Elevated Urinary AD7c-NTP Levels in Older Adults with Hypertension and Cognitive Impairment.

BACKGROUND: Hypertension, a common chronic disease, is associated with cognitive impairment. Cognitive impairment, especially Alzheimer's disease (AD), seriously affects older adults' quality of life and aggravates the burden of disease on society and families. Elevated Alzheimer-associated neuronal thread protein (AD7c-NTP) has been observed in the urine of patients with AD and mild cognitive impairment; however, it is not clear whether this protein can be used as a biomarker for cognitive impairment in older hypertensive patients. OBJECTIVE: To explore the value of urinary AD7c-NTP, and the association of urinary AD7c-NTP with cognitive function in older hypertensive patients. METHODS: This was a cross-sectional study. In total, 134 hypertensive patients aged ≥60 years were divided into two groups: Lower Cognitive Function group (LCF group, n = 89) and Normal Control group (NC group, n = 45) based on the Montreal Cognitive Assessment (MoCA). Urinary AD7c-NTP, blood glucose, serum insulin, superoxide dismutase (SOD) and malondialdehyde (MDA) levels were measured. RESULTS: Urinary AD7c-NTP level was significantly higher in the LCF group than in the NC group [0.48 (0.21-1.00) versus 0.25 (0.04-0.44) ng/ml, p < 0.001]. The LCF group had lower SOD level [(43.07±23.74) versus (53.12±25.80) U/ml, p = 0.026] and higher homeostasis model assessment of insulin resistance (HOMA-IR) [7.17 (3.74-13.94) versus 6.01 (3.78-7.43), p = 0.033] than the NC group. Urinary AD7c-NTP level was associated with MoCA score and HOMA-IR but not with SOD, MDA, blood glucose, and insulin. CONCLUSION: The level of urinary AD7c-NTP is elevated in older hypertensive patients with lower cognitive function, and insulin resistance may be involved in the process.

Urine Formaldehyde Predicts Cognitive Impairment in Post-Stroke Dementia and Alzheimer's Disease.

Although Alzheimer's disease (AD) was first described over 100 years ago, there is still no suitable biomarker for diagnosing AD in easily collectable samples (e.g., blood plasma, saliva, and urine). Here, we investigated the relationship between morning urine formaldehyde concentration and cognitive impairment in patients with post-stroke dementia (PSD) or AD in this cross-sectional survey for 7 years. Cognitive abilities of the study participants (n = 577, four groups: 231 controls, 61 stroke, 65 PSD, and 220 AD) were assessed by Mini-Mental State Examination (MMSE). Morning urine formaldehyde concentrations were measured by high performance liquid chromatography (HPLC). Gender- and age-matched participants were selected from the four groups (n = 42 in each group). Both semicarbazide-sensitive amine oxidase (SSAO, a formaldehyde-generating enzyme) and formaldehyde levels in the blood and urine were analyzed by using an enzyme-linked immunosorbent assay (ELISA) and HPLC, respectively. We found that morning urine formaldehyde levels were inversely correlated with MMSE scores. The threshold value (the best Cut-Off value) of formaldehyde concentration for predicting cognitive impairment was 0.0418 mM in patients with PSD (Sensitivity: 92.3%; Specificity: 77.1%), and 0.0449 mM in patients with AD (Sensitivity: 94.1%; Specificity: 81.8%), respectively. The results of biochemical analysis revealed that the observed increase in urine formaldehyde resulted from an overexpression of SSAO in the blood. The findings suggest that measuring the concentration of formaldehyde in overnight fasting urine could be used as a potentially noninvasive method for evaluating the likelihood of ensuing cognitive impairment or dementia.

Impact of prenatal exposure to cadmium on cognitive development at preschool age and the importance of selenium and iodine.

The evidence regarding a potential link of low-to-moderate iodine deficiency, selenium status, and cadmium exposure during pregnancy with neurodevelopment is either contradicting or limited. We aimed to assess the prenatal impact of cadmium, selenium, and iodine on children's neurodevelopment at 4 years of age. The study included 575 mother-child pairs from the prospective "Rhea" cohort on Crete, Greece. Exposure to cadmium, selenium and iodine was assessed by concentrations in the mother's urine during pregnancy (median 13 weeks), measured by ICPMS. The McCarthy Scales of Children's Abilities was used to assess children's general cognitive score and seven different sub-scales. In multivariable-adjusted regression analysis, elevated urinary cadmium concentrations (≥0.8 µg/L) were inversely associated with children's general cognitive score [mean change: -6.1 points (95 % CI -12; -0.33) per doubling of urinary cadmium; corresponding to ~0.4 SD]. Stratifying by smoking status (p for interaction 0.014), the association was restricted to smokers. Urinary selenium was positively associated with children's general cognitive score [mean change: 2.2 points (95 % CI -0.38; 4.8) per doubling of urinary selenium; ~0.1 SD], although the association was not statistically significant. Urinary iodine (median 172 µg/L) was not associated with children's general cognitive score. In conclusion, elevated cadmium exposure in pregnancy of smoking women was inversely associated with the children's cognitive function at pre-school age. The results indicate that cadmium may adversely affect neurodevelopment at doses commonly found in smokers, or that there is an interaction with other toxicants in tobacco smoke. Additionally, possible residual confounding cannot be ruled out.

Serum ethanolamine plasmalogens improve detection of cognitive impairment among elderly with high excretion levels of urinary myo-inositol: A cross-sectional study.

BACKGROUND: Several reports have implicated myo-inositol (MI) in myelin formation. We hypothesized that MI is involved in this process through facilitating the biosynthesis of ethanolamine plasmalogens (PlsEtns), which are the major component of myelin membranes, and essential for myelin formation and function. Excessive MI urinary excretion possibly causes PlsEtn deficiency, leading to demyelinating diseases including dementia. METHODS: We examined the association between cognitive impairment, serum levels of PlsEtn, and baseline levels of urinary MI excretion, in the enrollment of 55 memory clinic outpatients and 107 cognitively normal elderly. RESULTS: Serum PlsEtns were independently associated with cognitive impairment, and significantly reduced in memory clinic outpatients, especially in those with high urinary MI, as compared to normal elderly. On the other hand, there was no direct association between urinary MI and cognitive impairment, but urinary MI was significantly associated with serum hemoglobin A1c and amyloid ß 1-40. The interaction between PlsEtn and urinary MI for cognitive impairment was statistically confirmed, and their combined usage improved diagnosis of cognitive impairment. CONCLUSIONS: We proposed the involvement of MI and PlsEtn in cognitive impairment pathology. In conclusion, serum PlsEtn may be useful in detecting cognitive decline among elderly with hyperglycemia.

Low Levels of a Urinary Biomarker of Dietary Polyphenol Are Associated with Substantial Cognitive Decline over a 3-Year Period in Older Adults: The Invecchiare in Chianti Study.

OBJECTIVES: To investigate the association between total urinary polyphenols (TUPs) and total dietary polyphenols (TDPs) and cognitive decline in an older population. DESIGN: The Invecchiare in Chianti (InCHIANTI) study, a cohort study with 3 years of follow-up. SETTING: Tuscany, Italy. PARTICIPANTS: Individuals without dementia aged 65 and older (N=652). MEASUREMENTS: TUP and TDP concentrations were analyzed at baseline using the Folin-Ciocalteu assay and a validated food frequency questionnaire, respectively. Cognition was assessed using the Mini-Mental State Examination (MMSE) and Trail-Making Test (TMT) at baseline and after 3 years of follow-up. Substantial cognitive decline was defined as a reduction in MMSE score of three or more points and an increase of at least 29 seconds on the TMT Part A (TMT-A) and 68 seconds on the TMT Part B (TMT-B) (the worst 10% of the distribution of decline) or as test discontinued because of multiple mistakes on the TMT A and B at follow-up. RESULTS: Higher TUP levels were associated with lower risk of substantial cognitive decline on the MMSE (odds ratio (OR) comparing extreme tertiles=0.53, 95% confidence interval (CI)=0.34-0.85, P-trend=.008) and on the TMT-A (OR=0.52, 95% CI=0.28-0.96, P-trend=.03), but not on TMT-B in a logistic regression model that adjusted for baseline cognitive score and potential confounding factors. TDP did not affect the development of substantial cognitive decline in either test. CONCLUSION: High concentrations of polyphenols, a nutritional biomarker of polyphenol intake, were associated with lower risk of substantial cognitive decline in an older population studied over a 3-year period, suggesting a protective effect against cognitive impairment.

Belief in life after death, salivary 3-methoxy-4-hydroxyphenylglycol, and well-being among older people without cognitive impairment dwelling in rural Japan.

OBJECTIVES: Research has found that spirituality/religiosity has a salutary association with mental/physical health. However, the association of belief in life after death with well-being has rarely been studied, and the same is true of its association with biological indices, such as monoamine transmitters. Therefore, we examined the associations between well-being and religiosity, salivary 3-methoxy-4-hydroxyphenylglycol (sMHPG), and demographic characteristics. METHODS: The participants were 346 community-dwelling people, aged 65 years or older, without cognitive or mental deficits, in rural Japan. Measures of religiosity consisted of belief in life after death, attachment to life, and experiences related to death and religion. The measures were assessed by scales specifically suited for Japanese religious orientations. Participants' well-being was assessed by a life satisfaction scale containing two subscales. We also measured sMHPG, a major metabolite of noradrenaline that is thought to reflect certain psychological states, such as psychomotor retardation and effortful attention. RESULTS: One subscale of life satisfaction was positively associated with belief in life after death and sMHPG, and the other life satisfaction subscale was positively associated with education and death/religion-related experiences (e.g., visiting family graves or loss of a friend). Gender differences were found in afterlife beliefs and each life satisfaction subscale. CONCLUSIONS: These results suggest that religiosity, including belief in life after death and death/religion-related experiences, is salubriously associated with mental health among older people, especially women, living in rural Japan. The basal level of sMHPG was positively associated with life satisfaction, but not with belief in life after death.

A disease modification effect of APOE E4 on the association between urinary albumin excretion and cognition in Korean adults.

BACKGROUND: No previous study examined a disease modifying effect of APOE E4 status on the association between the urinary albumin-to-creatinine ratio (UACR) and cognition. This study aimed to investigate whether APOE E4 modified the association in Korean adults. METHODS: We performed a cross-sectional study in adults aged 45 to 74 who were living in Namwon City, Republic of Korea. Cognitive function was measured with the Korean version of modified Mini-Mental State Examination (K-mMMSE) and cognitive impairment was defined as scores falling below the 25th percentile of the K-mMMSE according to age, sex, and educational attainments. RESULTS: A total of 10,190 participants (4006 men and 6184 women) were analyzed in the present study. Of these, 1698 subjects (16.7%) were APOE E4 carriers. The UACR values were negatively associated with the K-mMMSE scores, even after adjusting for potential confounders including age, sex, education, and vascular risk factors. APOE E4 modified the association significantly, resulting in a steeper decline of cognitive function with the increase in UACR in E4 carriers (P for interaction = 0.021). CONCLUSION: Higher UACR values were significantly associated with cognitive dysfunction in the general Korean population, with cognition in APOE E4 carriers being more severely affected by increased UACR.

Endocrine biomarkers and symptom clusters during the menopausal transition and early postmenopause: observations from the Seattle Midlife Women's Health Study.

OBJECTIVE: During the menopausal transition and early postmenopause, participants in the Seattle Midlife Women's Health Study were likely to belong to one of three symptom severity classes: severe hot flashes with moderate sleep, mood, cognitive, and pain symptoms (high-severity hot flash); moderate levels of all but hot flashes (moderate severity); and low levels of all (low severity). We tested models of the differential effects of hypothalamic-pituitary-ovarian (HPO) axis, hypothalamic-pituitary-adrenal (HPA) axis, and autonomic nervous system (ANS) biomarkers on the three symptom severity classes. METHODS: The Seattle Midlife Women's Health Study participants recorded symptoms monthly in diaries and provided overnight urine samples several times per year that were analyzed for estrone, follicle-stimulating hormone (FSH), cortisol, testosterone, epinephrine, and norepinephrine. Multilevel latent class analysis with multinomial regression was used to determine the effects of HPO axis, HPA axis, and ANS biomarkers on symptom severity class membership. RESULTS: Having lower estrogen and higher FSH levels was significantly associated with belonging to the high-severity hot flash class versus the low-severity class. Having lower epinephrine and higher norepinephrine levels increased the likelihood of belonging to the high-severity hot flash class versus the low-severity class. Having lower epinephrine levels was significantly associated with belonging to the moderate-severity class versus the low-severity class. Cortisol and testosterone were unrelated to symptom severity class membership. CONCLUSIONS: The association of HPO axis biomarkers (estrogen and FSH) with the high-severity hot flash class is anticipated based on prior hot flash research, and the associations of HPA axis biomarkers are as expected based on earlier laboratory studies. The association of lower epinephrine levels with the moderate-severity class suggests that these symptoms may be mediated by the ANS.

Serotonergic, noradrenergic and dopaminergic markers are related to cognitive function in adults with 22q11 deletion syndrome.

Patients with 22q11 deletion syndrome (22q11DS) have a high prevalence of psychiatric disorders and intellectual disability. At present the neurobiology underlying psychopathology in 22q11DS is still not understood. In the present study, we analyzed urinary serotonergic, dopaminergic and noradrenergic markers in 67 adults with 22q11DS. Levels of serotonin and the catecholamine metabolite homovanillic acid were significantly lower in the 22q11DS subjects compared to healthy controls. Within the 22q11DS group, levels of dopamine, homovanillic acid, norepinephrine, vanillyl mandelic acid and serotonin positively correlated with Full Scale Intelligence Quotient scores. Our results suggest that cognitive deficits in 22q11DS are associated with abnormal function of several neurotransmitters.

Associations between urine excretion of isoflavonoids and cognition in postmenopausal women in the Women's Isoflavone Soy Health clinical trial.

OBJECTIVES: To determine effect of change in urine excretion of isoflavonoids on cognitive change. DESIGN: Post hoc analysis of isoflavonoid exposure (mean 2.7 years) during the randomized, placebo-controlled, double-blind Women's Isoflavone Soy Health trial. SETTING: General community. PARTICIPANTS: Healthy postmenopausal women (N = 350). INTERVENTION: Twenty-five grams of isoflavone-rich soy protein (91 mg of aglycone weight isoflavones: 52 mg genistein, 36 mg daidzein, 3 mg glycitein) or milk protein-matched placebo provided daily. MEASUREMENTS: Overnight urine excretion, fasting plasma levels of isoflavonoids, and cognitive function measured at baseline and endpoint. RESULTS: Three hundred women (age: mean 61, range 45-92) completed both cognitive assessments and did not use hormone replacement therapy during the trial. Mean on-trial change from baseline in urine excretion of isoflavonoids was not significantly associated with change in a composite score of global cognition (P = .39). Secondary analyses indicated that change in urine excretion of isoflavonoids was inversely associated with change in a factor score representing general intelligence (P = .02) but not with factor scores representing verbal or visual episodic memory. Mean differences in this general intelligence factor score between women in the lowest and highest quartiles of isoflavonoid change were equivalent to an approximate 4.4-year age-associated decline. Analyses based on plasma isoflavonoid levels yielded similar but attenuated results. CONCLUSION: In healthy postmenopausal women, long-term changes in isoflavonoids are not associated with global cognition, supporting clinical trial results, although greater isoflavonoid exposure from dietary supplements is associated with decrements in general intelligence but not memory; this finding requires confirmation in future studies.

Alexithymia is linked to neurocognitive, psychological, neuroendocrine, and immune dysfunction in persons living with HIV.

The neuropathological changes resulting from Human Immunodeficiency Virus (HIV) infection may manifest in alexithymia (AL), a multidimensional trait characterized by impairments in the cognitive assimilation of feelings and emotions. A sample of 93 HIV survivors scoring high, i.e., ⩾74 on the 26-item Toronto Alexithymia Scale (TAS-26), were compared to 79 low AL (TAS-26⩽54) survivors on measures of neurocognitive, psychological, neuroendocrine and immune function. Neurocognitive function was evinced by a standardized test of psychomotor speed, cognitive flexibility and task switching ability, HIV Dementia and general cognitive status. Patients were also screened for levels of depression, anxiety and psychological stress. A 24-h urinary norepinephrine (NE) and cortisol (CORT) collection was taken; blood was drawn for T lymphocyte subset counts (CD4+CD3+) and HIV-1 viral load. Alexithymic patients exhibited higher levels of executive dysfunction, psychological distress, norepinephrine-to-cortisol (NE/CORT) ratio and viral load. Linear regression models accounting for sociodemographic and disease-related variables revealed two AL subscales, difficulties identifying and describing feelings, predicted and explained a significant proportion of variance in the outcome measures. Specifically, poorer executive task-switching/cognitive flexibility was associated with greater difficulty describing feelings; dysregulated autonomic response (high NE/CORT ratio) and depressive symptoms were predicted by difficulty identifying feelings; higher levels of anxiety and psychological stress were both predicted by greater difficulty describing and identifying feelings. Overall, the psychoneuroimmunological profile of alexithymia in HIV positive persons at mid-stage of infection suggests a greater vulnerability for disease progression.

Child Neurology: cognitive delay in a 7-year-old girl.

Organic acidurias are an important group of inherited metabolic disorders that affect the intermediary metabolic pathways of carbohydrate, amino acid, and fatty acid oxidation, leading to the accumulation of organic acids.(1) The 2-hydroxyglutaric acidurias are rare neurometabolic disorders characterized by developmental delay with or without other neurologic dysfunction. Three different subtypes have been described: d-2-hydroxyglutaric aciduria, l-2-hydroxyglutaric aciduria, and combined d-l-2-hydroxyglutaric aciduria. We describe the case of a child presenting with developmental delay who was found to have the classical biochemical, imaging, and genetic features of l-2-hydroxyglutaric aciduria.

Can urinary excretion rate of 8-isoprostrane and malonaldehyde predict postoperative cognitive dysfunction in aging?

Oxidative stress has been associated with mild cognitive impairment (MCI) and Alzheimer's disease (AD). However, little is known about oxidative stress in postoperative cognitive dysfunction (POCD) in aging. The aim of this study was to investigate urinary excretion rate of 8-isoprostane:creatinine (U8-isoPG:Cr) and malonaldehyde:creatinine (UMDA:Cr) to predict short-term POCD in elderly patients undergoing general and orthopedic surgery. 72 patients aged above 65 years were enrolled in this prospective observational study. Each patient underwent cognitive testing to determine POCD performed by an investigator before surgery and 1 week after surgery. Morning urine was collected at baseline, 1, 2, and 7 days postoperatively. U8-isoPG was performed using enzymelinked immunosorbent assay (ELISA), and UMDA levels were measured by chemiluminescence detection. Creatinine levels were also analyzed if differences in the oxidative biomarkers were observed in the urine creatinine concentration. (1). Of 72 patients who completed cognitive testing, postoperative cognitive dysfunction was detected in 29.2 % (n = 21) of patients in 7 days. (2) U8-isoPG:Cr levels in 7 days postoperatively were significantly higher in POCD patients compared with the non-POCD group (p = 0.01). When measuring change from baseline, U8-isoPG:Cr levels were higher than that of control groups (p = 0.01). (3) UMDA:Cr levels were significantly elevated in 1 and 2 days postoperatively in both groups (p < 0.05). U8-isoPG:Cr level seems to be a valuable marker to detect lipid peroxidation early in POCD patients. However, it will also be important to take into account or reduce potential confounders to improve the identification of changes in the status of oxidative stress as a marker for POCD.

Urinary neurotransmitters are selectively altered in children with obstructive sleep apnea and predict cognitive morbidity.

BACKGROUND: Pediatric obstructive sleep apnea (OSA) is associated with cognitive dysfunction, suggesting altered neurotransmitter function. We explored overnight changes in neurotransmitters in the urine of children with and without OSA. METHODS: Urine samples were collected from children with OSA and from control subjects before and after sleep studies. A neurocognitive battery assessing general cognitive ability (GCA) was administered to a subset of children with OSA. Samples were subjected to multiple enzyme-linked immunosorbent assays for 12 neurotransmitters, and adjusted for creatinine concentrations. RESULTS: The study comprised 50 children with OSA and 20 control subjects. Of the children with OSA, 20 had normal GCA score (mean ± SD) (101.2 ± 14.5) and 16 had a reduced GCA score (87.3 ± 13.9; P < .001). Overnight increases in epinephrine, norepinephrine, and γ-aminobutyric acid (GABA) levels emerged in children with OSA; taurine levels decreased. Using combinatorial approaches and cutoff values for overnight changes of these four neurotransmitters enabled prediction of OSA (area under the curve [AUC]: 0.923; P < .0001). Furthermore, GABA and taurine alterations, as well as overnight reductions in phenylethylamine, were more prominent in children with OSA and low GCA than in children with OSA and normal GCA (P < .001), and they reliably discriminated GCA status (AUC: 0.977; P < .0001). CONCLUSIONS: Pediatric OSA is associated with overnight increases in urinary concentrations of catecholamines indicative of heightened sympathetic outflow. Increases in GABA levels and decreases in taurine levels could underlie mechanisms of neuronal excitotoxicity and dysfunction. Combinatorial approaches using defined cutoffs in overnight changes in concentrations of selected neurotransmitters in urine may not only predict OSA but also the presence of cognitive deficits. Larger cohort studies appear warranted to confirm these findings.

Postoperative cognitive dysfunction is correlated with urine formaldehyde in elderly noncardiac surgical patients.

Post-operative cognitive dysfunction (POCD), especially in elderly patients, has been reported in many studies. Although increasing age, duration of anesthesia, postoperative infections, and respiratory complications were regarded as the risk factors for POCD, no extracerebral diagnostic biomarkers have been identified as indicators of POCD. Ninety-five patients, ages 65-80 years, scheduled for major orthopedic or abdominal surgery were enrolled. Twenty-two patients aged between 20 and 40 years undergoing the same procedures served as controls. Subjects received neuropsychological tests one-day prior and one week post procedure. To determine the presence of POCD, the criteria were used as described in most previous studies. Morning urine samples were obtained one day before surgery and on day 1, day 2 and day 7 post operatively. Urine formaldehyde was determined with high-performance liquid chromatography. The urine formaldehyde level of all patients with and without POCD increased on the first 2 days after surgery. But the formaldehyde concentration (on day 7) in patients with POCD was significantly higher than that in patients without POCD (p < 0.01). In the young control group, no patient was diagnosed with POCD. Although the changes in urine formaldehyde of young patients during perioperative period were similar to those in elderly patients without POCD, the formaldehyde concentrations measured at four time points were all significantly lower than those in elderly patients (p < 0.05). Levels of urine formaldehyde were elevated in the perioperative period, with the highest levels at day 7 in patients with POCD. This suggests that the increase on day 7 may provide a new physiologic marker along with neuropsychological assessments to assist in the diagnosis of POCD.

Polyphenol-rich foods in the Mediterranean diet are associated with better cognitive function in elderly subjects at high cardiovascular risk.

Brain oxidative processes play a major role in age-related cognitive decline, thus consumption of antioxidant-rich foods might help preserve cognition. Our aim was to assess whether consumption of antioxidant-rich foods in the Mediterranean diet relates to cognitive function in the elderly. In asymptomatic subjects at high cardiovascular risk (n = 447; 52% women; age 55-80 y) enrolled in the PREDIMED study, a primary prevention dietary-intervention trial, we assessed food intake and cardiovascular risk profile, determined apolipoprotein E genotype, and used neuropsychological tests to evaluate cognitive function. We also measured urinary polyphenols as an objective biomarker of intake. Associations between energy-adjusted food consumption, urinary polyphenols, and cognitive scores were assessed by multiple linear regression models adjusted for potential confounders. Consumption of some foods was independently related to better cognitive function. The specific associations [regression coefficients (95% confidence intervals)] were: total olive oil with immediate verbal memory [0.755 (0.151-1.358)]; virgin olive oil and coffee with delayed verbal memory [0.163 (0.010-0.316) and 0.294 (0.055-0.534), respectively]; walnuts with working memory [1.191 (0.061-2.322)]; and wine with Mini-Mental State Examination scores [0.252 (0.006-0.496)]. Urinary polyphenols were associated with better scores in immediate verbal memory [1.208 (0.236-2.180)]. Increased consumption of antioxidant-rich foods in general and of polyphenols in particular is associated with better cognitive performance in elderly subjects at high cardiovascular risk. The results reinforce the notion that Mediterranean diet components might counteract age-related cognitive decline.

Critical windows of exposure for arsenic-associated impairment of cognitive function in pre-school girls and boys: a population-based cohort study.

BACKGROUND: Exposure to arsenic through drinking water has been associated with impaired cognitive function in school-aged children in a few cross-sectional studies; however, there is little information on critical windows of exposure. METHODS: We conducted a population-based longitudinal study in rural Bangladesh. We assessed the association of arsenic exposure, based on urinary arsenic (U-As; twice during pregnancy and twice in childhood), with the development of about 1700 children at 5 years of age using Wechsler Pre-school and Primary Scale of Intelligence [intelligence quotient (IQ)]. RESULTS: Median maternal U-As in pregnancy was 80 µg/l (10-90 percentiles: 25-400 µg/l). Children's urine contained 35 (12-155) µg/l and 51 (20-238) µg/l at 1.5 and 5 years, respectively. Using multivariable-adjusted regression analyses, controlling for all potential confounders and loss to follow-up, we found that verbal IQ (VIQ) and full scale IQ (FSIQ) were negatively associated with (log) U-As in girls. The associations were consistent, but somewhat stronger with concurrent arsenic exposure [VIQ: B = -2.4, 95% confidence interval (CI) = -3.8 to -1.1; FSIQ: B = -1.4, 95% CI = -2.7 to -0.1, n = 817), compared with that at 1.5 years (VIQ: B = -0.85, 95% CI = -2.1 to 0.4; FSIQ: B = -0.74, 95% CI = -1.9 to 0.4, n = 902), late gestation (VIQ: B = -1.52, 95% CI = -2.6 to -0.4; FSIQ: B = -1.35, 95% CI = -2.4 to -0.3, n = 874) and early gestation (VIQ: B = -1.23, 95% CI = -2.4 to -0.06; FSIQ: B = -0.92, 95% CI = -2.0 to -0.2, n = 833). In boys, U-As showed consistently low and non-significant associations with all IQ measures. An effect size calculation indicated that 100 µg/l U-As was associated with a decrement of 1-3 points in both VIQ and FSIQ in girls. CONCLUSION: We found adverse effects of arsenic exposure on IQ in girls, but not boys, at 5 years of age.

Advanced glycation end product level, diabetes, and accelerated cognitive aging.

OBJECTIVE: Several studies report that diabetes increases risk of cognitive impairment; some have hypothesized that advanced glycation end products (AGEs) underlie this association. AGEs are cross-linked products that result from reactions between glucose and proteins. Little is known about the association between peripheral AGE concentration and cognitive aging. METHODS: We prospectively studied 920 elders without dementia, 495 with diabetes and 425 with normal glucose (mean age 74.0 years). Using mixed models, we examined baseline AGE concentration, measured with urine pentosidine and analyzed as tertile, and performance on the Modified Mini-Mental State Examination (3MS) and Digit Symbol Substitution Test (DSST) at baseline and repeatedly over 9 years. Incident cognitive impairment (a decline of >1.0 SD on each test) was analyzed with logistic regression. RESULTS: Older adults with high pentosidine level had worse baseline DSST score (p=0.05) but not different 3MS score (p=0.32). On both tests, there was a more pronounced 9-year decline in those with high and mid pentosidine level compared to those in the lowest tertile (3MS 7.0, 5.4, and 2.5 point decline, p overall <0.001; DSST 5.9, 7.4, and 4.5 point decline, p=0.03). Incident cognitive impairment was higher in those with high or mid pentosidine level than those in the lowest tertile (3MS: 24% vs 17%, odds ratio=1.55; 95% confidence interval 1.07-2.26; DSST: 31% vs 22%, odds ratio=1.62; 95% confidence interval 1.13-2.33). There was no interaction between pentosidine level, diabetes status, and cognitive decline. Multivariate adjustment for age, sex, race, education, hypertension, cardiovascular disease, estimated glomerular filtration rate, and diabetes diminished results somewhat but overall patterns remained similar. CONCLUSION: High peripheral AGE level is associated with greater cognitive decline in older adults with and without diabetes.