Phase II - IV Clinical

New Draft FDA Guidelines for Alzheimer´s Disease: Which Cognitive Testing Battery Guarantees Success? - May, 2013

Recently, there has been much debate over the consequences of the new draft FDA guidelines for Alzheimer´s disease, which give improvement in cognitive performance more weight for marketing approval. According to the draft legislation, demonstration of meaningful cognitive improvement early in the disease (prodromal AD), by means of a validated testing battery, may engender at least a transient marketing approval. Of course, such an improvement must be supported by clinical studies documenting functional consequences and possibly, biomarker changes indicating a slowing of disease progression.

But which is the ideal cognitive testing battery? Traditional instruments like ADAS-Cog will not work in an early disease population because of ceiling effects and more pronounced learning tiers, compared with a fully symptomatic cohort. New cognitive testing batteries, particularly computerized tests like CogState, CDR or CANTABⓇ, must be considered. Each of these batteries consists of a series of subtests focusing on particular cognitive domains. For a successful clinical trial, such testing batteries should be custom-tailored with attention to the drug’s potential effects on specific domains. Usually, a composed Z-Score change is defined as an outcome variable, with the understanding that important information knowledge of the compound’s differential cognitive effects might reveal could be lost.

Oddly, certain domains well known to be disturbed in early disease states are currently not being tested in humans, namely, spatial orientation, learning and memory. And yet, one of the most widely used behavioral paradigms for testing new compounds under development is the Morris water maze which tests these exact cognitive functions, in rodent models. To rectify this discrepancy, QPS is collaborating closely with a new cognitive testing company, Polyhymnia-Translational Research, headed by psychologist John Harrison, a well-known expert in neuropsychological testing. This company has developed a dry-land, human version of the water maze, using a blue velvet room (Figure 1). In this round testing arena, landmarks for orientation are projected onto the wall; a target is shown on the floor. The task is simple: after a short orientation phase, the patient is asked to move to the area where the target was projected. With appropriate use of the landmarks, healthy people can readily find the exact position. As with rodents, this paradigm tests hippocampal function (allo-centric orientation), but by switching off the land marks it can also test proprio-receptive function (egocentric orientation), which is a function of the parietal lobe and can be assessed. It turns out that this test is extremely sensitive for detection of patients in the early stage of AD, with a high sensitivity for identifying amnestic MCI, indicating usefulness for patient selection into studies. At the same time, this test also reacts sensitively to drug treatment, e.g. cholinesterase inhibitors. Because the maze is not useful for multicenter studies, a computerized version (CLIO) has been developed which shows a greater than 86 % correlation with results from the blue velvet room. Cross-correlation with other cognitive domains indicates that spatial function is an independent cognitive domain which is not adequately measured by other test systems.

This type of test is vastly advantageous in that it does not depend upon language or culture, and entails practically no learning bias. Spatial orientation is an important function disturbed early in Alzheimer’s disease.  It is our hope that these new test systems will enable a higher predictive translation from preclinical behavioral data to human cognitive function.

Together with other tests, these new paradigms could contribute to a meaningful and relevant battery that will address the requirements for cognitive testing procedures in clinical development of AD treatments.

Literature:

Gazova, I., K. Vlcek, et al. (2012). "Spatial navigation-a unique window into physiological and pathological aging." Front Aging Neurosci 4: 16.

Laczo, J., R. Andel, et al. (2012). "From Morris Water Maze to computer tests in the prediction of Alzheimer's disease." Neurodegener Dis 10(1-4): 153-157.

Laczo, J., R. Andel, et al. (2011). "Spatial navigation and APOE in amnestic mild cognitive impairment." Neurodegener Dis 8(4): 169-177.

Laczo, J., R. Andel, et al. (2010). "Human analogue of the morris water maze for testing subjects at risk of Alzheimer's disease." Neurodegener Dis 7(1-3): 148-152.

Hort, J., J. Laczo, et al. (2007). "Spatial navigation deficit in amnestic mild cognitive impairment." Proc Natl Acad Sci U S A 104(10): 4042-4047.

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Fig 1: Human analogue of Morris Water Maze - translating animal data and computerized testing of subjects at risk of Alzheimer disease

Healthy animals learn to find the direct track to the escape platform. This can be compared to healthy aged humans. But AD and MCI patients fail to learn target location in the blue velvet room. Hort et al., PNAS,  2007

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