Acquired equivalence is a phenomenon in which prior training to treat two stimuli as equivalent increases generalization between them. Previous studies demonstrated that the hippocampal region might play an important role in acquired equivalence associative learning. In this study, we tested the possibility that acquired equivalence learning is a sensitive marker of mild Alzheimer disease. Alzheimer's patients exhibited mild impairments in the training phase, whereas they were profoundly impaired on the acquired equivalence test. Associative knowledge could not be transferred to a more flexible retrieval condition. These results suggest that acquired equivalence learning is specifically impaired in early AD, which may indicate the pathology of the hippocampal region.

Computational modeling predicts that the hippocampus plays an important role in the ability to apply previously learned information to novel problems and situations (referred to as the ability to generalize information or simply as ‘transfer learning’). These predictions have been tested in humans using a computer-based task on which individuals with hippocampal damage are able to learn a series of complex discriminations with two stimulus features (shape and color), but are impaired in their ability to transfer this information to newly configured problems in which one of the features is altered. This deficit occurs despite the fact that the feature predictive of the reward (the relevant information) is not changed. The goal of the current study was to develop a mouse analog of transfer learning and to determine if this new task was sensitive to pathological changes in a mouse model of AD.We describe a task in which mice were able to learn a series of concurrent discriminations that contained two stimulus features (odor and digging media) and could transfer this learned information to new problems in which the irrelevant feature in each discrimination pair was altered. Moreover, we report age-dependent deficits specific to transfer learning in APP + PS1 mice relative to non-transgenic littermates. The robust impairment in transfer learning may be more sensitive to AD-like pathology than traditional cognitive assessments in that no deficits were observed in the APP + PS1 mice on the widely used Morris water maze task. These data describe a novel and sensitive paradigm to evaluate mnemonic decline in ADmouse models that has unique translational advantages over standard species-specific cognitive assessments (e.g., water maze for rodent and delayed paragraph recall for humans).

Johnson SC, Schmitz TW, Asthana S, Gluck MA, Myers CE (2008). Associative Learning Over Trials Activates the Hippocampus in Healthy Elderly but not Mild Cognitive Impairment. Aging, Neuropsychology, and Cognition, 15, 129-145.

The ability to form associations between choice alternatives and their contingent outcomes is an important aspect of learning that may be sensitive to hippocampal dysfunction in memory disorders of aging such as amnestic Mild Cognitive Impairment (aMCI), or early Alzheimer Disease. In this preliminary study we examined brain activation using functional magnetic resonance imaging (fMRI) in twelve healthy elderly participants and nine patients with aMCI during an associative learning task. Using a high-field 3.0 Tesla MRI scanner, we examined the dynamic neural response during associative learning over trials. The slope of signal attenuation associated with learning was analyzed for differences between groups within an a-priori defined hippocampal region. Results indicated dynamic signal attenuation associated with learning in the healthy elderly sample, but not in aMCI. The absence of an associative learning effect in the aMCI sample reaffirms an important link between the learning difficulties that are commonly encountered in aMCI and the medial temporal region.

Myers, C, E., Kluger, A., Golomb, J., Gluck, M. A, & Ferris, S. (2008) Learning and generalization tasks predict short-term cognitive outcome in non-demented elderly. Journal of Geriatric Psychiatry and Neurology. 21 (2). 93-103.

This study examines whether behavioral measures obtained in non-demented elderly can predict cognitive status at two-year follow-up. Prior studies have established that delayed paragraph recall can help predict short-term risk for decline to mild cognitive impairment (MCI) and Alzheimer's disease (AD). We examined whether prediction accuracy can be improved by adding a discrimination-and-generalization task that has previously been shown to be disrupted in non-demented elderly with hippocampal atrophy, a risk factor for AD. Fifty non-demented medically medically healthy elderly patients received baseline clinical diagnosis and cognitive testing; two years later, patients received a follow-up clinical diagnosis of normal, MCI, or probable AD. Two baseline variables, delayed paragraph recall and generalization performance, were predictive of follow-up outcome with sensitivity of 81% and specificity of 91% - better than the classification accuracy based on either of these measures alone. These preliminary results suggest that these behavioral tasks may be useful tools in predicting short-term cognitive outcome in non-demented elderly.

We have pursued an interdisciplinary research program to develop novel behavioral assessment tools for evaluating specific memory impairments following damage to the medial temporal lobe, including the hippocampus and associated structures that show pathology early in the course of Alzheimer's disease (AD). Our approach uses computational models to identify the functional consequences of hippocampal-region damage, leading to testable predictions in both rodents and humans. Our modeling argues that hippocampal-region dysfunction may selectively impair the ability to generalize when familiar information is presented in novel recombinations. Converging support for the relevance of these tasks to aging and Alzheimer's disease comes from our recent fMRI studies of individuals with mild cognitive impairment (MCI). A new mouse version of one of our tasks shows promise for translating these paradigms into rodents, allowing for future studies of therapeutic interventions in transgenic mouse models of AD.

As predicted by our prior computational models, we found a double dissociation between the associative learning deficits observed in patients with medial temporal damage (elderly with mild hipocampal atrophy) versus patients with basal ganglia dysfunction (mild Parkinson’s disease). On an “acquired equivalence” task based on animal conditioning paradigms, MT subjects were normal at initial learning, but impaired on a subsequent transfer generalization. In contrast, Parkinson’s patients were slow to learn the initial task, but then transferred normally. These results suggest distinct contributions of the medial temporal lobe and basal ganglia in learning and memory.