Moderate to severe cognitive impairment is common and undiagnosed in hemodialysis patients. Further studies are needed to determine whether dialysis exacerbates the cognitive impairment attributable to underlying disease. Cognitive testing in hemodialysis patients before dialysis initiation and periodically may be warranted.

Background-Active compression decompression cardiopulmonary resuscitation (ACD-CPR) plus a decrease in intrathoracic pressure during the decompression phase of CPR have been shown previously to result in improved hemodynamics when compared with standard CPR. We hypothesized that these interventions would increase survival rates with favorable neurologic function after out-of-hospital cardiac arrest (OOHCA) when compared with standard CPR.

Background Prevalence of moderate to severe cognitive impairment among hemodialysis patients is more than double the prevalence in the general population. This study describes cognitive impairment occurrence in a peritoneal dialysis cohort compared with a cohort without chronic kidney disease (CKD). Study Design Cross-sectional study. Setting and Participants 51 English-speaking peritoneal dialysis patients from two urban dialysis units, compared with 338 hemodialysis patients from 16 urban dialysis units and 101voluntary controls without CKD from urban general medicine clinics. Predictor A 45-minute battery of nine validated neuropsychological tests (cognitive domains memory, executive function, language). Outcomes Mild, moderate, or severe cognitive impairment, classified according to a previously designed algorithm. Results Of the peritoneal dialysis cohort, 33.3% had no or mild, 35.3% moderate, and 31.4% severe cognitive impairment; corresponding values were 60.4%, 26.7%, and 12.9% of the non-CKD cohort, and 26.6%, 36.4%, and 37.0% of the hemodialysis cohort. A logistic regression model including age, sex, race, education, hemoglobin, diabetes, and stroke showed that only non-white race (P = 0.002) and education (P = 0.002) were associated with moderate to severe cognitive impairment in the peritoneal dialysis cohort. Compared with hemodialysis patients, more peritoneal dialysis patients had moderate to severe memory impairment (60% vs. 52%), but fewer had impaired executive function (one-third vs. one-half). Peritoneal dialysis was associated with a more than 2.5-fold increased risk of moderate to severe cognitive impairment compared with no CKD (OR, 2.58; 95% confidence interval 1.02-6.53), as was hemodialysis (OR, 3.16; 95% CI, 1.91-5.24), in an adjusted logistic regression model. Limitations Small sample size, participation rate somewhat low. Conclusions Similar to hemodialysis patients, two-thirds of peritoneal dialysis patients had moderate to severe cognitive impairment, enough to interfere with safely self-administering dialysis and adhering to complex medication regimens. These patients could benefit from cognitive assessment before and periodically after dialysis initiation.

Clinical development of catechol-based orthosteric agonists of the dopamine D1 receptor has thus far been unsuccessful due to multiple challenges. To address these issues, we identified LY3154207 (3) as a novel, potent, and subtype selective human D1 positive allosteric modulator (PAM) with minimal allosteric agonist activity. Conformational studies showed LY3154207 adopts an unusual boat conformation, and a binding pose with the human D1 receptor was proposed based on this observation. In contrast to orthosteric agonists, LY3154207 showed a distinct pharmacological profile without a bell-shaped dose-response relationship or tachyphylaxis in preclinical models. Identification of a crystalline form of free LY3154207 from the discovery lots was not successful. Instead, a novel cocrystal form with superior solubility was discovered and determined to be suitable for development. This cocrystal form was advanced to clinical development as a potential first-in-class D1 PAM and is now in phase 2 studies for Lewy body dementia.

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As part of our ongoing research to identify novel agents acting at metabotropic glutamate 2 (mGlu2) and 3 (mGlu3) receptors, we have previously reported the identification of the C4α-methyl analog of mGlu2/3 receptor agonist 1 (LY354740). This molecule, 1S,2S,4R,5R,6S-2-amino-4-methylbicyclo[3.1.0]hexane-2,6-dicarboxylate 2 (LY541850), exhibited an unexpected mGlu2 agonist/mGlu3 antagonist pharmacological profile, whereas the C4β-methyl diastereomer (3) possessed dual mGlu2/3 receptor agonist activity. We have now further explored this structure-activity relationship through the preparation of cyclic and acyclic C4-disubstituted analogs of 1, leading to the identification of C4-spirocyclopropane 5 (LY2934747), a novel, potent, and systemically bioavailable mGlu2/3 receptor agonist which exhibits both antipsychotic and analgesic properties in vivo. In addition, through the combined use of protein-ligand X-ray crystallography employing recombinant human mGlu2/3 receptor amino terminal domains, molecular modeling, and site-directed mutagenesis, a molecular basis for the observed pharmacological profile of compound 2 is proposed.

Background The Brain in Kidney Disease (BRINK) Study aims to identify mechanisms that contribute to increased risk of cognitive impairment (CI) in chronic kidney disease (CKD) patients. 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 CI in CKD. The primary aim is to characterize the association between (a) baseline and incident stroke, white matter disease, estimated glomerular filtration rate (eGFR), inflammation, microalbuminuria, dialysis initiation, and (b) cognitive decline over 3 years in a CKD cohort with mean eGFR < 45 mL/min/1.73 m2. Setting & Participants Community-dwelling participants aged 45 years or older recruited from four health systems into two groups: reduced eGFR, defined as eGFR < 60 mL/min/1.73 m2 (non-dialysis-dependent), and control, defined as eGFR ≥ 60 mL/min/1.73 m2. 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 eGFR <45 (non-dialysis dependent, non-transplant), 45-<60, and ≥ 60 (controls) mL/min/1.73 m2, respectively. Mean eGFR in the reduced eGFR participants was 34.3 mL/min/1.73 m2. Baseline cognitive performance was significantly associated with eGFR in all domains except language. Participants with eGFR < 30 mL/min/1.73 m2 performed significantly worse than those with eGFR ≥ 30 mL/min/1.73 m2 on tests of memory, processing speed, and executive function. Participants with reduced eGFR overall scored worst on the Immediate Brief Visual-Spatial Memory Test-Revised. Limitations Healthy cohort bias, competing risk of death versus cognitive decline. Conclusions Cognitive function was significantly worse in participants with eGFR < 30 mL/min/1.73 m2. Future BRINK analyses will measure risk factors for cognitive decline using the longitudinal data.

Identification of orthosteric mGlu(2/3) receptor agonists capable of discriminating between individual mGlu2 and mGlu3 subtypes has been highly challenging owing to the glutamate-site sequence homology between these proteins. Herein we detail the preparation and characterization of a series of molecules related to (1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate 1 (LY354740) bearing C4-thiotriazole substituents. On the basis of second messenger responses in cells expressing other recombinant human mGlu2/3 subtypes, a number of high potency and efficacy mGlu2 receptor agonists exhibiting low potency mGlu3 partial agonist/antagonist activity were identified. From this, (1R,2S,4R,5R,6R)-2-amino-4-(1H-1,2,4-triazol-3-ylsulfanyl)bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 14a (LY2812223) was further characterized. Cocrystallization of 14a with the amino terminal domains of hmGlu2 and hmGlu3 combined with site-directed mutation studies has clarified the underlying molecular basis of this unique pharmacology. Evaluation of 14a in a rat model responsive to mGlu2 receptor activation coupled with a measure of central drug disposition provides evidence that this molecule engages and activates central mGlu2 receptors in vivo.