Human and Animal Research Gap Bridged by Memory Test for Alzheimer’s

Study seeks to improve translation of Alzheimer’s disease studies with virtual version of the Morris water maze — the most commonly used memory assessment in mice.

Clinical scientists at the University of California, San Francisco (UCSF) Memory and Aging Center have teamed up with preclinical researchers at the Gladstone Institutes to advance Alzheimer’s disease research by developing a comparable test of learning and memory for humans as the one most commonly used in mice. This cross-disciplinary collaboration is a first in neurological disease research.

Mouse models are useful for studying Alzheimer’s disease, but they have their limitations when comparing results in humans. To date, all promising drugs that cured or prevented dementia in mice have failed in the clinic. One potential reason for this discrepancy is that the laboratory tests used in animal models of the disease do not resemble the clinical assessments given to patients, and thus are not predictive of human memory performance.

In the new study, published in the Journal of Clinical Investigation, preclinical and clinical scientists came together to address this problem. They developed a virtual version of the Morris water maze–a widely used method of assessing learning and memory in mice–so that results could be compared more easily and accurately across species.

“So far, there has been a poor track record of moving things from preclinical discoveries into successful clinical trials,” says senior author Steve Finkbeiner, MD, PhD, a senior investigator at the Gladstone Institute of Neurological Disease and a professor of neurology and physiology at UCSF. “The motivation for this research was to assess how similar the two species are in terms of problem-solving and learning in order to improve the translation of research between mice and humans. The insights we gain can help us better understand how outcomes from drug trials in a mouse might translate to a human.”

The study compared the performance of normal and Alzheimer’s disease (AD) model mice on the Morris water maze with the performance of healthy control subjects and early-stage AD patients on a video game version of the task. In the maze, mice must swim to a platform that is hidden in the water. The animals execute the task several times, which requires remembering where the platform is located based on visual cues around the pool. In the video game version, participants hunt for buried treasure in a circular field, also using visual cues from the environment to remember where the treasure is hidden.

Image shows the differences between a mouse and human hippocampus.
Both assessments test spatial learning and require proper activation of the hippocampus, a brain structure that is one of the regions affected earliest in Alzheimer’s disease. Both the patients and AD model mice were significantly impaired in terms of the distance traveled and the time it took for them to locate the hidden object. Image is adapted from the UCSF Memory and Aging Center video.

Both assessments test spatial learning and require proper activation of the hippocampus, a brain structure that is one of the regions affected earliest in Alzheimer’s disease. Both the patients and AD model mice were significantly impaired in terms of the distance traveled and the time it took for them to locate the hidden object.

Previous adaptations of the Morris water maze for humans varied significantly from the original in their design and performance measures. In contrast, the current virtual version included the same design and metrics as the water maze. The study also used different statistical methods than previous investigations, critically analyzing the animal and human data together, which improved test sensitivity across the two species.

“The beauty of this translational work is that we merged the studies and performed all of the analysis using the same methodology, so for the first time we were able to compare deficits directly across species,” says co-first author Pascal Sanchez, PhD, a staff research scientist at Gladstone. “It was fascinating to observe that both mouse models of Alzheimer’s disease and patients in the early stage of this condition had very similar levels of deficits on the task. We can now test therapeutic strategies using the same memory test across species.”


Numerous clinical trials for Alzheimer’s disease have been motivated by promising results from mouse models, but these trials have failed to produce any disease-modifying therapies for Alzheimer’s disease. One concern in the field is that the measures of disease severity or treatment efficacy used in mice do not translate well to humans. In other words, a basic science researcher might show that a treatment improves performance on the Morris Water Maze, but then an entirely different outcome (like the ADAS-cog) is used the test the therapeutic in human patients. If we had similar outcome measures across species, we may be able to better predict which treatments that work in mice will also work in humans. With this in mind, we created a virtual version of the Morris Maze and administered it to humans with and without very early Alzheimer’s disease, and compared the data to data from mice with a form of Alzheimer’s disease on the standard Morris Water Maze. Based on our findings, we recommend the best ways to administer the Morris Maze and analyze the data across species. To our knowledge, this is the first time that a behavioral assay such as the Morris Maze has been examined across species.

The new test is being used in research programs at the UCSF Memory and Aging Center, which employs advanced diagnostic techniques, including genetics, imaging, behavioral assessments, neurology, and neuropsychology to treat people with age-related brain diseases. “It is exciting to integrate the basic science research of the Gladstone Institutes with the clinical science of the Memory and Aging Center,” says co-first author Kate Possin, PhD, an assistant professor of neuropsychology at the UCSF Memory and Aging Center. “We think that this type of close collaboration will lay the groundwork for finding a cure for Alzheimer’s disease.”

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Other researchers on the study include Clifford Anderson-Bergman, Allyson Davis, and Iris Lo from the Gladstone Institutes, and Erica Johnson, Nick Bott, Tom Kiely, Michelle Fenesy, Bruce Miller, and Joel Kramer from the UCSF Memory and Aging Center. Scientists from Stanford University and Microsoft Research also took part in the work.

Funding: Funding was provided by the National Institute on Aging, the National Institute of Neurological Disorders and Stroke, a National Institutes of Health Extramural Research Facilities Improvement Program Project, the Larry L. Hillblom Foundation, the Hellman Family Foundation, the Taube/Koret Center for Neurodegenerative Diseases, the American Federation for Aging Research, and the McKnight Endowment Fund for Neuroscience.

Source: Dana Smith – Gladstone Institute
Image Source: The image is adapted from the UCSF Memory and Aging Center video
Video Source: The video is available at the UCSF Memory and Aging Center YouTube page
Original Research: Full open access research for “Cross-species translation of the Morris maze for Alzheimer’s disease” by Katherine L. Possin, Pascal E. Sanchez, Clifford Anderson-Bergman, Roland Fernandez, Geoffrey A. Kerchner, Erica T. Johnson, Allyson Davis, Iris Lo, Nicholas T. Bott, Thomas Kiely, Michelle C. Fenesy, Bruce L. Miller, Joel H. Kramer, and Steven Finkbeiner in Journal of Clinical Investigation. Published online January 19 2016 doi:10.1172/JCI78464


Abstract

Cross-species translation of the Morris maze for Alzheimer’s disease

Analogous behavioral assays are needed across animal models and human patients to improve translational research. Here, we examined the extent to which performance in the Morris water maze — the most frequently used behavioral assay of spatial learning and memory in rodents — translates to humans. We designed a virtual version of the assay for human subjects that includes the visible-target training, hidden-target learning, and probe trials that are typically administered in the mouse version. We compared transgenic mice that express human amyloid precursor protein (hAPP) and patients with mild cognitive impairment due to Alzheimer’s disease (MCI-AD) to evaluate the sensitivity of performance measures in detecting deficits. Patients performed normally during visible-target training, while hAPP mice showed procedural learning deficits. In hidden-target learning and probe trials, hAPP mice and MCI-AD patients showed similar deficits in learning and remembering the target location. In addition, we have provided recommendations for selecting performance measures and sample sizes to make these assays sensitive to learning and memory deficits in humans with MCI-AD and in mouse models. Together, our results demonstrate that with careful study design and analysis, the Morris maze is a sensitive assay for detecting AD-relevant impairments across species.

“Cross-species translation of the Morris maze for Alzheimer’s disease” by Katherine L. Possin, Pascal E. Sanchez, Clifford Anderson-Bergman, Roland Fernandez, Geoffrey A. Kerchner, Erica T. Johnson, Allyson Davis, Iris Lo, Nicholas T. Bott, Thomas Kiely, Michelle C. Fenesy, Bruce L. Miller, Joel H. Kramer, and Steven Finkbeiner in Journal of Clinical Investigation. Published online January 19 2016 doi:10.1172/JCI78464

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