Association of Plasma ß-Amyloid with Cognitive Performance and Decline in Chronic Kidney Disease.

Decreased ß-amyloid (Aß) clearance from the brain has been suggested to contribute to cerebral Aß accumulation in Alzheimer's disease. Based on the idea of a dynamic Aß equilibrium in different body compartments, plasma Aß levels have been investigated as biomarker candidates for preclinical Alzheimer's pathology, yet with inconsistent results. Since the kidneys are involved in Aß elimination from the blood, we evaluated how chronic kidney disease (CKD) affects the association between plasma Aß and cognitive deficits and cognitive decline. In 28 CKD patients, stages 3-5D, and 26 control subjects with comparable vascular risk profile from the New Tools for the Prevention of Cardiovascular Disease in Chronic Kidney Disease (NTCVD) cohort, plasma total Aß was determined with a highly sensitive electrochemiluminescence immunoassay. Cognition was evaluated using a comprehensive battery of ten neuropsychological tests at baseline and 2-year follow-up. Subjects with high plasma Aß level (above median) demonstrated a significantly worse baseline cognitive performance than subjects exhibiting low Aß level (summary score of global cognitive performance at baseline z = -0.46 ± 0.76 vs z = -0.08 ± 0.57, p = 0.045). Cognitive performance moderately decreased over the 2-year follow-up in subjects with high plasma Aß level (Δz = -0.13 ± 0.51), but increased in subjects with low plasma Aß level (Δz = 0.16 ± 0.41, p = 0.023). In linear regression analyses, baseline plasma Aß was significantly associated with cognitive decline both in unadjusted analyses (ß = -0.28, 95% CI = -0.55 to -0.01) and analyses adjusted for age (ß = -0.27, 95% CI = -0.54 to -0.01). Our results suggest the utility of plasma Aß level in predicting cognitive decline in patients suffering from CKD.

Cognitive Performance Is Highly Stable over a 2-Year-Follow-Up in Chronic Kidney Disease Patients in a Dedicated Medical Environment.

BACKGROUND: As kidney and brain functions decline with aging, chronic kidney disease (CKD) and dementia are becoming increasing health burdens worldwide. Among the risk factors for cognitive impairment, CKD is increasingly recognized. The precise impact of CKD on the development of cognitive impairment is poorly understood. METHODS: In the New Tools for the Prevention of Cardiovascular Disease in Chronic Kidney Disease (NTCVD) cohort, which was recruited in a dedicated nephrology department, we examined the 2-year course of cognitive performance in 120 patients (73 patients with CKD stages 3-5D, 47 control patients without CKD with similar vascular risk profile) using a comprehensive battery of 10 neuropsychological tests. RESULTS: Kidney function, vascular risk factors and cognitive performance were highly stable both in CKD and control patients. The summary score of cognitive performance in CKD patients was very similar at baseline (z = -0.63±0.76) and follow-up (z = -0.54±0.79, p = 0.113), as was cognitive performance in control patients (z = -0.01±0.59 and 0.01±0.70, p = 0.862, at baseline and follow-up, respectively). Total serum cholesterol (199.6±36.0 and 186.0±32.9, p = 0.005 in controls; 194.4±46.1 and 181.2±41.2, p = 0.008 in CKD) and common carotid intima-media thickness (0.87±0.18 and 0.84±0.17, p = 0.351 in controls; 0.88±0.21 and 0.82±0.16, p = 0.002 in CKD) moderately but significantly decreased during the follow-up. In multivariable regression analyses, high age (ß = -0.28, 95%CI = -0.48 to 0.08, p = 0.007) predicted decrease in cognitive performance. CONCLUSIONS: In this well-defined cohort receiving state-of-the-art therapy, cognitive performance did not decrease over 2 years. Our data emphasize the aspect of risk factor control, suggesting that dedicated medical care might prevent cognitive decline in CKD patients.

Vascular Risk Factors and Diseases Modulate Deficits of Reward-Based Reversal Learning in Acute Basal Ganglia Stroke.

BACKGROUND: Besides motor function, the basal ganglia have been implicated in feedback learning. In patients with chronic basal ganglia infarcts, deficits in reward-based reversal learning have previously been described. METHODS: We re-examined the acquisition and reversal of stimulus-stimulus-reward associations and acquired equivalence in eleven patients with acute basal ganglia stroke (8 men, 3 women; 57.8±13.3 years), whose performance was compared eleven healthy subjects of comparable age, sex distribution and education, who were recruited outside the hospital. Eleven hospitalized patients with a similar vascular risk profile as the stroke patients but without stroke history served as clinical control group. RESULTS: In a neuropsychological assessment 7±3 days post-stroke, verbal and spatial short-term and working memory and inhibition control did not differ between groups. Compared with healthy subjects, control patients with vascular risk factors exhibited significantly reduced performance in the reversal phase (F[2,30] = 3.47; p = 0.044; post-hoc comparison between risk factor controls and healthy controls: p = 0.030), but not the acquisition phase (F[2,30] = 1.01; p = 0.376) and the acquired equivalence (F[2,30] = 1.04; p = 0.367) tasks. In all tasks, the performance of vascular risk factor patients closely resembled that of basal ganglia stroke patients. Correlation studies revealed a significant association of the number of vascular risk factors with reversal learning (r = -0.33, p = 0.012), but not acquisition learning (r = -0.20, p = 0.121) or acquired equivalence (r = -0.22, p = 0.096). CONCLUSIONS: The previously reported impairment of reward-based learning may be attributed to vascular risk factors and associated diseases, which are enriched in stroke patients. This study emphasizes the necessity of appropriate control subjects in cognition studies.

Factors Responsible for Plasma ß-Amyloid Accumulation in Chronic Kidney Disease.

Disturbed brain-to-blood elimination of ß-amyloid (Aß) promotes cerebral Aß accumulation in Alzheimer's disease. Considering that the kidneys are involved in Aß elimination from the blood, we evaluated how chronic kidney disease (CKD) affects plasma Aß. In 106 CKD patients stages 3-5 (including 19 patients on hemodialysis and 15 kidney recipients), 53 control subjects with comparable vascular risk profile and 10 kidney donors, plasma Aß was determined using electrochemiluminescence immunoassay and gel electrophoresis followed by Western blotting. Plasma Aß increased with CKD stage (control = 182.98 ± 76.73 pg/ml; CKD3A = 248.34 ± 103.77 pg/ml; CKD3B = 259.25 ± 97.74 pg/ml; CKD4 = 489.16 ± 154.16 pg/ml; CKD5 = 721.19 ± 291.69 pg/ml) and was not influenced by hemodialysis (CKD5D = 697.97 ± 265.91 pg/ml). Renal transplantation reduced plasma Aß (332.57 ± 162.82 pg/ml), whereas kidney donation increased it (251.51 ± 34.34 pg/ml). Gel electrophoresis confirmed stage-dependent elevation namely of Aß1-40, the most abundant Aß peptide. In a multivariable regression including age, sex, estimated glomerular filtration rate (eGFR), potassium, hemoglobin, urine urea, and urine total protein, the factors eGFR (ß = -0.42, p < 0.001), hemoglobin (ß = -0.17, p = 0.020), and urine protein (ß = 0.26, p = 0.008) were associated with plasma Aß. In a regression including age, sex, eGFR, potassium, hemoglobin and the vascular risk factors systolic blood pressure, smoking, LDL, HDL, HbA1c, body mass index, brain-derived natriuretic peptide and fibrinogen, the factors eGFR (ß = -0.53, p < 0.001), body mass index (ß = -0.17, p = 0.022), and fibrinogen (ß = 0.18, p = 0.024) were associated with plasma Aß. Our results demonstrate a stage-dependent plasma Aß increase that is augmented by loss of glomerulotubular integrity, low body weight, and inflammation, demonstrating a multifaceted role of renal dysfunction in Aß retention.

Physical, cognitive and emotional factors contributing to quality of life, functional health and participation in community dwelling in chronic kidney disease.

BACKGROUND: Quality of life (QoL) impairment is a well-known consequence of chronic kidney disease (CKD). The factors influencing QoL and late life functional health are poorly examined. METHODS: Using questionnaires combined with neuropsychological examinations, we prospectively evaluated physical, cognitive, and emotional factors influencing QoL, functional health and participation in community dwelling in 119 patients with CKD stages 3-5 including hemodialysis (61.5±15.7years; 63% men) and 54 control patients of the same age without CKD but with similar cardiovascular risk profile. RESULTS: Compared with control patients, CKD patients showed impairment of the physical component of QoL and overall function, assessed by the SF-36 and LLFDI, whereas disability, assessed by LLFDI, was selectively impaired in CKD patients on hemodialysis. Multivariable linear regressions (forced entry) confirmed earlier findings that CKD stage (ß = -0.24; p = 0.012) and depression (ß = -0.30; p = 0.009) predicted the QoL physical component. Hitherto unknown, CKD stage (ß = -0.23; p = 0.007), cognition (ß = 0.20; p = 0.018), and depression (ß = -0.51; <0.001) predicted disability assessed by the LLFDI, while age (ß = -0.20; p = 0.023), male gender (B = 5.01; p = 0.004), CKD stage (ß = -0.23; p = 0.005), stroke history (B = -9.00; p = 0.034), and depression (ß = -0.41; p<0.001) predicted overall function. Interestingly, functional health deficits, cognitive disturbances, depression, and anxiety were evident almost only in CKD patients with coronary heart disease (found in 34.2% of CKD patients). The physical component of QoL and functional health decreased with age and depressive symptoms, and increased with cognitive abilities. CONCLUSIONS: In CKD, QoL, functional health, and participation in community dwelling are influenced by physical, cognitive, and emotional factors, most prominently in coronary heart disease patients.

The prevalence, severity, and association with HbA1c and fibrinogen of cognitive impairment in chronic kidney disease.

Cognitive impairment is a frequent finding in patients with chronic kidney disease (CKD). We examined cognitive performance in a prospective study of 119 patients with CKD stages 3-5 (including dialysis) and 54 control patients of the same age without CKD but with similar vascular risk profiles. Analysis included a comprehensive test battery evaluating memory, information processing speed, executive function, language, and visuoconstructive function, in addition to depression and anxiety. Thirty percent of patients with CKD had cognitive deficits (one or more s.d. below control patient performance). Cognitive deficits (T-value related to published norm values) were mild but significantly decreased to 48.8 in patients with stage 3-5 CKD not requiring hemodialysis and 47.2 in patients with stage 5D disease requiring hemodialysis, compared with 51.5 in control patients. Linear regressions among patients with CKD (forced entry strategy) showed that age (ß=-0.50 per s.d.), HbA1c (ß=-0.18 per s.d.), and fibrinogen (ß=-0.18 per s.d.) predicted cognitive performance. Interestingly, HbA1c discriminated cognition in all age groups, while fibrinogen differentiated cognition particularly in patients over 70 years of age. Thus, our cross-sectional study suggests the severity of cognitive impairment in CKD is mild. As such, longitudinal studies are required to further characterize the role of cognitive deficits in CKD.