Affiliations: [a] Bracket LLC, Reading, UK
| [b] Wesnes Cognition Ltd, Streatley on Thames, UK
| [c] Medical School, University of Exeter, Exeter, UK
| [d] Department of Psychology, Northumbria University, Newcastle, UK
| [e] Centre for Human Psychopharmacology, Swinburne University, Melbourne, Australia
| [f] Bracket LLC, Boston, MA, USA
Correspondence:
[*]
Correspondence to: Pascal Goetghebeur, Bracket LLC. The Blade, 11th floor, Abbey Square, Reading RG1 3BE, United Kingdom. Tel.: +44 (0)118955 1740; E-mail: [email protected].
Abstract: Recent fMRI studies in human identified that pattern separation ability is associated with increased activity in the hippocampal dentate gyrus (DG), whereas no such DG changes are seen during pattern completion. Disruption to neurogenesis in the DG has been associated with Alzheimer’s disease (AD). In a post-hoc analysis of two large unsuccessful AD clinical trials, we examined the effect of D-cycloserine (DCS) on a specific object pattern separation measure, a component of the picture recognition task from the Cognitive Drug Research (CDR) system. This task yields a measure of pattern separation and a measure of pattern completion. Study data were available for 756 AD patients with dementia, randomized to several doses of DCS. Data were available at week 2, 6, 14, and 26 for 732, 707, 653, and 559 patients, respectively. None of the DCS doses had a statistically significant benefit over placebo on pattern completion. However, the DCS 15 mg BID dose significantly increased accuracy over placebo on the pattern separation measure by 5.1%. Further, the magnitude of the benefit of DCS 15 mg BID over placebo was almost doubled relative to the whole study population in a subset of patients whose pattern separation scores were≥2 standard deviations poorer than the CDR norm of age-matched healthy individuals at baseline. These post-hoc analyses suggest a potential value of the pattern separation task for evaluating compounds promoting neurogenesis. Further, the use of a restrictive pattern separation eligibility criterion might facilitate signal detection.
