Neural and cognitive substrates of Alzheimer's disease-related navigation deficits.

摘要

Navigation impairments are common among Alzheimer's disease (AD) patients and have a devastating impact on daily functioning. To understand the neural and cognitive bases for these impairments, I studied spatial disability in human patients and a transgenic mouse model of AD. Mice were tested with a specialized maze that distinguished allocentric (world-based) hippocampus-dependent strategies from egocentric (self-based) striatum-dependent strategies. I also measured AD-related pathology in the hippocampus and striatum of these mice. Whereas almost all nontransgenic mice used allocentric strategies, more than half of transgenic mice engaged egocentric strategies. In transgenic mice, the hippocampus had significantly lower levels of synaptic activity-dependent proteins and higher levels of amyloid-beta (Abeta) than the striatum, which was relatively spared, paralleling the strategy alterations. Transgenic mice that used hippocampus-independent strategies learned better than those that persistent engaged the hippocampus. Therefore, flexibility in selecting learning strategies may impact the severity of navigation deficits in AD. Encouraging transgenic mice and potentially AD patients to engage hippocampus-independent strategies could alleviate some spatial disability. To study humans, I used a route-learning task to test mild AD and mild cognitive impairment (MCI) patients, and voxel-based morphometry to assess structural changes in brain regions critical for human navigation. AD and MCI patients recalled having seen landmarks, but not when or where they saw them. About half of the patients got lost on the route, though traditional measures of disease severity did not predict who got lost. Patients who got lost had significant atrophy in putative neural components of the human navigation network, including the right posterior hippocampus. Thus, distinct patterns of atrophy may yield specific cognitive deficits. Knowing what neural regions are damaged by disease may predict which patients are at risk for navigational disability. In summary, parallel investigations in transgenic mice and human patients suggested a central role of hippocampal dysfunction in AD-related spatial disability and elucidated mechanisms that could be potential therapeutic targets.