Association of Urinary Cadmium Concentration With Cognitive Impairment in US Adults: A Longitudinal Cohort Study.

BACKGROUND AND OBJECTIVES: Studies have indicated that cadmium (Cd) exposure is associated with neurotoxicity. However, data linking Cd exposure to cognitive impairment are sparse. We aimed to investigate the association between urinary Cd concentration and cognitive impairment in US adults. METHODS: The REasons for Geographic and Racial Differences in Stroke (REGARDS) study is an ongoing population-based prospective cohort study that enrolled 30,239 Black and White US adults aged 45 years or older at baseline (2003-2007). In a randomly selected subcohort of REGARDS participants who were free of cognitive impairment or stroke at baseline, certain trace element concentrations, including urinary creatinine-corrected Cd, were measured using biospecimens collected and stored at baseline. During an average of 10 years of follow-up, global cognitive impairment was assessed annually using the Six-Item Screener, and domain-based cognitive impairment, including verbal learning, memory, and executive function, was evaluated every other year using the Enhanced Cognitive Battery. Multivariable-adjusted logistic regression models were used to examine the association between urinary Cd concentration and the odds of global or domain-based cognitive impairment. RESULTS: A total of 2,172 participants (mean age: 64.1 ± 9.0 years; female: 54.8%; Black participants: 38.7%) with available data on urinary Cd concentration, including 195 cases of global cognitive impairment and 53 cases of domain-based cognitive impairment, were included in the analyses. While there was no association between Cd and cognitive impairment in the full sample, there was a significant positive association of urinary Cd concentration with global cognitive impairment among White but not Black participants. The odds of cognitive impairment for White participants in the high urinary Cd concentration group (≥median) were doubled compared with those in the low urinary Cd group (odds ratio 2.07, 95% CI 1.18-3.64). Sex, age, region, smoking pack-years, alcohol consumption, and other related metals did not materially modify the associations of interest. DISCUSSION: Findings from this prospective cohort study suggest that urinary Cd concentrations are associated with global cognitive impairment among White but not Black individuals. Further studies with repeatedly measured Cd exposure, larger sample sizes, and longer duration are needed to confirm our findings and explore the potential explanations for the observed racial discrepancy, such as the impact of smoking.

Associations of Chronic Kidney Disease Markers with Cognitive Function: A 12-Year Follow-Up Study.

BACKGROUND: The role of chronic kidney disease (CKD) as a risk factor for cognitive impairment independent of their shared antecedents remains controversial. OBJECTIVE: To determine whether kidney damage (indicated by albuminuria) or kidney dysfunction (estimated glomerular filtration rate [eGFR] <60 ml/min/1.73 m2) predict future (12-year) cognitive function independently of their shared risk factors. METHODS: We studied 4,128 individuals from the 1999/00 population-based Australian Diabetes, Obesity, and Lifestyle (AusDiab) Study who returned in 2011/12 for follow-up cognitive function testing. Albuminuria was defined by urinary albumin:creatinine≥3.5 (women) or≥2.5 mg/mmol (men). Kidney dysfunction was indicated by eGFR <60 ml/min/1.73 m2. Cognitive function domains assessed included memory (California Verbal Learning Test [CVLT]) and processing speed (Symbol Digit Modalities Test [SDMT]). RESULTS: Baseline albuminuria and kidney dysfunction were identified in 142 (3.4%) and 39 (0.9%) individuals, respectively, with minimal overlap (n = 7). Those with albuminuria demonstrated concurrently reduced 12-year SDMT (p = 0.084) and CVLT scores (p = 0.005) following adjustment for age, sex, and education. However, only CVLT performance remained worse (p = 0.027) following additional adjustment for myocardial infarction, stroke, and related risk factors (hypertension, diabetes, dyslipidemia, smoking, BMI, physical activity, and alcohol intake). Indeed, these collective covariates were responsible for 47% of the effect of albuminuria on SDMT, but only 21% of its effect on CVLT. Kidney dysfunction was not associated with either SDMT or CVLT performance (p > 0.10). CONCLUSIONS: Albuminuria predicted worse memory function at 12 years follow-up, whereas its effect on processing speed was driven largely by differences in cardiovascular risk. Kidney dysfunction based on eGFR predicted neither cognitive domain.

The association between urinary Alzheimer-associated neuronal thread protein and cognitive impairment in late-life depression: a controlled pilot study.

Accumulation of tau protein is associated with both Alzheimer's disease (AD) and late-life depression (LLD). Alzheimer-associated neuronal thread protein (AD7c-NTP), which is closely linked with the tau protein, is elevated in the cerebrospinal fluid and urine of AD patients. This study examined the association between urinary AD7c-NTP and late-life depression with cognitive impairment. One hundred and thirty-eight subjects were recruited into late-life depression with cognitive impairment (LLD-CI, n=52), late-life depression without cognitive impairment (LLD-NCI, n=29), AD (n=27), and healthy control (HC, n=30) groups. The level of urinary AD7c-NTP was measured using the enzyme-linked immunosorbent assay method. The Montreal Cognitive Assessment scale (MoCA), Hamilton Rating Scale for Depression (HRSD) and Hamilton Anxiety Rating Scale (HAMA) were used to assess cognitive functions and depressive and anxiety symptoms in the AD and LLD groups. Urinary levels of AD7c-NTP in the LLD-CI group (1.0±0.7ng/ml) were significantly higher than both the LLD-NCI (0.5±0.3ng/ml) and HC groups (0.5±0.3ng/ml), but lower than in the AD group (1.6±1.7 ng/ml). No significant associations were found in the level of urinary AD7c-NTP in relation to age, gender, education and MoCA in the LLD-CI group. The level of urinary AD7c-NTP appears to be associated with cognitive impairment in late-life depression and may be a potential biomarker for early identification of cognitive impairment in LLD.

Distinguishing mild cognitive impairment from Alzheimer's disease with acrolein metabolites and creatinine in urine.

BACKGROUND: We previously reported that the level of urinary 3-hydroxypropyl mercapturic acid (3-HPMA)/creatinine (Cre) was reduced following stroke. The aim of this study was to determine whether the level of 3-HPMA/Cre in urine was reduced in subjects with dementia. METHODS: The level of 3-HPMA was measured by LC-MS/MS, and that of amino acid conjugated acrolein (AC-Acro) was by ELISA. The study included 128 elderly subjects divided into 74 non-demented (control), 22 mild cognitive impairment (MCI) and 32 Alzheimer's disease (AD) subjects. RESULTS: The urinary 3-HPMA/Cre and AC-Acro/Cre in MCI plus AD subjects were significantly lower than those in control subjects. In addition, urinary Cre in AD subjects was significantly higher than that in MCI subjects, and 3-HPMA/Cre and AC-Acro/Cre in AD subjects were significantly lower than that in MCI subjects. Among these three markers, the lower 3-HPMA/Cre ratio was most strongly correlated with the decline of MMSE (Mini-Mental State Examination) and the increase in CDRsob (Clinical Dementia Rating Scale Sum of Boxes Scores). Furthermore, reduction in 3-HPMA/Cre in urine was well correlated with increase in Aß40/42 in plasma in demented subjects. CONCLUSION: The results indicate that 3-HPMA/Cre in urine is the most reliable biochemical marker to distinguish AD subjects from MCI subjects among three markers.

Proteinuria is associated with neurocognitive impairment in antiretroviral therapy treated HIV-infected individuals.

BACKGROUND: Proteinuria is a marker of vascular dysfunction that predicted increased cardiovascular mortality and is associated with neurocognitive impairment (NCI) in population-based studies. We examined associations between proteinuria and HIV-associated NCI. METHODS: Multivariable logistic regression was used to examine associations between NCI at the first neurocognitive assessment (baseline) and simultaneous, clinically significant proteinuria [as random spot urine protein-to-creatinine ratios (UP/Cr) ≥200 mg/g] in a prospective multicenter observational cohort study. Generalized estimating equations were used to examine associations between baseline proteinuria and subsequent NCI among subjects without NCI at baseline. NCI was defined as a Z-score, derived from the combination of normalized scores from the Trailmaking A and B and the Wechsler Adult Intelligence Scale-Revised Digit Symbol tests. RESULTS: A total of 1972 subjects were included in this analysis. Baseline proteinuria was associated with increased odds of NCI [odds ratio (OR): 1.41, 95% confidence interval (CI): 1.08 to 1.85; P = 0.01] and with subsequent NCI among subjects without NCI at baseline (OR: 1.39, 95% CI: 1.01 to 1.93; P = 0.046) in multivariable models adjusted for risk factors and potential confounders. Similar associations were evident when these analyses were limited to visits at which time study subjects maintained plasma HIV RNA levels <200 copies per milliliter. CONCLUSIONS: The association between proteinuria and NCI observed in this study adds to a growing body of evidence implicating contributions by vascular disease to NCI in antiretroviral treated individuals. Studies examining interventions that improve vascular function are warranted.