D-Cycloserine Improves Difficult Discriminations in a Pattern Separation Task in Alzheimer’s Disease Patients with Dementia

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.

Deficits in N-Methyl-D-Aspartate Receptor Function and Synaptic Plasticity in Hippocampal CA1 in APP/PS1 Mouse Model of Alzheimer’s Disease

“…For example, Aβ recruited internalization of synaptic NMDARs and the reduction of NMDAR-mediated currents in the cultured cortical neurons ( Snyder et al, 2005 ). In addition, some novel therapies modulating NMDAR function have been shown to restore cognitive function in clinical trials ( Goetghebeur et al, 2019 ; Lin et al, 2021 ). Taken together, there is growing evidence of NMDAR-associated synaptic abnormalities in AD, which is consistent with our results that NMDAR-mediated sEPSCs were reduced in hippocampal CA1 with impaired synaptic plasticity in APP/PS1 mice.…”

Therapeutics for neurodegenerative diseases by targeting the gut microbiome: from bench to bedside

“…These findings imply that the effects of antibiotics can vary depending on the timing, duration, and pharmacological actions of the antibiotics. A clinical trial revealed that both short-term and long-term treatment with D-cycloserine can improve the cognitive functions of AD patients [ 168 ]. However, retrospective studies have indicated that broad- and narrow-spectrum antibiotics increase the risks of overall dementia and AD [ 169 , 170 ].…”

A combined DHA-rich fish oil and cocoa flavanols intervention does not improve cognition or brain structure in older adults with memory complaints: results from the CANN randomized, controlled parallel-design study

“…Five composite measures of cognitive ability can then be derived from these tasks, as follows: Power (speed) of Attention, Continuity (accuracy) of Attention, Quality of Working Memory, Quality of Episodic Secondary Memory, and Speed of Memory. The primary efficacy endpoint was hippocampus dentate gyrus-sensitive cognitive function, assessed by the number of false-positives on the Picture Recognition Task of the CDR [ 38 ]. Details on how the cognitive composite scores were calculated can be found here [ 39 ].…”