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Background: Delay of progression from prodromal Alzheimer’s disease (AD) to dementia is an important outcome in AD trials. Centralized adjudication is intended to improve the consistency of dementia diagnosis but has not been scrutinized. Objective: To evaluate centralized adjudication for determining progression to dementia compared with Site Investigator opinion or change in Clinical Dementia Rating (CDR). Methods: We used data from the 2-year APECS trial of verubecestat versus placebo in 1,451 prodromal AD participants. Cases were triggered for central adjudication if: 1) the Site Investigator judged the participant had progressed to dementia, or 2) the participant’s CDR sum-of-boxes score increased ≥2 points from baseline. Post-hoc analyses were performed on pooled treatment-group data to compare methods of assessing progression. Results: 581/1,451 (40%) participants had changes triggering adjudication and most (83%) were confirmed as progression to dementia. Only 66% of those who met CDR criteria (regardless of whether they also met Site Investigator criteria) were adjudicated to have progressed to dementia and just 15% of those who met only CDR criteria were adjudicated to have progressed, representing 5% of progressors. In contrast, 99% of those who met Site Investigator criteria (regardless of whether they also met CDR criteria) were adjudicated to have progressed, and the same was true for those who met only Site Investigator criteria. Conclusion: A positive Site Investigator opinion is an excellent predictor for a positive adjudication decision regarding onset of dementia. Conversely, sole use of CDR sum-of-boxes change ≥2 is inadequate. The benefit of centralized adjudication appears doubtful.

In-clinic venous dried blood spot (DBS) pharmacokinetic (PK) sampling was incorporated into two phase 3 studies of verubecestat for Alzheimer's disease (EPOCH [NCT01739348] and APECS [NCT01953601]), as a potential alternative to plasma PK sampling. Initially, plasma and DBS PK samples were collected concurrently to better understand the DBS-plasma verubecestat concentration relationship, with the intention of discontinuing DBS or plasma sampling following interim analysis. Following initial analyses and comparison of results with prespecified selection criteria, plasma PK sampling was discontinued; however, a stability issue resulting in generally lower DBS verubecestat concentrations with longer collection-to-assay times was subsequently discovered (associated with non-compliance in DBS sample handling), prompting reintroduction of plasma sampling. To enable inclusion of DBS data in population PK analyses, a conversion algorithm for calculating plasma-equivalent concentrations (accounting for DBS sample instability) was developed using paired (time-matched) plasma and DBS data from the EPOCH study. Verubecestat population PK models developed from pooled phase 1/1b and EPOCH data using either (1) plasma-only data or (2) plasma and plasma-equivalent concentrations (calculated from non-paired DBS samples) yielded similar results. The algorithm robustness was demonstrated using DBS data from paired samples from the APECS study and comparison between plasma and plasma-equivalent concentrations. The population PK model was updated with APECS data (both plasma and, if no plasma sample available, plasma equivalents). The results demonstrated similar PK in the two phase 3 populations and exposures consistent with expectations from phase 1 data. This case study illustrates challenges with employing new sampling techniques in large, global trials and describes lessons learned.

The BACE inhibitor verubecestat was previously found to reduce amyloid load as assessed byThe analyses addressed (1) identification of an optimalThe optimal subcortical white matter and pons SUVr cutoffs were determined to be 0.69 and 0.62, respectively. The effect size to detect longitudinal change was higher for subcortical white matter (1.20) than pons (0.45). Hence, subcortical white matter was used as the reference region for the EPOCH PET substudy. In EPOCH, uncorrected baseline SUVr values correlated strongly with MZ PVC (rTreatment-relatedclinicaltrials.gov NCT01739348.

Background: We performed exploratory analyses of retinal thickness data from a clinical trial of the AβPP cleaving enzyme (BACE) inhibitor verubecestat in patients with Alzheimer’s disease (AD). Objective: To evaluate: 1) possible retinal thickness changes following BACE inhibition; and 2) possible association between retinal thickness and brain atrophy. Methods: Retinal thickness was measured using spectral-domain optical coherence tomography in a 78-week randomized placebo-controlled trial of verubecestat in 1,785 patients with mild-to-moderate AD. Changes from baseline in retinal pigment epithelium, macular grid retinal nerve fiber layer, central subfield retinal thickness, and macular grid volume were evaluated for verubecestat versus placebo. Correlation analyses were performed to investigate the potential association between macular grid retinal nerve fiber layer and central subfield retinal thickness with brain volumetric magnetic resonance imaging (vMRI) data at baseline, as well as correlations for changes from baseline at Week 78 in patients receiving placebo. Results: Verubecestat did not significantly alter retinal thickness during the trial compared with placebo. At baseline, mean macular grid retinal nerve fiber layer and central subfield retinal thickness were weakly but significantly correlated (Pearson’s r values≤0.23, p-values

Introduction The APECS and AMARANTH trials showed that beta-secretase (BACE) inhibitors verubecestat and lanabecestat failed to slow cognitive and functional decline in individuals with prodromal or early Alzheimer's disease. Here, the performance on secondary and exploratory cognitive measures in both studies is reported. Methods APECS (verubecestat) and AMARANTH (lanabecestat) were randomized, double-blind, placebo-controlled, parallel-group, 104-week clinical trials conducted by different sponsors. Measures included the 3-Domain Composite Cognition Score (CCS-3D), Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Letter/Category Fluency, and Digit Symbol Coding. Results Verubecestat showed worsening on the CCS-3D Total Score, Episodic Memory, and Attention/Processing Speed domains. Lanabecestat showed worsening on the RBANS Total Score, Immediate Memory, and Visuospatial/Constructional Indexes. Both BACE inhibitors showed worsening on Digit Symbol Coding and improvements on Letter/Category Fluency. Discussion In both studies, many measures showed treatment-associated cognitive worsening, whereas verbal fluency tasks showed improvement.

Introduction We evaluated the selective M1 muscarinic positive allosteric modulator, MK-7622, as adjunctive cognitive enhancing therapy in individuals with Alzheimer's disease. Methods A randomized, double-blind, proof-of-concept trial was performed. Participants with mild-to-moderate Alzheimer's disease, being treated with an acetylcholinesterase inhibitor, were randomized 1:1 to 45 mg of MK-7622 or placebo for 24 weeks. Endpoints included the mean change from baseline in Alzheimer's Disease Assessment Scale–Cognitive Subscale (ADAS-Cog11) at 12 weeks and Alzheimer's Disease Cooperative Study–Activities of Daily Living Inventory at 24 weeks. Results Two hundred forty participants were randomized. The trial was stopped for futility after meeting prospectively defined stopping criteria. MK-7622 did not improve cognition at 12 weeks (group difference in ADAS-Cog11: 0.18 [95% confidence interval: −1.0 to 1.3]) or function at 24 weeks (group difference in Alzheimer's Disease Cooperative Study–Activities of Daily Living Inventory: 0.06 [95% confidence interval: −2.4 to 2.5]). More participants taking MK-7622 discontinued study medication because of adverse events than those taking placebo (16% vs 6%) and who experienced cholinergically related adverse events (21% vs 8%). Discussion MK-7622 (45 mg) does not improve cognition or function when used as adjunctive therapy in mild-to-moderate Alzheimer's disease., Highlights • MK-7622 is a positive allosteric modulator of the M1 receptor. • MK-7622 did not improve cognition or function in Alzheimer's disease patients. • MK-7622 increased cholinergically related side effects in Alzheimer's disease patients. • M1 positive allosteric modulation is not useful for treating Alzheimer's disease.

Introduction Changes in cerebrospinal fluid (CSF) tau and amyloid β (Aβ)42 accompany development of Alzheimer's brain pathology. Robust tau and Aβ42 immunoassays were developed to establish a tau/Aβ42 cutoff distinguishing mild-to-moderate Alzheimer's disease (AD) subjects from healthy elderly control (HC) subjects. Methods A CSF tau/Aβ42 cutoff criteria was chosen, which distinguished the groups and maximized concordance with amyloid PET. Performance was assessed using an independent validation cohort. Results A tau/Aβ42 = 0.215 cutoff provided 94.8% sensitivity and 77.7% specificity. Concordance with PET visual reads was estimated at 86.9% in a ∼50% PET positive population. In the validation cohort, the cutoff demonstrated 78.4% sensitivity and 84.9% specificity to distinguish the AD and HC populations. Discussion A tau/Aβ42 cutoff with acceptable sensitivity and specificity distinguished HC from mild-to-moderate AD subjects and maximized concordance to brain amyloidosis. The defined cutoff demonstrated that CSF analysis may be useful as a surrogate to imaging assessment of AD pathology.

In the phase 3 EPOCH trial (Clinicaltrials.gov; NCT01739348), treatment with the BACE inhibitor verubecestat failed to improve cognition in patients with mild-to-moderate Alzheimer’s disease, but was associated with reduced hippocampal volume after 78 weeks as assessed by MRI. The aims of the present exploratory analyses were to: (i) characterize the effect of verubecestat on brain volume by evaluating the time course of volumetric MRI changes for a variety of brain regions; and (ii) understand the mechanism through which verubecestat might cause hippocampal (and other brain region) volume loss by assessing its relationship to measures of amyloid, neurodegeneration, and cognition. Participants were aged 55–85 years with probable Alzheimer’s disease dementia and a Mini Mental State Examination score ≥15 and ≤26. MRIs were obtained at baseline and at Weeks 13, 26, 52 and 78 of treatment. MRIs were segmented using Freesurfer and analysed using a tensor-based morphometry method. PET amyloid data were obtained with 18F-flutemetamol (Vizamyl®) at baseline and Week 78. Standardized uptake value ratios were generated with subcortical white matter as a reference region. Neurofilament light chain in the CSF was assessed as a biomarker of neurodegeneration. Compared with placebo, verubecestat showed increased MRI brain volume loss at Week 13 with no evidence of additional loss through Week 78. The verubecestat-related volumetric MRI loss occurred predominantly in amyloid-rich brain regions. Correlations between amyloid burden at baseline and verubecestat-related volumetric MRI reductions were not significant (r = 0.05 to 0.26, P-values > 0.27). There were no significant differences between verubecestat and placebo in changes from baseline in CSF levels of neurofilament light chain at Week 78 (increases of 7.2 and 14.6 pg/ml for verubecestat versus 19.7 pg/ml for placebo, P-values ≥ 0.1). There was a moderate correlation between volumetric MRI changes and cognitive decline in all groups including placebo at Week 78 (e.g. r = −0.45 to −0.55, P

Background Verubecestat, a BACE1 inhibitor that reduces Aβ levels in the cerebrospinal fluid of humans, was not effective in a phase 3 trial (EPOCH) of mild-to-moderate AD and was associated with adverse events. To assist in the development of BACE1 inhibitors, we report detailed safety findings from EPOCH. Methods EPOCH was a randomized, double-blind, placebo-controlled 78-week trial evaluating verubecestat 12 mg and 40 mg in participants with mild-to-moderate AD diagnosed clinically. The trial was terminated due to futility close to its scheduled completion. Of 1957 participants who were randomized and took treatment, 652 were assigned to verubecestat 12 mg, 652 to verubecestat 40 mg, and 653 to placebo. Adverse events and relevant laboratory, vital sign, and ECG findings were assessed. Results Verubecestat 12 mg and 40 mg were associated with an increase in the percentage of participants reporting adverse events versus placebo (89 and 92% vs. 82%), although relatively few participants discontinued treatment due to adverse events (8 and 9% vs. 6%). Adverse events that were increased versus placebo included falls and injuries, suicidal ideation, weight loss, sleep disturbance, rash, and hair color change. Most were mild to moderate in severity. Treatment differences in suicidal ideation emerged within the first 3 months but did not appear to increase after 6 months. In contrast, treatment differences in falls and injuries continued to increase over time. Conclusions Verubecestat was associated with increased risk for several types of adverse events. Falls and injuries were notable for progressive increases over time. While the mechanisms underlying the increased adverse events are unclear, they may be due to BACE inhibition and should be considered in future clinical development programs of BACE1 inhibitors. Trial registration ClinicalTrials.gov NCT01739348, registered on 29 November 2012. Electronic supplementary material The online version of this article (10.1186/s13195-019-0520-1) contains supplementary material, which is available to authorized users.

Prodromal Alzheimer's disease offers an opportunity to test the effect of drugs that modify the deposition of amyloid in the brain before the onset of dementia. Verubecestat is an orally administered β-site amyloid precursor protein-cleaving enzyme 1 (BACE-1) inhibitor that blocks production of amyloid-beta (Aβ). The drug did not prevent clinical progression in a trial involving patients with mild-to-moderate dementia due to Alzheimer's disease.We conducted a randomized, double-blind, placebo-controlled, 104-week trial to evaluate verubecestat at doses of 12 mg and 40 mg per day, as compared with placebo, in patients who had memory impairment and elevated brain amyloid levels but whose condition did not meet the case definition of dementia. The primary outcome was the change from baseline to week 104 in the score on the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB; scores range from 0 to 18, with higher scores indicating worse cognition and daily function). Secondary outcomes included other assessments of cognition and daily function.The trial was terminated for futility after 1454 patients had been enrolled; 485 had been assigned to receive verubecestat at a dose of 12 mg per day (the 12-mg group), 484 to receive verubecestat at a dose of 40 mg per day (the 40-mg group), and 485 to receive placebo. A total of 234 patients, 231 patients, and 239 patients per group, respectively, completed 104 weeks of the trial regimen. The estimated mean change from baseline to week 104 in the CDR-SB score was 1.65 in the 12-mg group, 2.02 in the 40-mg group, and 1.58 in the placebo group (P = 0.67 for the comparison between the 12-mg group and the placebo group and P = 0.01 for the comparison between the 40-mg group and the placebo group), suggesting a worse outcome in the higher-dose group than in the placebo group. The estimated rate of progression to dementia due to Alzheimer's disease was 24.5, 25.5, and 19.3 events per 100 patient-years in the 12-mg group, the 40-mg group, and the placebo group, respectively (hazard ratio for 40 mg vs. placebo, 1.38; 97.51% confidence interval, 1.07 to 1.79, not adjusted for multiple comparisons), favoring placebo. Adverse events were more common in the verubecestat groups than in the placebo group.Verubecestat did not improve clinical ratings of dementia among patients with prodromal Alzheimer's disease, and some measures suggested that cognition and daily function were worse among patients who received verubecestat than among those who received placebo. (Funded by Merck SharpDohme; ClinicalTrials.gov number, NCT01953601.).

Defining the environmental context in which genes enhance disease susceptibility can provide insight into the pathogenesis of complex disorders. We report that the intra-uterine environment modulates the association of schizophrenia with genomic risk (in this study, genome-wide association study–derived polygenic risk scores (PRSs)). In independent samples from the United States, Italy, and Germany, the liability of schizophrenia explained by PRS is more than five times greater in the presence of early-life complications (ELCs) compared with their absence. Patients with ELC histories have significantly higher PRS than patients without ELC histories, which is confirmed in additional samples from Germany and Japan. The gene set composed of schizophrenia loci that interact with ELCs is highly expressed in placenta, is differentially expressed in placentae from complicated in comparison with normal pregnancies, and is differentially upregulated in placentae from male compared with female offspring. Pathway analyses reveal that genes driving the PRS-ELC interaction are involved in cellular stress response; genes that do not drive such interaction implicate orthogonal biological processes (for example, synaptic function). We conclude that a subset of the most significant genetic variants associated with schizophrenia converge on a developmental trajectory sensitive to events that affect the placental response to stress, which may offer insights into sex biases and primary prevention.

Defining the environmental context in which genes enhance susceptibility can provide insight into the pathogenesis of complex disorders, like schizophrenia. Here we show that the intrauterine and perinatal environment modulates the association of schizophrenia with genomic risk, as measured with polygenic risk scores (PRS) based primarily on GWAS significant variants. Genomic risk interacts with intrauterine and perinatal complications (Early Life Complications, ELCs) in each of three independent samples from USA, Italy and Germany (overall n= 1693, p= 6e-05). In each sample, the liability of schizophrenia explained by PRS is nominally more than five times greater in the presence of a history of ELCs compared with its absence. In each sample, patients with positive ELC histories have higher PRS than patients without ELCs, which is further confirmed in two additional patient samples from Germany and Japan (overall n=2038, p= 1e-04). The gene set based on the schizophrenia loci interacting with ELCs is highly expressed in multiple placental compartments and dynamically regulated in placenta from complicated in comparison with normal pregnancies. The same genes are differentially up-regulated in placentae from male compared with female offspring. The interaction between genomic risk and ELCs is mainly driven by GWAS significant loci enriched for genes highly expressed in the various placenta samples. Molecular pathway analyses based on the genes not driving this interaction reflect previous analyses about schizophrenia risk-genes, while genes highly and differentially expressed in placentae implicate an orthogonal biology involving cellular stress. These results suggest that the most significant genetic variants detected by current schizophrenia GWAS contribute to risk in part by converging on a developmental trajectory sensitive to events affecting placentation, which may underlie the male preponderance of schizophrenia and offer new insights into primary prevention.

Background Early life events influence later susceptibility to many adult diseases and may contribute to define the environmental context in which genes enhance risk for complex disorder like schizophrenia. Here we analyze the role of intrauterine and perinatal environment in modulating the association of schizophrenia with genomic risk. Methods We evaluated whether genomic risk for schizophrenia interacts with intrauterine and perinatal complications (Early Life Complications, ELCs) on case-control status, in three independent samples of healthy subjects and patients with schizophrenia from USA (n=501), Italy (n=273) and Germany (n=919). We further analyzed the relationship between genomic risk and ELCs in two samples of only patients with schizophrenia from Germany (n=1019) and Japan (n=172). Genomic risk was measured with polygenic risk profile scores based on GWAS-significant alleles (PRS), while ELCs history was assessed with the McNeil-Sjöström Scale. We tested whether genes overlapping the schizophrenia loci interacting with ELCs are enriched in placenta and differentially expressed in placental samples from complicated pregnancies, in 8 independent placental datasets. Finally, we evaluated whether GWAS SNPs marking loci containing genes highly expressed and dynamically modulated in placenta (PlacPRS genes) drive the interaction between PRS and ELCs, and performed pathway analyses on PlacPRS genes. Results PRS interacts with ELCs on case-control status, in the three independent samples from USA (p= p=0.004), Italy (p=0.018) and Germany (p=0.018); in each sample the variance of schizophrenia explained by PRS is multiplicatively higher in the presence of a history of ELCs compared with the absence of such events. The relationship between genomic risk and ELCs is further replicated in the two independent samples of only cases from Germany (p=0.047) and Japan (p=0.044). The gene-set based on PRS loci interacting with ELCs is highly expressed in multiple placental tissues (p

Studies of patients with Parkinson’s disease receiving dopamimetics report conflicting evidence for early learning of probabilistic cue–outcome associations that elicits frontal–striatal activity. Previous studies of probabilistic association learning in patients with schizophrenia administered antipsychotics have displayed conflicting evidence for normal and abnormal learning. The role of dopaminergic treatment (dopamimetic versus dopamine antagonistic) effects on probabilistic association learning in these diseases that directly impact the dopamine system is not fully understood. The current study examined the effects of dopaminergic therapies on probabilistic association learning in 13 patients with schizophrenia and 8 patients with Parkinson’s disease under two conditions: after withdrawal from dopaminergic treatment and following administration of appropriate dopaminergic treatment. Medication order was counterbalanced in both groups. Patients with Parkinson’s disease failed to demonstrate any significant improvement over 150 trials, under both conditions (receiving or withdrawn from dopamimetics). Patients with schizophrenia withdrawn from antipsychotics displayed significant improvement during later trials only. These results demonstrate an effect of dopamine (DA) signaling on probabilistic association learning in that: (1) dopamine replacement therapy in Parkinson’s disease is insufficient to significantly improve probabilistic association learning and (2) DA receptor blockade impairs and removal of DA receptor blockade significantly improves frontal–striatal-dependent probabilistic association learning in schizophrenia, which is a novel finding and is opposite to the effects shown following removal of DA receptor blockade on other cognitive domains reported previously.

Background Current antipsychotic treatments have little impact on the cognitive deficits associated with schizophrenia. It has been proposed that agents which promote histamine release may enhance cognition. We evaluated whether the H3 inverse agonist MK-0249 might improve cognitive deficits in patients with schizophrenia. Methods Outpatients (N = 55) with schizophrenia between ages 21 and 55 who were clinically stable, experienced no more than mild to moderate overall symptoms (PANSS score total 36–75), and were taking a stable dose of antipsychotic medication were randomized to MK-0249 10 mg and placebo in a multi-center, randomized, double-blind, 2-period (4-weeks per period), cross-over study. The primary efficacy endpoint was the mean change from baseline at 4-weeks of treatment in the total cognitive score on the Brief Assessment of Cognition in Schizophrenia (BACS) Battery. Other assessments of cognition were also performed. Results A total of 46 patients completed the study. MK-0249 10 mg did not demonstrate a statistically significant difference compared to placebo in the mean change from baseline in the total cognitive score on the BACS battery after 4-weeks of treatment (− 0.1, 95% CI: − 2.3, 2.1) or with regard to secondary measures of attention/processing speed, episodic memory, or working memory after 4-weeks of treatment. The incidence of adverse events was greater during the MK-0249 treatment period (25/52 patients, 48.1%) compared to the placebo treatment period (15/51 patients, 29.4%). Conclusion MK-0249 10 mg once daily was not superior to placebo in the treatment of cognitive impairment in patients with schizophrenia after 4-weeks. (Clinicaltrials.gov: NCT00506077 )

Objective This study aimed to evaluate whether the T-type calcium channel antagonist MK-8998 was effective in treating acute psychosis in patients with schizophrenia. Methods This was a randomized, double-blind, parallel-group study. After a placebo lead-in, acutely psychotic inpatients with schizophrenia were randomized to 4weeks of MK-8998 12/16mg daily (N=86), olanzapine 10/15mg daily (N=47), or placebo (N=83). The primary efficacy measure was score on the Positive and Negative Syndrome Scale (PANSS). Results Out of 216 randomized patients, 158 completed the 4-week study: MK-8998=58 (67.4%), olanzapine=38 (80.9%), and placebo= 62 (74.7%). The mean changes from baseline in PANSS score at week 4 for MK-8998 and olanzapine were not significantly different from placebo: MK-8998–placebo difference=0.6 [95% confidence interval (CI): 7.0, 5.8], p=0.9; olanzapine–placebo difference=4.3 [95% CI: 11.7, 3.1), p=0.3. A responder rate analysis (≥20% improvement from baseline in PANSS score) suggested an advantage of olanzapine over placebo (odds ratio=2.20 [95% CI: 0.95, 5.09], p=0.07) but no effect of MK-8998 over placebo (odds ratio=1.28 [95% CI: 0.62, 2.64], p=0.5). Treatments were generally well tolerated, but more patients reported adverse events for MK-8998 (47.7%) and olanzapine (48.9%) than placebo (37.3%). Conclusions MK-8998 was not effective in treating acutely psychotic inpatients with schizophrenia, as measured by PANSS score at week 4. Because of the limited efficacy of the active comparator, we cannot exclude the possibility that T-type calcium channel antagonists could prove to be effective in schizophrenia. Copyright © 2013 John Wiley & Sons, Ltd. key words—MK-8998; olanzapine; schizophrenia; randomized trial; T-type calcium channel antagonist

Antagonism of the central opioid receptor like-1 receptor (ORL1) has been implicated in cognition, and has been a focus of drug discovery efforts to ameliorate the cognitive deficits that remain during the stable treatment of schizophrenia with current antipsychotics. In order to facilitate dose selection for phase II clinical testing an ORL1-specific PET tracer was developed to determine drug plasma concentration versus occupancy relationships in order to ensure that the doses selected and the degree of target engagement were sufficient to ensure adequate proof of concept testing. MK-0911 is a selective, high affinity antagonist for the ORL1 receptor radiolabeled with high specific activity 18F for positron emission tomography (PET) studies. Evaluation of [18F]MK-0911 in rhesus monkey PET studies showed a pattern of brain uptake which was consistent with the known distribution of ORL1. In vitro autoradiography with [18F]MK-0911 in rhesus monkey and human brain tissue slices showed a regional distribution that was consistent with in vivo imaging results in monkey. Pre-treatment of rhesus monkeys with high doses of structurally diverse ORL1 antagonists MK-0584, MK-0337, or MK-5757 achieved blockade of [18F]MK-0911 in all gray matter regions. Baseline PET studies with [18F]MK-0911 in healthy human subjects showed tracer distribution and kinetics similar to that observed in rhesus monkey. Quantification of [18F]MK-0911 uptake in repeat human baseline PET studies showed a test–retest variability in volume of distribution (VT) averaging 3% across brain regions. Humans dosed orally with MK-5757 showed reduced [18F]MK-0911 tracer concentration in brain proportional with MK-5757 dose and plasma level. [18F]MK-0911 was useful for determining MK-5757-induced receptor occupancy of ORL1 to guide MK-5757 dose-selection for clinical proof-of-concept studies. Additionally, [18F]MK-0911 may be a useful tool for studying the pharmacology of ORL1 in various human populations and disease states.

β-Amyloid (Aβ) peptides are thought to be critically involved in the etiology of Alzheimer's disease (AD). The aspartyl protease β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is required for the production of Aβ, and BACE1 inhibition is thus an attractive target for the treatment of AD. We show that verubecestat (MK-8931) is a potent, selective, structurally unique BACE1 inhibitor that reduced plasma, cerebrospinal fluid (CSF), and brain concentrations of Aβ40, Aβ42, and sAPPβ (a direct product of BACE1 enzymatic activity) after acute and chronic administration to rats and monkeys. Chronic treatment of rats and monkeys with verubecestat achieved exposures40-fold higher than those being tested in clinical trials in AD patients yet did not elicit many of the adverse effects previously attributed to BACE inhibition, such as reduced nerve myelination, neurodegeneration, altered glucose homeostasis, or hepatotoxicity. Fur hypopigmentation was observed in rabbits and mice but not in monkeys. Single and multiple doses were generally well tolerated and produced reductions in Aβ40, Aβ42, and sAPPβ in the CSF of both healthy human subjects and AD patients. The human data were fit to an amyloid pathway model that provided insight into the Aβ pools affected by BACE1 inhibition and guided the choice of doses for subsequent clinical trials.

We performed a clinical trial to evaluate the effects of the histamine subtype-3 receptor inverse agonist MK- 0249 on cognition in AD patients. Mild-to-moderate AD patients were randomized 1:1 to 4 weeks of double-blind daily treatment with oral MK-0249 5-mg or placebo. Pharmacokinetic and PET data suggested that MK-0249 5-mg daily would achieve approximately 85% brain receptor occupancy at Cmax in elderly patients. Primary efficacy measures were the short Computerized-Neuropsychological-Test-Battery (CNTB) summary score and ADAS-Cog score. A secondary efficacy measure was a Cognition Summary Score summarizing results from 7 cognitive tests. Of 144 patients randomized, 132 completed 4 weeks (MK-0249 = 65, placebo = 67). Most patients (88.2%) were on concomitant symptomatic AD treatment. There were no significant differences between treatments on primary and secondary endpoints at week 4: short CNTB summary score = 0.89 (95% CI: -0.74,2.52); ADAS-Cog score s -0.25 (95% CI: -1.61,1.11); Cognition Summary Score = 1.38 (95% CI: -0.64,3.40). MK-0249 was generally well tolerated but was associated with an increased percentage of patients with adverse events (41/73; 56.2) versus placebo (18/70; 25.7%). Adverse events in > 5% of patients on MK-0249 were diarrhea (8.2% vs. 2.9%), headache (8.2% vs. 1.4%), muscle spasms (5.5% vs. 0%), insomnia (5.5% vs. 0%) and stomach discomfort (5.5% vs. 0%). MK-0249 5-mg once daily over 4 weeks was not effective in improving cognitive function in mild to moderate AD patients who were on concomitant symptomatic AD treatment. (ClinicalTrials.gov trial registration, NCT00420420).

Background Research has implicated IQ and executive function (EF) as contributors to episodic memory impairments in schizophrenia. However, it has been difficult to quantitatively apportion the respective contributions of these factors . We conducted a series of analyses to objectively parse the associated variance and to determine to what extent episodic memory impairment in schizophrenia is independent of IQ and EF. Methods Participants included 323 schizophrenia patients and 327 healthy controls from the National Insitute of Mental Health Sibling Study. Neurocognitive tests assessing IQ, EF, and episodic memory were administered. We examined group differences while controlling for IQ or EF in analyses of covariance, we used linear regression to quantify the amount of variance not explained by IQ or EF, and we matched control and patient subgroups on IQ or EF to determine if memory measures remained different. Results Analyses of covariance revealed significant group differences between schizophrenia individuals and healthy control subjects across multiple episodic memory measures after controlling for IQ or EF. Furthermore, regressions with IQ and/or EF factors entered left more than 50% of variance in memory unaccounted. Follow-up true score variance analyses indicated that the majority of this variance was directly related to memory function. Matched subgroups also yielded subgroup differences on all memory measures. Conclusions Findings across the multiple statistical strategies suggested that the mechanisms underlying the memory impairment in schizophrenia are fully attributable neither to IQ nor EF. Rather, they most likely reflect compromises in episodic memory processing itself and, by inference, the medial temporal system.

Organized neuronal firing is crucial for cortical processing and is disrupted in schizophrenia. Using rapid amplification of 5' complementary DNA ends in human brain, we identified a primate-specific isoform (3.1) of the ether-a-go-go-related K(+) channel KCNH2 that modulates neuronal firing. KCNH2-3.1 messenger RNA levels are comparable to full-length KCNH2 (1A) levels in brain but three orders of magnitude lower in heart. In hippocampus from individuals with schizophrenia, KCNH2-3.1 expression is 2.5-fold greater than KCNH2-1A expression. A meta-analysis of five clinical data sets (367 families, 1,158 unrelated cases and 1,704 controls) shows association of single nucleotide polymorphisms in KCNH2 with schizophrenia. Risk-associated alleles predict lower intelligence quotient scores and speed of cognitive processing, altered memory-linked functional magnetic resonance imaging signals and increased KCNH2-3.1 mRNA levels in postmortem hippocampus. KCNH2-3.1 lacks a domain that is crucial for slow channel deactivation. Overexpression of KCNH2-3.1 in primary cortical neurons induces a rapidly deactivating K(+) current and a high-frequency, nonadapting firing pattern. These results identify a previously undescribed KCNH2 channel isoform involved in cortical physiology, cognition and psychosis, providing a potential new therapeutic drug target.

Functional neuroimaging studies of probabilistic category learning in healthy adults report activation of cortical-striatal circuitry. Based on previous findings of normal learning rate concurrent with an overall performance deficit in patients with schizophrenia, we hypothesized that relative to healthy adults, patients with schizophrenia would display preserved caudate nucleus and abnormal prefrontal cortex activation during probabilistic category learning. Forty patients with schizophrenia receiving antipsychotic medication and 25 healthy participants were assessed on interleaved blocks of probabilistic category learning and control tasks while undergoing blood oxygenation level-dependent functional magnetic resonance imaging. In addition to the whole sample of patients with schizophrenia and healthy adults, a subset of patients and healthy adults matched for good learning was also compared. In the whole sample analysis, patients with schizophrenia displayed impaired performance in conjunction with normal learning rate relative to healthy adults. The matched comparison of patients and healthy adults classified as good learners revealed greater caudate and dorsolateral prefrontal cortex activity in the healthy adults and greater activation in a more rostral region of the dorsolateral prefrontal, cingulate, parahippocampal and parietal cortex in patients. These results demonstrate that successful probabilistic category learning can occur in the absence of normal frontal-striatal function. Based on analyses of the patients and healthy adults matched on learning and performance, a minority of patients with schizophrenia achieve successful probabilistic category learning and performance levels through differential activation of a circumscribed neural network which suggests a compensatory mechanism in patients showing successful learning. Copyright © 2009 Society for Neuroscience.

BACKGROUND: Verbal and visual memory deficits are prominent trait markers for schizophrenia, with impairments also observed in first-degree relatives [Snitz, B.E., Macdonald, A.W., 3rd, & Carter, C.S. (2006). Cognitive deficits in unaffected first-degree relatives of schizophrenia patients: a meta-analytic review of putative endophenotypes. Schizophr Bull, 32(1), 179–194]. It remains unclear whether deficits lie in encoding or savings, and whether the deficit is heritable. OBJECTIVE: To determine which features of memory performance are impaired in both patients and their healthy siblings, possibly reflecting shared genetic effects. METHOD: We tested episodic memory using Logical Memory (LM) and Visual Reproduction (VR) tasks of the Wechsler Memory Scale (Revised). Participants included patients with schizophrenia (n=162), their nonpsychotic siblings (n=146), and controls (n=205), recruited for the “CBDB/NIMH Sibling Study”. We assessed immediate encoding and 30 minute and 24 hour delayed recall as well as savings scores for the “short delay” (immediate to 30 min) and “long delay” (30 min to 24 h) intervals. RESULTS: We observed marked verbal recall deficits in both patients and siblings compared to controls for all stages (p

There is comparatively little information about premorbid maturational brain abnormalities in schizophrenia (SCZ). We investigated whether a history of childhood enuresis, a well-established marker of neurodevelopmental delay, is associated with SCZ and with measures of brain abnormalities also associated with SCZ. A Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) based history of enuresis, volumetric brain MRI scans and neuropsychological testing were obtained in patients with SCZ, their non-psychotic siblings (SIB) and non-psychiatric controls (NC). The subjects were 211 patients (79.6% male), 234 of their SIB (43.2% male) and 355 controls (39.2% male). Frequency of enuresis was compared across groups and correlated with cognitive measures. Total and regional brain volumes were determined using voxel-based morphometry on matched subsets of probands (n = 82) with or without enuresis (n = 16, n = 66, respectively) and controls (n = 102) with or without enuresis (n = 11, n = 91, respectively). Patients with SCZ had higher rates of childhood enuresis (21%) compared with SIB (11%; chi(2) = 6.42, P = 0.01) or controls (7%; chi(2) = 23.65, P0.0001) and relative risk for enuresis was increased in SIB (lambda(S) = 2.62). Patients with enuresis performed worse on two frontal lobe cognitive tests [Letter Fluency (t = 1.97, P = 0.05, df = 200) and Category Fluency (t = 2.15, P = 0.03, df = 200)] as compared with non-enuretic patients. Voxel-based morphometry analysis revealed grey matter volume reductions in several frontal regions (right BA 9, right BA 10 and bilateral BA 45) and right superior parietal cortex (BA 7) in patients with a history of enuresis as compared with non-enuretic patients (all t3.57, all P0.001). The high frequency of childhood enuresis associated with SCZ and abnormalities in prefrontal function and structure in patients with a childhood history of enuresis suggest that childhood enuresis may be a premorbid marker for neurodevelopmental abnormalities related to SCZ. These findings add to the evidence implicating prefrontal dysmaturation in this disorder, potentially related to genetic risk factors.

Imaging genetics provides an enormous amount of functional-structural data on gene effects in living brain, but the sheer quantity of potential phenotypes raises concerns about false discovery. Here, we provide the first empirical results on false positive rates in imaging genetics. We analyzed 720 frequent coding SNPs without significant association with schizophrenia and a subset of 492 of these without association with cognitive function. Effects on brain structure (using voxel-based morphometry, VBM) and brain function, using two archival imaging tasks, the n-back working memory task and an emotional face matching task, were studied in whole brain and regions of interest and corrected for multiple comparisons using standard neuroimaging procedures. Since these variants are unlikely to impact relevant brain function, positives obtained provide an upper empirical estimate of the false positive association rate. In a separate analysis, we randomly permuted genotype labels across subjects, removing any true genotype-phenotype association in the data, to derive a lower empirical estimate. At a set correction level of 0.05, in each region of interest and data set used, the rate of positive findings was well below 5% (0.2-4.1%). There was no relationship between the region of interest and the false positive rate. Permutation results were in the same range as empirically derived rates. The observed low rates of positives provide empirical evidence that the type I error rate is well controlled by current commonly used correction procedures in imaging genetics, at least in the context of the imaging paradigms we have used. In fact, our observations indicate that these statistical thresholds are conservative.

Background Shared neuropathological characteristics of patients with schizophrenia and their siblings might represent intermediate phenotypes that could be used to investigate genetic susceptibility to the illness. We sought to discover previously unidentified gray matter volume differences in patients with schizophrenia and their siblings with optimized voxel-based morphometry. Methods We studied 169 patients with schizophrenia, 213 of their unaffected siblings, and 212 healthy volunteers from the Clinical Brain Disorders Branch/National Institute of Mental Health Genetic Study of Schizophrenia with magnetic resonance imaging. Results Patients with schizophrenia had significant regional gray matter decreases in the frontal, temporal, and parietal cortices compared with healthy volunteers. Their unaffected siblings tended to share gray matter decreases in the medial frontal, superior temporal, and insular cortices, but these decreases were not significant after correction for multiple comparisons, even when we looked at a subgroup of siblings with a past history of mood disorder. As an exploratory analysis, we estimated heritability with regions of interest from the VBM analysis as well as from the hippocampus. Hippocampal volume was significantly correlated within sibling-pairs. Conclusions Our findings confirm and extend previous voxel-based morphometry analyses in ill subjects with schizophrenia. Furthermore, these data argue that although siblings might share some regional gray matter decreases with their affected siblings, the pattern of regional differences might be a weak intermediate phenotype for schizophrenia.

A functional polymorphism at the val66met locus in the BDNF gene has significant effects on the pro-form of the protein in intracellular trafficking and activity-dependent, but not constitutive, secretion. These differences are thought to underlie several findings in humans related to this polymorphism, including markers of neuronal viability, BOLD activation in medial temporal lobe regions, and some aspects of behavior. However, many important questions remain about the impact of BDNF on various mnemonic subprocesses at the behavioral level. In this study, we examined the impact of the val/met polymorphism in a verbal recognition memory paradigm involving manipulation of depth of encoding and differential delays for recall and analyses of hits for previously presented target words and correct rejections of foils. Twenty-four human val homozygous individuals and 24 met carrier individuals comprised the sample. All were healthy controls. IQ between the groups was equivalent. In the encoding phase of the study, words were presented and encoded either by a decision as to whether they were living or nonliving ("deep") or if they contained the letter "A" (shallow). After this phase, recognition was tested immediately, half an hour, and 24h later. BDNF genotype had significant effects on hits and discriminability (d'), accounting for at least 10% of the variance, but not on correct rejections or beta. BDNF did not interact with level of encoding, nor did it interact with delay. In sum, BDNF genotypes impacted "hits" in a recognition memory paradigm, findings consistent with the general notion that BDNF plays a prominent role in memory subprocesses thought to engage the medial temporal lobe.

Background Catechol-O-methyltransferase (COMT) val 108/158 met ( rs4680 ) is thought to affect dopamine regulated prefrontal cortical activity during working memory (WM) tasks, and to weakly increase risk for developing schizophrenia. Recently, other single nucleotide polymorphisms (SNPs) across the gene have emerged as additional risk factors for schizophrenia: namely rs737865 , rs165599 , and rs2097603 . In a large sample, we examined whether these SNPs affect WM. Methods Schizophrenic probands ( n = 325), their nonpsychotic siblings ( n = 359), and normal control subjects ( n = 330) completed tests of WM function. Data were analyzed with a series of mixed model analyses of variance (ANOVAs). Results Val homozygotes performed most poorly on all conditions of the n-back, irrespective of diagnosis. Additionally, there was a trend towards a disease-only val 108/158 met effect on a test of attentional set-shifting; val homozygote probands performed most poorly. Significant or near-significant effects of rs737865 were found on all conditions of the n-back, with G homozygotes performing worst. There also was a disease-only COMT rs737865 effect on the 0-back. None of the other SNPs showed main effects by themselves. A haplotype constructed from promoter and val 108/158 met SNPs showed main effects on WM parameters, consistent with inverted U models of dopamine signaling. Conclusions We extended earlier findings of a val 108/158 met effect on WM function, and suggest that combinations of alleles within COMT may modulate the val 108/158 met effect in a nonlinear manner.

BackgroundFrontal release signs, a subset of neurological soft signs, are common in schizophrenia.AimsTo explore the relationship between frontal release signs and neuropsychological tests of frontal lobe function in people with schizophrenia, their siblings and healthy controls.MethodNeuropsychological tests and frontal release signs were measured in a cohort of index cases (n=302), their siblings (n=240) and healthy controls (n=346).ResultsThe mean total score of frontal release signs was 1.5 (s.d. = 1.58) in the schizophrenia group, 0.54 (s.d.=0.92) for siblings and 0.42 (s.d.=0.77) for controls. Schizophrenia group scores were greater than healthy control or sibling cohort scores (P< 0.0001), which did not differ. In all three cohorts, right grasp reflex scores positively correlated with number of perseverative errors on the Wisconsin Card Sort Task (PR= −0.199,PConclusionsOur findings of relationships between frontal release signs and cognitive assays of cortical dysfunction and the increased frequency of these signs in people with schizophrenia implicate a cortical origin for these clinical signs and evidence of frontal lobe dysfunction in this disorder.

Large batteries of neuropsychological tests are typically necessary to identify cognitive deficits in schizophrenia and routinely examine multiple cognitive processes, with many tests often yielding more than one measure of interest. This study investigates the feasibility of a partial solution to the problem of multiple comparisons: the use of factor analysis to reduce the number of phenotypic variables and to better understand the underlying cognitive architecture in schizophrenia. Using a principle components analysis followed by a varimax rotation, we identified factor structures for schizophrenic patients (n=99), their unaffected siblings (n=167), and control subjects (n=131), both separately and as a composite group. Exploratory factor analysis of the full sample yielded a 7-factor model that included verbal memory, working memory, visual memory, IQ/speed/fluency, executive function, attention and digit span. A confirmatory factor analysis (CFA) with maximum likelihood estimation revealed that the 7-factor model fit observed data from the three groups adequately. Since we identified a factor structure representative of all groups that reduced 24 original variables to 7 variables of interest, factor analysis was useful in reducing the complexity of large batteries of cognitive measures to more manageable numbers of phenotypic variables. Furthermore, these findings provide the first confirmation that cognitive structure is comparable in family members of schizophrenia patients, as well as in patients themselves and controls. © 2007 Published by Elsevier B.V.

Regulator of G-protein signaling 4 (RGS4) modulates postsynaptic signal transduction by affecting the kinetics of Gα-GTP binding. Linkage, association, and postmortem studies have implicated the gene encoding RGS4 (RGS4) as a schizophrenia susceptibility factor. Using a multimodal neuroimaging approach, we demonstrate that genetic variation inRGS4is associated with functional activation and connectivity during working memory in the absence of overt behavioral differences, with regional gray and white matter volume and with gray matter structural connectivity in healthy human subjects. Specifically, variation at oneRGS4single nucleotide polymorphism that has been associated previously with psychosis (rs951436) impacts frontoparietal and frontotemporal blood oxygenation level-dependent response and network coupling during working memory and results in regionally specific reductions in gray and white matter structural volume in individuals carrying the A allele. These findings suggest mechanisms in brain for the association ofRGS4with risk for psychiatric illness.