Friday, May 11, 2007

The Overuse Theory of Alzheimer's Disease

"Past and Future Self" by Austin Houldsworth
Exploring the parallels between an expanding/contracting universe and human development.
Shown at the 2006 Darklight Festival (among other places). View the 1 min video at perpetual art machine.

As part of the symposium on Projecting the Past Into the Future: The Cognitive Neuroscience of Prospective Thought, Randy L. Buckner from the Howard Hughes Medical Institute at Harvard University spoke about his previously published hypothesis (Buckner et al., 2005; Buckner & Vincent, 2007) on how "overuse" of the default brain network contributes to the development of Alzheimer's disease [see also an earlier paper by Greicius et al., 2004]: the high metabolism of the "default mode" areas induces a toxic cellular cascade that can lead to the formation of plaques.

To quickly review, the default mode of brain function (Raichle et al., 2001) engages a certain network of brain regions (posterior cingulate and precuneus and medial prefrontal cortex) during "rest." These regions become DEactivated when people are engaged in the typical types of cognitive tasks they're asked to do in a scanner. So it's really only a "resting state" when compared to performing some active task. When asked to rest and stare at a plus sign, you may think about what you'll do over the weekend or remember where you went for dinner last night.

This default network shows a high level of resting activity (Buckner et al., 2005).

amyloid beta-containing plaques in the brain of a person who had Alzheimer's disease.
One possibility is that lifetime cerebral metabolism associated with regionally specific default activity predisposes cortical regions to AD-related changes, including amyloid deposition, metabolic disruption, and atrophy.

taken from Figure 6 (Buckner et al. , 2005): Convergence and hypothetical relationships across molecular, structural, and functional measures. Each image represents the projection of data ... onto the cortical surface of the left hemisphere. Three patterns emerge. First, regions showing default activity in young adults are highly similar to those showing amyloid deposition in older adults with AD, including both posterior cortical regions and anterior regions. Second, atrophy and metabolism disruption in AD prominently affect the posterior cortical regions also affected by amyloid deposition and less so the anterior regions. Third, the regions affected in AD and those active in default states in young adults overlap memory networks showing retrieval success effects during recognition in young adults.

Figure 7 (Buckner et al. , 2005): A schematic illustration of one possible configuration of lifelong events that lead to AD. Conducive metabolic conditions, associated with default mode activity patterns, may lead to regionally specific amyloid deposition. In turn, atrophy and dementia may then result. This metabolism cascade should be considered a hypothesis.

Plausible or not?? The posterior cortical areas are especially affected, but medial prefrontal cortex not so much. And what is the toxic cellular cascade that leads to amyloid deposition?


Buckner RL, Snyder AZ, Shannon BJ, LaRossa G, Sachs R, Fotenos AF, Sheline YI, Klunk WE, Mathis CA, Morris JC, Mintun MA. (2005). Molecular, structural, and functional characterization of Alzheimer's disease: evidence for a relationship between default activity, amyloid, and memory. J Neurosci. 25:7709-17.

Buckner RL, Vincent JL. (2007). Unrest at rest: Default activity and spontaneous network correlations. Neuroimage Jan 25; [Epub ahead of print]

Greicius MD, Srivastava G, Reiss AL, Menon V. (2004). Default-mode network activity distinguishes Alzheimer's disease from healthy aging: evidence from functional MRI. Proc Natl Acad Sci 101:4637-42.

Raichle ME, MacLeod AM, Snyder AZ, Powers WJ, Gusnard DA, Shulman GL. (2001). A default mode of brain function. Proc. Natl. Acad. Sci. 98: 676–682.

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