Cristina Lopez-Lopez

Examining face and construct validity of a noninvasive model of panic disorder in Lister-hooded rats.

RationaleIncreasing evidence suggests that defensive escape behavior in Lister-hooded (LH) rats induced by ultrasound application may be an animal model of panic disorder.ObjectiveThe objectives of this study were to further explore the face and construct validity of ultrasound-induced escape behavior by characterizing the autonomic and neuroendocrine response to ultrasound, and to examine the underlying neuronal structures by comparing the effects of the anxiolytic with panicolytic properties, diazepam, with a preclinical anxiolytic without panicolytic-like activity, the NOP agonist Ro 64-6198.Materials and methodsLH rats were implanted with telemetry transmitters to monitor heart rate and core body temperature before, during, and after ultrasound application. Blood samples were taken after ultrasound application for corticosterone analysis. Ultrasound-induced c-Fos expression was measured in different periaqueductal gray (PAG) and amygdala subregions after treatment with diazepam or Ro 64-6198.ResultsUltrasound application increased heart rate and body temperature, but did not alter plasma corticosterone levels. Ultrasound application increased c-Fos expression in the dorsal and dorsolateral PAG (dPAG, dlPAG) and amygdaloid subregions. Diazepam, but not Ro 64-6198, reduced c-Fos expression in the dPAG/dlPAG, while Ro 64-6198, but not diazepam, reduced c-Fos expression in the central amygdala.ConclusionsSimilar to human panic attacks, ultrasound application to LH rats activated the autonomic, but not the neuroendocrine, stress system. Also, like in humans, the current data confirm and extend that the dPAG/dlPAG plays a key role in ultrasound-induced escape behavior. These observations suggest that ultrasound-induced escape behaviors in LH rats have face and construct validity for panic disorders.

RESULTS FROM A FIRST-IN-HUMAN STUDY WITH THE BACE INHIBITOR CNP520

Luc Tritsmans, Luc Van Nueten, Niels Andreassen, Sebastiaan Engelborghs, Janssen Research & Development, Beerse, Belgium; 2 Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, M€ olndal, Sweden; Ortho-McNeil Pharmaceutical, Raritan, NJ, USA; Janssen Research & Development, Titusville, NJ, USA; 5 Hospital Mutua de Terrasa, Servicio de Neurologia, Terrassa, Spain; Hospital Universitario La Paz, Madrid, Spain; Hospital Clinico San Carlos, Servicio de Neurologia, Madrid, Spain; Fundaci o ACE, Barcelona, Alzheimer Treatment & Research Center, Barcelona, Spain; 9 Hospital Universitari La Fe Avinguda Abril Martorell, Valencia, Spain; Karolinska Institutet, Stockholm, Sweden; Department of Neurology and Memory Clinic, Hospital Network Antwerp (ZNA) Middelheim and Hoge Beuken, Antwerp, Belgium. Contact e-mail: jstreffe@its.jnj.com

Task-related fMRI responses to a nicotinic acetylcholine receptor partial agonist in schizophrenia: A randomized trial

INTRODUCTION AQW051, an α7-nicotinic acetylcholine receptor partial agonist, enhanced cognitive function in rodent models of learning and memory. This study evaluated brain activation during performance of a working memory task (WMT) and an episodic memory task (EMT), and the effect of AQW051 on task-related brain activation and performance in subjects with schizophrenia. METHODS This was a double-blind, randomized, placebo-controlled, multicenter, 2-period cross-over trial (NCT00825539) in participants with chronic, stable schizophrenia. Participants, stratified according to smoking status, were randomized (1:1:1:1:1:1) to 1 of 6 sequence groups that determined the study drug dose (AQW051 7.5mg, 50mg or 100mg) and order of administration versus placebo. The primary outcome was brain activation in a priori target regions of interest (ROIs) during performance of the WMT and EMT, measured using functional magnetic resonance imaging. The effect of AQW051 on task-related (EMT and WMT) brain activation and performance was also assessed, as were safety and tolerability. RESULTS Overall, 60 of 68 enrolled participants completed the study (AQW051 then placebo: 7.5mg n=9; 50mg n=11; 100mg n=10. Placebo then AQW051: 7.5mg n=10; 50mg n=11; 100mg n=9). Significant task-related brain activation (5% significance level) was observed with placebo. During the WMT, a medium effect size was observed in the inferior prefrontal cortex with AQW051 100mg versus placebo (0.431; p=0.105). During the EMT encoding phase, a large effect size was observed in the anterior hippocampus (0.795; p=0.007) and a medium effect size in the posterior hippocampus (0.476; p=0.079) with AQW051 7.5mg. No other medium/large effect sizes were observed with any dose on either task. Effects on brain activation were generally not associated with changes in cognitive performance. AQW051 was well tolerated with an acceptable safety profile. CONCLUSIONS Overall, no consistent effects of AQW051 on brain regions involved in the performance of a WMT or EMT were observed; however, this study presents a model for evaluating potential response to pharmacological interventions for cognitive impairment in schizophrenia.

WHY AND HOW WE THINK THAT CLINICAL TRIALS OF THERAPIES FOR ALZHEIMER’S DISEASE CAN BE SUCCESSFUL: A SIMULATION PLATFORM FOR PRECLINICAL AD

population had DDIs (average of 7.12 per person, SD 6.7), and 37% had DGIs (average of 1.98 per person, SD 1.3). 9% of the population had an ACB score of three or higher. The algorithm then provided actionable advice for physicians to revise medication issues. Conclusions:MM is a complex task, amplified when dealing with an older population who are not only on more medications, but also have existing comorbidities and alternate pharmacokinetics. CDSS can better enable MM, through its ability to consider a full list of medications, comorbidities, and complex medical recommendations (such as Beers Criteria), reduce redundancies, reduce DDIs and DGIs, and recommend better alternatives. CDSS can generate effective and highly-usable guidelines for each recommended change (deprescribing methodologies, changing dosages or formulations, replacing with alternatives, and scheduling). Continued study of the impact of medications on this population with cognitive decline is warranted.

INSIGHTS TO MODEL ALZHEIMER’S PROGRESSION IN REAL LIFE (IMAP): RATIONALE, OBJECTIVE, AND METHODOLOGY

Background: Investigative treatment strategies in Alzheimer’s disease (AD) are now focused on testing disease modifying therapies (DMTs) in pre-dementia stages including subjects at risk of developing AD. The APCC (Alzheimer’s Prevention Initiative Cognitive Composite) and RBANS (Repeatable Battery for the Assessment of Neuropsychological Status) are two sensitive cognitive function scales aimed at tracking changes in pre-dementia AD. In order to better understand the clinical meaningfulness of early APCC and RBANS score changes, disease models are needed to help predict long-term outcomes. The intend of the study is to collect realworld, longitudinal data in order to develop an empirically-derived disease model and to validate the clinical primary endpoint, APCC Test Score and the secondary endpoint, RBANS. Methods: IMAP (Insights to Model Alzheimer’s Progression in real life) is a 5-year, prospective, longitudinal, non-interventional cohort study in AD that intends to collect real-world data to increase the understanding of the disease, help develop robust disease models, and validate the APCC and RBANS instruments. In this non-interventional cohort study, approximately 1300 subjects will be included from ongoing cohort studies across the US and Europe, and will be followed annually for 5 years. Participants (age >60-80 years) will be recruited irrespective of the disease stage and will be categorized by clinical diagnostic group and APOE status. The study should enable simulation of an individual throughout the full spectrum of the disease until death, including early measures of cognitive decline (APCC), APOE genotype, age, biomarkers, cognitive function, functional ability and behavioral symptoms. Results: IMAP will provide an opportunity to better understand the natural history of AD and demonstrate how changes in APCC and RBANS as separate measures of early decline in cognitive function predict long term, clinically meaningful, outcomes or events. Conclusions: This study will provide updated disease progression data on the full continuum of AD that might help better understand the relationship between outcomes in the different disease stages andmodel the individual trajectory over the full AD spectrum.