 (18.6%)	179 (22.9%)	199 (25.5%)	240 (30.7%)
Non-Hispanic White	399 (51.1%)	337 (43.1%)	374 (47.9%)	340 (43.5%)
Other Hispanic	73 (9.35%)	82 (10.5%)	87 (11.1%)	80 (10.2%)
Other	84 (10.8%)	104 (13.3%)	57 (7.30%)	60 (7.68%)
BMI (kg/m², mean ± SD)	28.2 ± 5.91	28.6 ± 6.00	29.4 ± 6.60	29.9 ± 6.66	<0.001	< 0.001
Cognitive Status (n, %)					<0.001	< 0.001
Cognitive impairment	388 (49.7%)	462 (59.2%)	450 (57.6%)	482 (61.7%)
Cognitively normal	393 (50.3%)	319 (40.8%)	331 (42.4%)	299 (38.3%)
Dysglycemia (n, %)					0.001	< 0.001
DM	219 (28.0%)	257 (32.9%)	274 (35.1%)	309 (39.6%)
IFG	36 (4.61%)	26 (3.33%)	32 (4.10%)	35 (4.48%)
IGT	46 (5.89%)	39 (4.99%)	45 (5.76%)	47 (6.02%)
No	480 (61.5%)	459 (58.8%)	430 (55.1%)	390 (49.9%)
CKD (n, %)					<0.001	< 0.001
No	523 (69.5%)	469 (64.1%)	454 (61.2%)	426 (58.3%)
Yes	229 (30.5%)	263 (35.9%)	288 (38.8%)	305 (41.7%)
eGFR (ml/min/1.73m²)	75.7 ± 18.2	74.5 ± 19.3	72.7 ± 20.3	70.9 ± 21.6	<0.001	< 0.001
Uric acid (umol/L)	332 ± 84.5	338 ± 87.1	339 ± 87.6	348 ± 91.4	0.007	0.001
Stroke (n, %)					0.012	0.004
No	734 (94.2%)	713 (91.4%)	720 (92.3%)	699 (89.7%)
Yes	45 (5.78%)	67 (8.59%)	60 (7.69%)	80 (10.3%)
CVD (n, %)					<0.001	< 0.001
No	641 (82.1%)	606 (77.6%)	599 (76.7%)	562 (72.1%)
Yes	140 (17.9%)	175 (22.4%)	182 (23.3%)	218 (27.9%)
Hypertension (n, %)					<0.001	< 0.001
No	247 (31.6%)	226 (28.9%)	232 (29.7%)	173 (22.2%)
Yes	534 (68.4%)	555 (71.1%)	549 (70.3%)	608 (77.8%)
Hyperlipidemia (n, %)					0.055	0.014
No	159 (20.4%)	164 (21.0%)	145 (18.6%)	125 (16.0%)
Yes	622 (79.6%)	617 (79.0%)	636 (81.4%)	656 (84.0%)
Smoke (n, %)					<0.001	< 0.001
No	716 (91.7%)	684 (87.6%)	675 (86.5%)	648 (83.1%)
Yes	65 (8.32%)	97 (12.4%)	105 (13.5%)	132 (16.9%)

We applied the logistic regression analysis to investigate the relationship between DII and cognitive impairment risk, using quartile 1 as a reference and cognitive impairment as an outcome measure (Table 3). In model 1, which was adjusted for age and gender, the odds ratios (ORs) of quartiles 2–4 were statistically significant: 0.69 (95%CI 0.56–0.85, p < 0.001), 0.68 (95%CI 0.55–0.84, p < 0.001), and 0.56 (95%CI 0.45–0.69, p < 0.001), respectively. Model 2 included additional adjustments for BMI, PIR, and ethnicity; in this model only the OR of quartile 4 remained statistically significant at 0.75 (95% CI 0.59–0.95, p = 0.02). However, in model 3 where we further adjusted for dysglycemia, CVD, stoke, CKD, hypertension, and smoking status, the OR values were not statistically significant (p > 0.05). Despite no positive results being obtained from logistic regression model 3, it is our belief that these findings still suggest that higher DII scores (a more pro-inflammatory diet) are related to increased risk of cognitive impairment overall.

Table 3

The results of logistic regression analysis.
	OR	95%CI	P value
Model 1
Quartile 1	1 (reference)
Quartile 2	0.69	0.56–0.85	< 0.001
Quartile 3	0.68	0.55–0.84	< 0.001
Quartile 4	0.56	0.45–0.69	< 0.001
Model 2
Quartile 1	1 (reference)
Quartile 2	0.90	0.71–1.14	0.389
Quartile 3	0.81	0.64–1.02	0.079
Quartile 4	0.75	0.59–0.95	0.020
Model 3
Quartile 1	1 (reference)
Quartile 2	0.85	0.66–1.09	0.191
Quartile 3	0.81	0.63–1.03	0.087
Quartile 4	0.79	0.61–1.02	0.070

CKD mediated the association between pro-inflammatory diet and cognitive impairment

We further performed a mediation analysis to understand if CKD mediated the association between DII and cognitive performance. In the CKD mediation model, the total effect of DII on cognitive performance was − 0.052 (p = 0.004), with a direct effect of -0.037 (p = 0.028) and an indirect effect of -0.015 (p = 0.002), and an estimated 29.19% of the total association between cognitive performance and DII was mediated by CKD (p = 0.006, Fig. 2A). We further evaluated the mediating effect of eGFR and uric acid. In the eGFR model, DII had a total effect of -0.024 (p < 0.001), in which the direct effect was − 0.02 (p < 0.001) and the indirect effect was − 0.003 (p < 0.001), eGFR was estimated to mediate 14.08% of the association between cognitive performance and DII (p < 0.001, Fig. 2B). In the uric acid model, the total effect of DII was − 0.024 (p < 0.001), the direct effect was − 0.023 (p < 0.001), the indirect effect was − 0.0006 (p = 0.05), and uric acid was estimated to explain 2.58% of the association between cognitive performance and DII (p = 0.05, Fig. 2C). The above results indicate that DII is negatively associated with cognitive performance, and this associated is partly mediated by CKD.

In this study, we first analyzed the relationship between cognitive impairment and a pro-inflammatory diet. Our findings indicate that individuals with cognitive impairment had a significantly higher mean DII than those without. Additionally, as the level of DII increased, there was a gradual increase in the proportion of individuals with cognitive impairment. Logistic regression analysis also revealed that higher DII scores were related to an increased risk of cognitive impairment. Although logistic regression model 3 did not show a significant correlation between DII and risk of cognitive impairment when all covariates were included, we believe this may be due to the limited sample size and presence of mediating variables. Overall, our results suggest that high DII (a pro-inflammatory diet) is associated with cognitive impairment. These findings are in agreement with previous studies.^[31–33]

A pro-inflammatory diet can lead to increased levels of circulating inflammatory cytokines such as IL-1β, IL-6, TNF-α, and CRP,^[20] which are associated not only with the metabolic disorders it causes (hyperinsulinemia, insulin resistance, dyslipidemia, hyperglycemia, and hypertension), but also with the resulting dysbiosis of the intestinal ecology, increased intestinal permeability, intestinal barrier dysfunction, and leakage of toxic bacterial metabolites into the circulatory system.^{[8] [34]} This induction and amplification of systemic inflammation by a pro-inflammatory diet is considered to be related to cognitive impairment.^{[31, 35, 36]} Systemic inflammation can impact cognitive function through various pathological pathways. Inflammatory factors circulating in the periphery can cross the blood-brain barrier, resulting in adverse effects on hippocampal circuits and cognition.^[37] Additionally, systemic inflammation can activate microglia and induce neuroinflammation, leading to long-term potentiation defects in the hippocampus.^[38] Systemic inflammation can cause damage and increased permeability of the blood-brain barrier, which may lead to an imbalance in amyloid homeostasis between blood and brain, increasing amyloid brain load.^[8] In addition, systemic inflammation may affect cognitive function through cerebrovascular disease-related events, such as microbleeds and infarction.^[39]

In this study, we found for the first time that CKD mediates the association between pro-inflammatory diet and cognitive impairment. Pro-inflammatory diet is related to decreased renal function and a high prevalence of CKD,^{[15, 40]} and increases 5-year all-cause mortality in patients with CKD.^[41] Increased levels of systemic inflammation caused by a pro-inflammatory diet not only interfere with intrarenal microcirculation regulation and perfusion distribution, but also induce the production of a range of renal tubular toxins, leading to tubular damage, nephron shedding, and CKD.^{[42, 43]} In addition, inflammation can induce oxidative stress, leading to dysfunction of the endoplasmic reticulum that maintains protein homeostasis, and impairs renal function.^[44] Increased levels of inflammation-related markers are associated with progressive loss of renal function during CKD.^[45]

CKD is one of the few established causes of cognitive impairment. The mechanisms by which CKD leads to cognitive impairment are complex and diverse. Cerebrovascular disease caused by CKD is an important cause of cognitive decline. CKD accelerates atherosclerosis and increases the risk of acute ischemic. Subclinical cerebrovascular diseases, such as cerebral microhemorrhage, white matter lesions, asymptomatic cerebral infarction, and cerebral atrophy, are also more common in CKD patients.^[46] In CKD, many of the molecular mediators responsible for brain injury are retained in the circulation due to reduced clearance of potential neurotoxins, affecting multiple brain regions and cell types and impairing multiple cognitive domains. For example, an elevated level of neuropeptide Y causes brain capillary endothelial dysfunction and blood-brain barrier alterations, leading to sleep disturbances and brain dysfunction. The high level of parathyroid hormone in CKD patients can induce tau protein to bind to muscarinic receptors of hippocampal neurons, triggering their apoptosis. Increased level of fibroblast growth factor 23 causes decreased levels of calcitriol and alpha-Klotho, leading to the dysfunction of serotonergic neurons.^[17] In addition, thiamine deficiency and anemia participated in the pathogenesis of CKD-related cognitive impairment.^[47]

The strength of this study is that it is based on sample survey data from a national sample of U.S. adults, which makes the findings representative at the population level. In addition, multiple tests were used to assess cognitive function, making this study sensitive to the perception of cognitive impairment. Of course, this study also has some limitations. First, due to the nature of the cross-sectional design of this study, we were unable to perform the extrapolation of causality. Second, the food intake data were based on a 24-hour dietary recall, recall bias was unavoidable, and they do not reflect daily changes in food intake. Furthermore, the self-reported covariate information obtained from the NHANES questionnaires may be subjectively biased. Finally, due to limitations in the availability of some food parameters in the NHANES database, this study used only 28 of the 45 food parameters available for calculating DII, which may have biased the results.

In this study, we first analyzed the relationship between cognitive impairment and a pro-inflammatory diet. Our findings indicate that individuals with cognitive impairment were more likely to have a higher DII than those who had normal cognitive. Additionally, as the level of DII increased, there was a gradual increase in the proportion of individuals with cognitive impairment. Logistic regression analysis also revealed that higher DII scores were related to an increased risk of cognitive impairment. Although logistic regression model 3 did not show a significant correlation between DII and risk of cognitive impairment when all covariates were included, we believe this may be due to the limited sample size and stringency of the statistical approach. Overall, our results suggest that high DII (a pro-inflammatory diet) is associated with cognitive impairment. These findings are in good agreement with results described in previous studies..^[31–33]

A pro-inflammatory diet can lead to an increase in circulating inflammatory cytokines such as IL-1β, IL-6, TNF-α, and CRP,^[20] which are associated not only with the metabolic disorders which may cause hyperinsulinemia, insulin resistance, dyslipidemia, hyperglycemia, or hypertension, but also with the result in the dysbiosis of the intestinal ecology, including increased intestinal permeability, intestinal barrier dysfunction, and leakage of toxic bacterial metabolites into the circulatory system.^{[8] [34]} This induction and amplification of systemic inflammation by a pro-inflammatory diet is considered to be related to cognitive impairment.^{[31, 35, 36]} Systemic inflammation can impact cognitive function through various pathological pathways. Inflammatory factors circulating in the periphery can cross the blood-brain barrier, resulting in adverse effects on hippocampal circuits and cognition.^[37] Additionally, systemic inflammation can activate microglia and induce neuroinflammation, leading to long-term potentiation defects in the hippocampus.^[38] Systemic inflammation can cause damage and increased permeability of the blood-brain barrier, which may lead to an imbalance in amyloid homeostasis between blood and brain, increasing amyloid brain load.^[8] In addition, systemic inflammation may affect cognitive function through cerebrovascular disease-related events, such as microbleeds and infarction.^[39]

In this study, we found for the first time that kidney function mediates the association between pro-inflammatory diet and cognitive impairment. Pro-inflammatory diet is related to decreased renal function and a high prevalence of CKD,^{[15, 40]} and increases 5-year all-cause mortality in patients with CKD.^[41] Increased levels of systemic inflammation caused by a pro-inflammatory diet not only interfere with intrarenal microcirculation regulation and perfusion distribution, but also induce the production of a range of renal tubular toxins, leading to tubular damage, nephron shedding, and finally to CKD.^{[42, 43]} In addition, inflammation can induce oxidative stress, leading to dysfunction of the endoplasmic reticulum that maintains protein homeostasis, and impairs renal function.^[44] Increased levels of inflammation-related markers are associated with progressive loss of renal function during CKD.^[45]

CKD is one of the few established causes of cognitive impairment. The mechanisms by which CKD leads to cognitive impairment are complex and diverse. Cerebrovascular disease caused by CKD is an important cause of cognitive decline. CKD accelerates atherosclerosis and increases the risk of acute ischemic. Subclinical cerebrovascular diseases, such as cerebral microhemorrhage, white matter lesions, asymptomatic cerebral infarction, and cerebral atrophy, are also more common in CKD patients.^[46] In CKD, many of the molecular mediators responsible for brain injury are retained in the circulation due to reduced clearance of potential neurotoxins, affecting multiple brain regions and cell types and impairing multiple cognitive domains. For example, an elevated level of neuropeptide Y causes brain capillary endothelial dysfunction and blood-brain barrier alterations, leading to sleep disturbances and brain dysfunction. The high level of parathyroid hormone in CKD patients can induce tau protein to bind to muscarinic receptors of hippocampal neurons, triggering their apoptosis. Increased level of fibroblast growth factor 23 causes decreased levels of calcitriol and alpha-Klotho, leading to the dysfunction of serotonergic neurons.^[17] In addition, thiamine deficiency and anemia participated in the pathogenesis of CKD-related cognitive impairment.^[47]

The strength of this study is that it is based on sample survey data from a national sample of U.S. adults, which makes the findings representative at the population level. In addition, multiple tests were used to assess cognitive function, making this study sensitive to the perception of cognitive impairment. Of course, this study also has some limitations. First, due to the nature of the cross-sectional design of this study, we were unable to perform the extrapolation of causality. Second, the food intake data were based on a 24-hour dietary recall, recall bias was unavoidable, and they do not reflect daily changes in food intake. Furthermore, the self-reported covariate information obtained from the NHANES questionnaires may be subjectively biased. Finally, due to limitations in the availability of some food parameters in the NHANES database, this study used only 28 of the 45 food parameters available for calculating DII, which may have biased the results.

In general, the results of this study suggests that a pro-inflammatory diet is associated with cognitive impairment, pro-inflammatory diet reduces glomerular filtration rate, which aggravates CKD stage, which partially mediates the relationship between pro-inflammatory and cognitive impairment.

OR

odds ratio

CI

confidence interval

PIR

poverty income ratio

BMI

body mass index

DM

dysglycemia

CKD

chronic kidney disease

CVD

cardiovascular disease.

Ethics approval and consent to participate

The NCHS Ethics Review Committee approved the implementation of NHANES, and all participants provided their written informed consent. Given that this study was based on the publicly available data of NHANES, it was considered exempt from ethical review.

Consent for publication

Not applicable

Availability of data and materials

If other readers need these data and materials, they can apply to corresponding writer by a valid reason.

Competing Interests

no conflict of interest here.

Funding

This research was supported by the Science Foundation of AMHT group (NO.2022YK04).

Author Contributions

Weiwei Duan wrote this article, Bo Yuan participated this process of the figures making, Zhiwei Xia conducted this article.

Data Availability Statement

All data generated or analyzed during this study are included in this article. Further enquiries can be directed to the corresponding author.

Acknowledgments

No available.

Disclosure

The author reports no conflicts of interest in this work.

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No competing interests reported.

The role of kidney function in the association between pro- inflammatory diet and cognitive impairment: NHANES from 2011 - 2014

Status:

Version 1

Abstract

Figures

Introduction

Material and methods

Study Population

Dietary Inflammatory Index

Cognitive Ability Tests

Study Covariates

Mediation Analysis

Statistical Analysis

Results

Association of DII and cognitive performance

CKD mediated the association between pro-inflammatory diet and cognitive impairment

Discussion

Conclusion

Abbreviations

Declarations