09 Mar 2007

Alzheimer disease brings on a tendency to wander, and patients sometimes become disoriented even in the most familiar surroundings. What’s less well known is that problems getting around start very early in the disease. A study out in the March 6 PNAS raises the possibility that measuring subtle changes in a person’s ability to navigate could give an early warning of impending AD. This could impart a new, quite literal poignancy to Auguste D.’s famous complaint of “I have lost myself.”

In the study, Jakub Hort and colleagues at Charles University, Prague, Czech Republic, along with Jan Bures and Kamil Vlcek at the Academy of Sciences of the Czech Republic in Prague, tested elderly people in a dry-land equivalent of the Morris water maze. They found that people with mild cognitive impairment (MCI) were distinctly worse at finding a hidden goal than were their normal counterparts.

The test uncovered deficits only in people with the amnestic subtype of mild cognitive impairment, generally considered a prodromal phase of AD, not in those with non-amnestic MCI, which is not a prodrome of AD. These results raise the prospect that subtle problems with navigation might predict the onset of clinical AD. In addition, the test might be useful for longitudinal monitoring of disease, since spatial memory and navigation decline further as the disease progresses.

The researchers tested 65 patients with varying degrees of documented memory loss (probable AD, amnestic MCI where either memory only, or multiple domains were affected, non-amnestic MCI, or subjective memory complaints), plus 26 controls. The people completed a test that mimicked the Morris water maze, where mice are taught the location of a platform in a pool. The platform is then hidden or removed, and the researchers assess how well the mice remember the location by where the animals swim.

The Czech researchers developed a human analog (Kalova et al., 2005), where people are asked to go to and mark an invisible target inside a small circular arena. They learn the location of the target spot by viewing a map of the test area on a computer beforehand. Depending on just how the test is done, researchers can evaluate two different types of navigation—one where the person locates the goal relative to their own starting position (called egocentric navigation) or one where the person relies on markers on the chamber wall for guidance (allocentric navigation).

People with AD fared poorly at both types of navigation, as did people with amnestic MCI who showed impairments in multiple cognitive domains. In contrast, people with amnestic MCI who only had impaired memory (single domain amnestic MCI) did fine when they navigated from a known starting position. However, when the navigation relied on visual cues (allocentric type), or when there was a delay between viewing the map and completing the task, that group had problems. They still did better than those with AD or multi-domain MCI, and showed evidence of learning during the repeated trials, in contrast to more severely affected patients. People with non-amnestic MCI or subjective memory complaints performed as well as controls.

These results are consistent with a pathway of disease progression from early single-domain amnestic MCI through multi-domain MCI and on to AD. The navigational problems seem to stem from impaired spatial memory, suggesting that, just like episodic memory, this faculty declines before other symptoms of AD appear. A live test might be cumbersome for screening large numbers of patients, so it is reassuring that researchers obtained similar results if the volunteers performed the task on a computer rather than in the actual arena.

The selective defect in allocentric navigation in amnestic MCI presumably reflects the importance of hippocampal function in this form of navigation. It is consistent with studies in mouse models of AD where failure of allocentric navigation and impaired hippocampal function have been linked (Deipolyi et al., 2006).—Pat McCaffrey

Comments

1. • Ron Petersen
     Mayo Clinic
   • Posted: 13 Mar 2007

   This is an interesting approach to the assessment of early diagnostic tests for AD. As for the MCI aspect of the study, I think it is a nice demonstration of deficits in spatial memory in amnestic MCI, which certainly would be consistent with the underlying construct. However, if one were to include spatial navigation relatively independently of spatial memory, then that would implicate another, non-memory, domain, and suggest amnestic multiple domain MCI. As I interpret the results, the authors are postulating the former rather than the latter. I think this is an interesting approach to early diagnosis, but I am not sure how practical it might be in a clinical setting. Nevertheless, as a proof of principle, it is an unique finding.

   View all comments by Ron Petersen
2. • Mohammed Zaim
     Innovation Developpement Pierre Fabre
   • Posted: 17 Mar 2007

   This article confirms the results obtained by Ritter and the importance of spatial memory in amnestic MCI.

   References:

   Ritter E, Després O, Monsch AU, Manning L. Topographical recognition memory sensitive to amnestic mild cognitive impairment but not to depression. Int J Geriatr Psychiatry. 2006 Oct;21(10):924-9. PubMed.

   View all comments by Mohammed Zaim

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References

Paper Citations

1. Kalová E, Vlcek K, Jarolímová E, Bures J. Allothetic orientation and sequential ordering of places is impaired in early stages of Alzheimer's disease: corresponding results in real space tests and computer tests. Behav Brain Res. 2005 Apr 30;159(2):175-86. PubMed.
2. Deipolyi AR, Fang S, Palop JJ, Yu GQ, Wang X, Mucke L. Altered navigational strategy use and visuospatial deficits in hAPP transgenic mice. Neurobiol Aging. 2008 Feb;29(2):253-66. PubMed.

Further Reading

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