A new type of testing maze for laboratory mice, developed at Cedars-Sinai, shows promise for helping investigators study and identify early dysfunctions of Alzheimer's disease, according to a recent study published in the journal Scientific Reports.

The behavioral visual-stimuli four-arm maze (ViS4M) is an X-shaped enclosure with controlled colored lights or grayscale objects that precisely tests the animals' reactions to changing light intensity, color and contrast.

In experiments, the maze piqued the natural curiosity of healthy mice into exploring the multicolored corridors and tested their ability to recall previous entries. Aged mice and genetically engineered mouse models of Alzheimer's disease were less able to recall the last entry arm, so they alternated less frequently between arms. This behavior, which was dependent on the specific color or contrast-object stimulation, exhibited impaired color and contrast vision.

Alzheimer's disease is a devastating, progressive neurodegenerative disorder that impacts critical thought and memory. Symptoms typically start after age 60, with the risk increasing with advancing age. As the population in the U.S. ages, cases are predicted to increase.

"Currently, there are few ways to detect early Alzheimer’s disease, and clinical diagnosis has been largely focused on cognitive and psychiatric decline," said Maya Koronyo-Hamaoui, PhD, principal investigator of the study and associate professor of Neurosurgery and Biomedical Sciences. "But studies have shown that retinal abnormalities and visual impairments can appear early in disease progression. We designed our new maze with the goal of discovering visual abnormalities and the potential relationship with retinal and brain damage related to Alzheimer’s disease."

Utilizing their own curcumin imaging technology, the investigators had previously demonstrated the capacity to noninvasively detect and quantify amyloid plaque pathology in the Alzheimer’s retina.

Koronyo-Hamaoui, Yosef Koronyo, MSc, LLB and Keith L. Black, MD, professor and chair of Neurosurgery and the Ruth and Lawrence Harvey Chair in Neuroscience, are co-inventors of ViS4M maze. For the acquisition and analysis of data, they turned to the Biobehavioral Research Core at Cedars-Sinai. Jean-Philippe Vit, the former director of the core and the study's first author, and Sandrine Fuchs, a senior research associate in the Koronyo-Hamaoui lab, were instrumental in developing the optimal testing conditions to detect visual and cognitive impairments using this novel maze.

To explore color vision changes or impairments that occur in normal-aging mice versus the Alzheimer's-bred mice, the research team constructed a maze consisting of four sections that were bathed in different predefined LED colors and light intensities. Each specific color wavelength activates a unique population of retinal cells—known as photoreceptor subtypes—that are important for different visual functions and color discrimination.

The X-maze takes into account the dichromatic vision of mice and the distribution of the photoreceptor subtypes across the mouse retina. The maze also is utilized to assess contrast sensitivity through the use of various grayscale shaded objects.

Upon entering the ViS4M, the mice were fully immersed in a visual stimuli space that they could explore freely, with no forced choices, introduction of rewards or prior training—important features of the study. The investigators collected data related to spatial memory recall or cognitive function, locomotor activity (i.e., speed) and color vision. This data included time spent and number of entries in each colored arm as well as transitions from one arm to another and back again.

The team found that the normal mice explored all the corridors of the maze in very specific sequential patterns, suggesting that they not only remembered the arms they had previously visited but also detected changes in color and intensity of light. By contrast, the Alzheimer’s-model mice were less able to alternate and transitioned more often between the same two arms. Repetitious movements made by these mice were not random but linked to wavelength- and intensity-specific loss of visual discrimination, reminiscent of defects documented in some Alzheimer’s patients.

To confirm their hypothesis that vision deficits were behind the behavior changes, the team scanned the retinas of the Alzheimer’s mice using noninvasive amyloid plaque imaging and precisely measured the spectral features of each arm, which activate specific rod and cone cell populations and enable animals to see light, color and shadowed objects.

"We identified early and progressive impairments in color vision and contrast sensitivity in the Alzheimer's mice," said Koronyo-Hamaoui. "Some of these vision changes were detected in the youngest age group and preceded cognitive decline in these mice."

Going forward, Koronyo-Hamaoui added, the modular X-maze could allow vision and cognitive behavioral scientists to make discoveries in rodent studies that could potentially be translated to improved human visual testing and early diagnosis of Alzheimer's disease.

Funding: Research reported in this publication was supported by the National Institute on Aging of the National Institutes of Health under award numbers R01 AG055865 and R01 AG056478, the Saban Family Foundation, the Paul Marciano Foundation and the Don S. Levin Trust.

Competing interests: Cedars-Sinai has licensed the "Visual Stimuli Maze Test for Detecting Visual Abnormalities in Prodromal Alzheimer's Disease and in Alzheimer's Disease" to Maze Engineers, 5250 Old Orchard Road, Skokie, Illinois. Ariel Angel, Aharon Levy and Itschak Lamensdorf are employees of Pharmaseed 762 Ltd., 9 Hamazmera St., Ness Ziona 74047, Israel.