Scott Small, M.D.

Research Summary
fMRI is used to investigate normal and abnormal hippocampal function. Investigating hippocampal circuits during normal memory and memory failure.

The hippocampal formation functions as a three-dimensional network. We have been developing MRI approaches that allow us to interrogate the hippocampus as a circuit in humans and, most recently, in mice. Our interests are split between using these imaging approaches to understand how the hippocampus functions during normal associative memory, and how the hippocampus fails during aging and Alzheimer’s disease. We have focused on the longitudinal axis of the hippocampus in our studies of normal memory where we have human subjects process auditory and visual stimuli, in isolation or paired in time. Results from these studies suggest specific circuit mechanisms for how the hippocampus encodes and combines information during associative memory. We are currently extending this area of investigation into mice, which will allow us to uncover potential cellular and molecular mechanisms that underlie these circuit mechanisms.

We have focused on the transverse axis of the hippocampal formation in our efforts to understand how the hippocampus fails in aging and Alzheimer’s disease. Toward this goal, we have developed novel imaging approaches that measure hippocampal function with microscopic resolution. These approaches allow us to assess the multiple hippocampal subregions that make up the transverse circuit-- individually to pinpoint the site of dysfunction, and simultaneously to correct for circuit-wide effects. We have used this approach to generate patterns of hippocampal dysfunction in humans with Alzheimer’s disease and normal aging, as well as in mouse models with Alzheimer’s disease and normal aging. Taken together, the results suggest that MRI maps of hippocampal dysfunction can dissociate causes of memory decline. We are currently testing whether these MRI approaches can be used as a diagnostic tool for early Alzheimer’s disease, and whether these MRI approaches can be exploited for drug development.

Selected Publications:
1. Davis HP, Small SA, Stern Y, Mayeux R, Feldstein SN, Keller FR. Acquisition, recall, and forgetting of verbal information in long-term memory by young, middle-aged, and elderly individuals. Cortex. 2003 Sep-Dec;39(4-5):1063-91.

2. Small, S.A. (2002). The longitudinal axis of the hippocampal formation: Its anatomy, circuitry and role in cognitive function. Rev. Neurosci., 13: 183-194

3. Small, S.A., Tsai, W.Y., DeLaPaz, R., Mayeux, R., Stern, Y. (2002). Imaging hippocampal function across the human life span: Is memory decline normal or not? Ann. Neurol., 51: 290-295.

4. Small, S.A., Nava, A.S., Tsai, W.Y., DeLaPaz, R., Mayeux, R., Stern, Y. (2001). Circuit mechanisms underlying memory encoding and retrieval in the long axis of the hippocampal formation. Nature Neuro., 442-449.

5. Small, S.A., Wu, E.X., Bartsch, D., Perera, G.M., Lacefield, C.O., DeLaPaz, R., Mayeux, R., Stern, Y., and Kandel, E.R. (2000). Imaging physiologic dysfunction of individual hippocampal subregions in humans and genetically modified mice. Neuron, 28: 653-664.

6. Small, S.A., Perera, G.M., DeLaPaz, R., Mayeux, R., and Stern, Y. (1999). Differential regional dysfunction of the hippocampal formation among elderly with memory decline and Alzheimer’s disease. Ann. Neurol., 45: 466-472.

1. Longitudinal analysis of age related memory decline
In a series of preliminary studies the candidate has recently identified an experimental design that demonstrates age-related memory decline using longitudinal data. The first research goal of this proposal is for the candidate to apply this knowledge to community- based elderly individuals followed prospectively, in an attempt to better document age-related memory decline. The causes of age-related memory decline remain unknown but likely include early Alzheimer's disease (AD) as well as other physiological processes that change in an age-dependant manner. The candidate has recently developed a method using functional magnetic resonance imaging (fMRI) to study elderly individuals with memory decline. Preliminary findings suggest that this method can dissociate individuals into those with an AD-like pattern of brain dysfunction and those with a separate pattern of dysfunction. The second research goal is to validate-that the fMRI method can dissociate different etiologies by following the clinical course of individuals with memory decline prospectively.
National Institute on Aging
9/30/2000-8/31/2005

Honors and Awards

Irving Center Scholar Award

AFAR Paul Beeson Physician Faculty Scholar in Aging Research Award: Functional analysis of the hippocampal formation in age-related memory decline.

Alzheimer's disease, aging, hippocampus, memory disorder, short term memory, entorhinal cortex, longitudinal human study, behavioral /social science research tag, clinical research, functional magnetic resonance imaging, human middle age (35-64), human old age (65+), human subject, neuropsychological test, postmortem