Kidney-Metabolic Factors Associated with Cognitive Impairment in Chronic Kidney Disease: A Pilot Study.

INTRODUCTION: The associations of kidney-metabolic biomarkers with cognitive impairment (CI) beyond the estimated glomerular filtration rate (eGFR, in mL/min/1.73 m2) and albuminuria levels are not well understood. In exploratory analysis, our objective was to determine the extent that three kidney-metabolic factors, previously proposed as mechanisms of CI and commonly abnormal in chronic kidney disease (CKD), were associated with prevalent CI in CKD participants, adjusted for kidney function measures. METHODS: The study cohort included community-dwelling individuals aged ≥45 years with CKD (eGFR <60), not requiring dialysis, recruited from four health systems. We examined the serum biomarkers bicarbonate (CO2), TNFαR1, and cholesterol as primary exposures. A structured neuropsychological battery conducted by trained staff measured global and domain-specific cognitive performance. Logistic regression analyses estimated the cross-sectional associations between kidney-metabolic measures and global and cognitive domain-specific moderate/severe (Mod/Sev) CI, adjusted for the eGFR, urinary albumin-creatinine ratio (UACR, mg/g), demographics, comorbid conditions, and other kidney-metabolic biomarkers commonly abnormal in CKD. RESULTS: Among 436 CKD participants with mean age 70 years, 16% were Black, the mean eGFR was 34, and the median [IQR] UACR was 49 [0.0, 378] mg/g. In adjusted models, increased TNFαR1 was associated with global Mod/Sev CI (odds ratio [95% confidence interval] = 1.40 [1.02, 1.93]; p = 0.04); low bicarbonate (CO2 <20 mEq/L) with Mod/Sev memory impairment (3.04 [1.09, 8.47]; p = 0.03), and each 10-mg/dL lower cholesterol was associated with Mod/Sev executive function/processing speed impairment (1.12 [1.02, 1.23]; p = 0.02). However, after adjustment for multiple comparisons, these associations were no longer significant nor were any other kidney-metabolic factors significant for any CI classification. CONCLUSION: In exploratory analyses in a CKD population, three kidney-metabolic factors were associated with CI, but after adjustment for multiple comparisons, were no longer significant. Future studies in larger CKD populations are needed to assess these potential risk factors for CI.

Assessment of acute head injury in an emergency department population using sport concussion assessment tool - 3rd edition.

Sport Concussion Assessment Tool version 3 (SCAT-3) is one of the most widely researched concussion assessment tools in athletes. Here normative data for SCAT3 in nonathletes are presented. The SCAT3 was administered to 98 nonathlete healthy controls, as well as 118 participants with head-injury and 46 participants with other body trauma (OI) presenting to the ED. Reference values were derived and classifier functions were built to assess the accuracy of SCAT3. The control population had a mean of 2.30 (SD = 3.62) symptoms, 4.38 (SD = 8.73) symptom severity score (SSS), and 26.02 (SD = 2.52) standardized assessment of concussion score (SAC). Participants were more likely to be diagnosed with a concussion (from among healthy controls) if the SSS > 7; or SSS ≤ 7 and SAC ≤22 (sensitivity = 96%, specificity = 77%). Identification of head injury patients from among both, healthy controls and body trauma was possible using rule SSS > 7 and headache or pressure in head present, or SSS ≤ 7 and SAC ≤ 22 (sensitivity = 87%, specificity = 80%). In this current study, the SCAT-3 provided high sensitivity to discriminate acute symptoms of TBI in the ED setting. Individuals with a SSS > 7 and headache or pressure in head, or SSS ≤ 7 but with a SAC ≤ 22 within 48-hours of an injury should undergo further testing.

Prevalence and Risk of Severe Cognitive Impairment in Advanced Chronic Kidney Disease.

Background: Our primary goal is to describe the prevalence, severity, and risk of cognitive impairment (CI) by estimated glomerular filtration rate (eGFR, in mL/min/1.73 m2) in a cohort enriched for advanced chronic kidney disease (CKD; eGFR < 45), adjusting for albuminuria, as measured by urine albumin-to-creatinine ratio (UACR, in mg/g). As both eGFR and albuminuria are associated with CI risk in CKD, we also seek to determine the extent that eGFR remains a useful biomarker for risk of CI in those with CKD and concomitant albuminuria. Methods: Chi-square tests measured the prevalence of severe CI and mild cognitive impairment (MCI) by eGFR level. Logistic regression models and generalized linear models measured risk of CI by eGFR, adjusted for UACR. Results: Participants were 574 adults with a mean age of 69; 433 with CKD (eGFR < 60, nondialysis) and 141 controls (eGFR ≥ 60). Forty-eight percent of participants with CKD had severe CI or MCI. The prevalence of severe CI was highest (25%) in those with eGFR < 30. eGFR < 30 was only associated with severe CI in those without albuminuria (UACR < 30; OR = 3.3; p = .02) and was not associated with MCI in similar models. Conclusions: One quarter of those with eGFR < 30 had severe CI. eGFR < 30 was associated with over threefold increased odds of severe CI in those with UACR < 30, but not with UACR > 30, suggesting that eGFR < 30 is a valid biomarker for increased risk of severe CI in those without concomitant albuminuria.

The Brain in Kidney Disease (BRINK) Cohort Study: Design and Baseline Cognitive Function.

BACKGROUND: The Brain in Kidney Disease (BRINK) Study aims to identify mechanisms that contribute to increased risk for cognitive impairment in patients with chronic kidney disease (CKD). We describe the rationale, design, and methods of the study and report baseline recruitment and cognitive function results. STUDY DESIGN: Longitudinal observational cohort study of the epidemiology of cognitive impairment in CKD. The primary aim is to characterize the association between (1) baseline and incident stroke, white matter disease, estimated glomerular filtration rate (eGFR), inflammation, microalbuminuria, and dialysis initiation and (2) cognitive decline over 3 years in a CKD cohort with a mean eGFR<45 mL/min/1.73 m(2). SETTING & PARTICIPANTS: Community-dwelling participants 45 years or older recruited from 4 health systems into 2 groups: reduced eGFR, defined as eGFR<60 mL/min/1.73 m(2) (non-dialysis dependent), and control, defined as eGFR≥60 mL/min/1.73 m(2). PREDICTOR: eGFR group. OUTCOMES: Performance on cognitive function tests and structural brain magnetic resonance imaging. MEASUREMENTS: Sequential cognitive and physical function testing, serum and urine biomarker measurement, and brain magnetic resonance images over 3 years. RESULTS: Of 554 participants, mean age was 69.3 years; 333, 88, and 133 had eGFRs<45 (non-dialysis dependent, nontransplantation), 45 to <60, and ≥60 (controls) mL/min/1.73 m(2), respectively. Mean eGFR in reduced-eGFR participants was 34.3 mL/min/1.73 m(2). Baseline cognitive performance was significantly associated with eGFR in all domains except language. Participants with eGFRs<30 mL/min/1.73 m(2) performed significantly worse than those with eGFRs≥30 mL/min/1.73 m(2) on tests of memory, processing speed, and executive function. Participants with reduced eGFRs overall scored worst on the Immediate Brief Visual-Spatial Memory Test-Revised. LIMITATIONS: Healthy cohort bias, competing risk for death versus cognitive decline. CONCLUSIONS: Cognitive function was significantly worse in participants with eGFRs<30 mL/min/1.73 m(2). Future BRINK analyses will measure risk factors for cognitive decline using the longitudinal data.

Treatment of non-traumatic out-of-hospital cardiac arrest with active compression decompression cardiopulmonary resuscitation plus an impedance threshold device.

BACKGROUND: A recent out-of-hospital cardiac arrest (OHCA) clinical trial showed improved survival to hospital discharge (HD) with favorable neurologic function for patients with cardiac arrest of cardiac origin treated with active compression decompression cardiopulmonary resuscitation (CPR) plus an impedance threshold device (ACD+ICD) versus standard (S) CPR. The current analysis examined whether treatment with ACD+ITD is more effective than standard (S-CPR) for all cardiac arrests of non-traumatic origin, regardless of the etiology. METHODS: This is a secondary analysis of data from a randomized, prospective, multicenter, intention-to-treat, OHCA clinical trial. Adults with presumed non-traumatic cardiac arrest were enrolled and followed for one year post arrest. The primary endpoint was survival to hospital discharge (HD) with favorable neurologic function (Modified Rankin Scale score ≤ 3). RESULTS: Between October 2005 and July 2009, 2738 patients were enrolled (S-CPR=1335; ACD+ITD=1403). Survival to HD with favorable neurologic function was greater with ACD+ITD compared with S-CPR: 7.9% versus 5.7%, (OR 1.42, 95% CI 1.04, 1.95, p=0.027). One-year survival was also greater: 7.9% versus 5.7%, (OR 1.43, 95% CI 1.04, 1.96, p=0.026). Nearly all survivors in both groups had returned to their baseline neurological function by one year. Major adverse event rates were similar between groups. CONCLUSIONS: Treatment of out-of-hospital non-traumatic cardiac arrest patients with ACD+ITD resulted in a significant increase in survival to hospital discharge with favorable neurological function when compared with S-CPR. A significant increase survival rates was observed up to one year after arrest in subjects treated with ACD+ITD, regardless of the etiology of the cardiac arrest.

Standard cardiopulmonary resuscitation versus active compression-decompression cardiopulmonary resuscitation with augmentation of negative intrathoracic pressure for out-of-hospital cardiac arrest: a randomised trial.

BACKGROUND: Active compression-decompression cardiopulmonary resuscitation (CPR) with decreased intrathoracic pressure in the decompression phase can lead to improved haemodynamics compared with standard CPR. We aimed to assess effectiveness and safety of this intervention on survival with favourable neurological function after out-of-hospital cardiac arrest. METHODS: In our randomised trial of 46 emergency medical service agencies (serving 2·3 million people) in urban, suburban, and rural areas of the USA, we assessed outcomes for patients with out-of-hospital cardiac arrest according to Utstein guidelines. We provisionally enrolled patients to receive standard CPR or active compression-decompression CPR with augmented negative intrathoracic pressure (via an impedance-threshold device) with a computer-generated block randomisation weekly schedule in a one-to-one ratio. Adults (presumed age or age ≥18 years) who had a non-traumatic arrest of presumed cardiac cause and met initial and final selection criteria received designated CPR and were included in the final analyses. The primary endpoint was survival to hospital discharge with favourable neurological function (modified Rankin scale score of ≤3). All investigators apart from initial rescuers were masked to treatment group assignment. This trial is registered with ClinicalTrials.gov, number NCT00189423. FINDINGS: 2470 provisionally enrolled patients were randomly allocated to treatment groups. 813 (68%) of 1201 patients assigned to the standard CPR group (controls) and 840 (66%) of 1269 assigned to intervention CPR received designated CPR and were included in the final analyses. 47 (6%) of 813 controls survived to hospital discharge with favourable neurological function compared with 75 (9%) of 840 patients in the intervention group (odds ratio 1·58, 95% CI 1·07-2·36; p=0·019]. 74 (9%) of 840 patients survived to 1 year in the intervention group compared with 48 (6%) of 813 controls (p=0·03), with equivalent cognitive skills, disability ratings, and emotional-psychological statuses in both groups. The overall major adverse event rate did not differ between groups, but more patients had pulmonary oedema in the intervention group (94 [11%] of 840) than did controls (62 [7%] of 813; p=0·015). INTERPRETATION: On the basis of our findings showing increased effectiveness and generalisability of the study intervention, active compression-decompression CPR with augmentation of negative intrathoracic pressure should be considered as an alternative to standard CPR to increase long-term survival after cardiac arrest. FUNDING: US National Institutes of Health grant R44-HL065851-03, Advanced Circulatory Systems.

Chapter 53: rehabilitation therapies.

This chapter retraces the history and evolution of rehabilitative efforts by physicians and other health professionals to alleviate the symptoms and disabilities associated with neurological disorders. Rehabilitation therapies often provide interventions that go beyond traditional medical treatment aimed at treating impairments, and help those with neurological injuries and illness to re-establish themselves as productive and socially-integrated citizens by reducing their functional disabilities. The chapter considers the early history of practical treatments developed in Greek and Roman times, reviews the scattered attempts at treatment during the Middle Ages and Renaissance, examines the more recent development of specific rehabilitative techniques and disciplines in the 20th century, and also provides discussion of the contemporary application of empirically validated rehabilitation strategies and techniques that emphasize treatment efficacy. The evolution of medical and physical rehabilitation, occupational and vocational rehabilitation, aphasia and cognitive rehabilitation, are all discussed, with additional review of the influence of some of the military conflicts and wars in history that have stimulated the advancement of the clinical practice of rehabilitation. A critique of the benefits of comprehensive rehabilitative programs for traumatic brain injury and stroke is specifically included. The varied skepticism and optimism of treating neurological disorders throughout history is also highlighted.

Acute variation in cognitive function in hemodialysis patients: a cohort study with repeated measures.

BACKGROUND: Although cognitive function in hemodialysis patients is believed to be best 24 hours after the dialysis session, the extent of variation during the dialysis cycle is unknown. STUDY DESIGN: Cohort study with repeated measures. SETTING & PARTICIPANTS: Hemodialysis centers; patients aged 55 years or older. PREDICTOR: Time of assessment related to the dialysis session. Time 1 (T1) occurred approximately 1 hour before the dialysis session; T2, 1 hour into the session; T3, 1 hour after; and T4, the next day. OUTCOMES: Measures of cognitive function using a 45-minute cognitive battery. An average composite score was calculated to measure global cognitive function, equal to the average of subjects' standardized scores on all tests given at each test time. Times were classified as best and worst according to composite scores. MEASUREMENTS: Testing was conducted on average over 2 dialysis sessions to avoid test fatigue. The cognitive battery included tests of verbal fluency, immediate and delayed verbal and visual memory, and executive function, administered at 4 times. RESULTS: In the 28 subjects who completed testing at 3 or 4 testing times, mean age was 66.7 +/- 9.5 years and mean dialysis vintage was 44.7 +/- 33.3 months. Using a general linear model for correlated data, the composite score was significantly lower (poorer) during dialysis (T2) than shortly before the session (T1) or on the next day (T4; P < 0.001 for both). LIMITATIONS: Relatively small sample size, testing delays, results may not be generalizable. CONCLUSION: Global cognitive function varies significantly during the dialysis cycle, being worst during dialysis and best shortly before the session or on the day after. Clinician visits may be most effective at these times.

Preclinical pharmacology of FMPD [6-fluoro-10-[3-(2-methoxyethyl)-4-methyl-piperazin-1-yl]-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene]: a potential novel antipsychotic with lower histamine H1 receptor affinity than olanzapine.

FMPD [6-fluoro-10-[3-(2-methoxyethyl)-4-methyl-piperazin-1-yl]-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene] is a potential novel antipsychotic with high affinity for dopamine D2 (Ki= 6.3 nM), 5-HT(2A) (Ki= 7.3 nM), and 5-HT6 (Ki= 8.0 nM) human recombinant receptors and lower affinity for histamine H1 (Ki= 30 nM) and 5-HT2C (Ki= 102 nM) human recombinant receptors than olanzapine. Oral administration of FMPD increased rat nucleus accumbens 3,4-dihyroxyphenylacetic acid concentrations (ED200 = 6 mg/kg), blocked 5-HT2A agonist-induced increases in rat serum corticosterone levels (ED50= 1.8 mg/kg), and inhibited the ex vivo binding of [125I]SB-258585 [4-iodo-N-[4-methoxy-3-(4-methyl-piperazin-1-yl)-phenyl]-benzenesulfonamide] to striatal 5-HT6 receptors (ED50= 10 mg/kg) but failed to inhibit ex vivo binding of [3H]pyrilamine to hypothalamic histamine H1 receptors at doses of up to 30 mg/kg. In electrophysiology studies, acute administration of FMPD selectively elevated the number of spontaneously active A10 (versus A9) dopamine neurons and chronic administration selectively decreased the number of spontaneously active A10 (versus A9) dopamine neurons. FMPD did not produce catalepsy at doses lower than 25 mg/kg p.o. In Fos-induction studies, FMPD had an atypical antipsychotic profile in the striatum and nucleus accumbens and increased Fos expression in orexin-containing neurons of the hypothalamus. FMPD produced only a transient elevation of prolactin levels. These data indicate that FMPD is an orally available potent antagonist of dopamine D2, 5-HT2A, and 5-HT6 receptors and a weak antagonist of H1 and 5-HT2C receptors. FMPD has the potential to have efficacy in treating schizophrenia and bipolar mania with a low risk of treatment-emergent extrapyramidal symptoms, prolactin elevation, and weight gain. Clinical trials are needed to test these hypotheses.

Bicyclo[2.2.1]heptanes as novel triple re-uptake inhibitors for the treatment of depression.

A series of substituted naphthyl containing chiral [2.2.1] bicycloheptanes were prepared utilizing asymmetric Diels-Alder chemistry. This paper describes structure-activity relationships in this series. The N-methyl 2-naphthyl analogue (16d) and its des-methyl analogue (17d) are active triple re-uptake inhibitors both in vivo and in vitro.