26 September 2005. One of the earliest problems many Alzheimer patients experience is a tendency to get lost. But rather than blame failing memory, it is more likely that wanderers are impaired in their ability to tune out disruptions and focus enough brain power onto the complex task of using visual information to get them where they want to go. That’s the conclusion of a study that used PET imaging to compare the brain function of healthy older adults to those with mild cognitive impairment or AD while each navigated via computer through a virtual environment.
In healthy people, navigation based on visual cues is accompanied by activation of the visual cortex and a simultaneous deactivation of the auditory cortex. In other words, they tune out sound to focus on processing visual cues. In people with MCI or AD, however, deactivation of auditory regions was weaker or missing entirely. The report, from Alexander Drzezga and colleagues in Munich, Germany, and published September 20 in PloS suggests that failure to tone down auditory cortex activity during a visual navigation task could explain why the AD patients took longer and had to work harder to make their way through the test environment. The early appearance of deactivation deficits in MCI also suggests these changes might be useful as an early sign of incipient AD.
Another imaging study used multiple modes of brain imaging, including PET-PIB for visualizing amyloid, to tie together the biochemical, functional, and anatomical changes that take place in AD brains. The results, appearing in the August 24 Journal of Neuroscience, reveal that different techniques converge to paint a default activity network in the brain as an early and important locus of amyloid deposition and pathological changes in AD.
In the first paper, Drzezga and colleagues devised a novel method to watch the brains of healthy people or people with MCI or AD as they handled a visual navigation task. The subjects, with their heads in a PET scanner, were asked to make their way through a suite of virtual rooms via mouse clicks. Normal subjects did best on the task, successfully getting through in just over a minute on average. Those with MCI, however, averaged over 2 minutes and the AD patients took nearly 3 minutes to complete the same task.
During the test, brain activity was measured by assessing regional cerebral blood flow by PET. Patterns of brain activation showed that normal people used higher order visual processing and more automation of tasks than did MCI or AD patients, who had the highest activity in primary visual cortex and lower brain structures.
But for this study, the investigators looked further, at areas of the brain that were deactivated during the task. In the past, researchers have separately measured activation and deactivation in the AD brain, but no one had looked at both in the same task. Regression analysis showed a linear relation between MMSE scores and the extent of auditory cortex deactivation, suggesting a direct association of failure of deactivation and reduced ability in spatial navigation.
The failure of cross-inhibition showed up clearly in people with MCI, a group who are at risk for AD but have not yet converted. The authors describe a pilot study with 15 patients with MCI who were evaluated for deactivation and then followed for 2 years. None of the eight with an intact deactivation response had progressed to AD after 2 years, while all seven of the others had. “Differences in cerebral activation patterns have been previously considered to be useful for the early diagnosis of AD; the present results indicate that it may be even more effective to direct one’s attention to changes in cerebral deactivation patterns,” they conclude.
The other imaging study, this one from Randy Buckner and colleagues including John Morris and Mark Mintun at Washington University in St. Louis, along with Bill Klunk and Chet Mathis at the University of Pittsburgh, also implicates a neural network in AD progression and pathology. By comparing data from five different in vivo imaging modalities, including PIB-PET scans for amyloidal and other anatomic and functional measures, the researchers tried to connect the dots between amyloid protein deposition, brain structure, and compromised function in AD.
In the final analysis, all indicators pointed to important changes occurring mainly in posterior cortical regions. Overlapping patterns of amyloid deposition, atrophy, and metabolic abnormalities suggested the presence in that region of some sort of network that is disrupted early in AD.
There was also a surprising concordance between areas of amyloid deposition in older adults and the areas that showed default activity in young adults. Default activity is defined as what the brain does when it’s not really doing anything. Sometimes likened to daydreaming, or a way of internal monitoring of brain activity, the default pathway seems to be important in memory, and the authors show by fMRI that parts of this region take part in successful memory retrieval in young subjects. While it is known that default network activity is disrupted in AD (see ARF related news story), Buckner and colleagues go further to show that the anatomical regions involved in default activity also accumulate amyloid and eventually display metabolic abnormalities and structural changes. Putting this all together, the authors speculate that there may be a relationship between levels of brain or metabolic activity over many years and subsequent amyloid deposition in the posterior cortical areas. The damage done early in this region could be part of the reason AD strikes preferentially at memory functions.
The imaging data from both these studies point to a shift in how researchers understand AD pathology, according to Harvard’s Reisa Sperling. Attention is turning away from just looking at the temporal lobe and parts of the brain that are activated by specific tasks, to looking at broader areas, default activity, and deactivation for clues to how AD brings down not just neurons, but whole networks as well.—Pat McCaffrey.
Buckner RL, Snyder AZ, Shannon BJ, LaRossa G, Sachs R, Fotenos AF, Sheline YI, Klunk WE, Mathis CA, Morris JC, Mintun MA. Molecular, structural, and functional characterization of Alzheimer's disease: evidence for a relationship between default activity, amyloid, and memory. J Neurosci. 2005 Aug 24;25(34):7709-17. Abstract
Drzezga A, Grimmer T, Peller M, Wermke M, Siebner H, Rauschecker JP, Schwaiger M, Kurz A. Impaired Cross-Modal Inhibition in Alzheimer Disease. PLoS Med. 2005 Sep 20;2(10):e288 [Epub ahead of print] Abstract