Considering how combinatorial interventions may promote neurocognitive plasticity

307 Dementia is a looming and costly target for treatment and prevention given its current irreversibility. In the United States, the prevalence of Alzheimer’s disease (AD) is expected to rise fourfold, to 8.6 million, over the next 50 years (Ziegler-Graham et al., 2008 ). Effective interventions are critically needed in early AD and preclinical stages of mild cognitive impairment (MCI; Petersen et al., 2001 ), when neural architecture may be suffi ciently plastic, to help slow declines in both cognitive and independent functioning. At present, acetyl cholinesterase inhibitors (ChEIs; donepezil, rivastigmine, and galantamine) remain among the most effective pharmacologic agents to treat clinical symptoms of AD. ChEIs increase neural plasticity through increases in intracellular calcium to improve the effi ciency of synapses broadly (Gu, 2003 ; McCormick & Prince, 1985 ). However, long-term treatment with donepezil in MCI patients has not been effi cacious in mitigating progression to AD (Jack et al., 2008 ; Petersen et al., 2005 ). The introduction of behavioral cognitive training interventions in early AD and MCI is not without challenges either and has yielded equivocal support (Clare et al., 2003 ). Such interventions, as currently designed, train to a specifi c skill and have observed limited transfer and short-lived cognitive benefi ts (Loewenstein et al., 2004 ; Verhaeghen et al., 1992 ). In healthy older adults, the largest randomized trial of processspecifi c cognitive training, the Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE) study (Jobe et al., 2001 ), led to improved or maintained training-specifi c gains in memory, inductive reasoning, or speed of processing outcomes through 2and 5-year follow-ups (Ball et al., 2002 ; Willis et al., 2006 ). The reasoning training arm also resulted in less self-reported functional decline. However, there was no transfer of training, thereby restricting yield for more generalized benefi ts. In addition to limited transfer, recruitment to and implementation of cognitive interventions are more labor, resource, and cost-intensive than are pharmacologic interventions. As a result, any null fi ndings may serve to further dampen enthusiasm for future efforts. In this context, it is important to consider how to optimize cognitive training effects in order to boost memory and other abilities important to independent function. Some studies have recently found that memory strategy training and socialization (Bottino et al., 2005 ) and multidomain cognitive test training (Rozzini et al., 2007 ) produce evidence of short-term benefi t in MCI and AD patients taking ChEIs. In this issue of JINS , Gonzalez-Rothi et al. report on an innovative Phase I study over a 3-month interval in six patients with probable AD and taking donepezil. They theorized that this ChEI may potentiate learning during daily life and that targeted learning opportunities may amplify the effects of ChEI on language naming abilities in AD. These individuals participated in targeted word production practice using an “errorless learning” strategy (Baddeley & Wilson, 1994 ; Bottino et al., 2005 ). Briefl y, following baseline assessment of confrontation naming ability, participants received two sequential types of confrontation naming training that varied level of trainer support. In the fi rst “simultaneous” condition, the trainer named the picture as it was presented, and in the second “delayed” condition, the trainer waited 3 s to allow participants to name the object, if able. Three of the six participants (50%) showed signifi cant improvements in verbal naming of trained items relative to baseline. No improvements were observed for a control, Clock Drawing, task. Nonresponsiveness to training among the other three participants may have been due to differences in baseline dementia severity, as indexed by poorer global and domain-specifi c cognitive functions, and living conditions. Overall, these fi ndings suggest that cognitive training may be effective when paired with ChEIs. These promising initial fi ndings in individuals with early AD provide compelling support for next-level studies using this combinatorial intervention approach, randomizing AD and MCI patients to a combined or a donepezil-only control group. NEUROBEHAVIORAL GRAND ROUNDS—INTRODUCTION