The data reinforce the idea that AD is a network disease that affects the whole brain, said Ashish Raj at Weill Cornell Medical College, New York City (see ARF Webinar). He was not involved in the research. Raj pointed out that structural MRI studies show brainwide shrinkage as AD progresses (see, e.g., Apostolova et al., 2007; Apostolova and Thompson, 2008), which suggests to him that function may also decline across the brain. “I’m really happy that this has now been demonstrated with resting-state data. It’s a valuable contribution,” Raj said.

The brain’s default-mode network (DMN) has garnered the lion’s share of the attention in previous functional studies. This set of connected regions occupies a central position in the brain and is most active when a person is not engaged in a specific task. Numerous studies have shown that DMN connectivity drops as AD progresses (see, e.g., ARF related news story on Greicius et al., 2004; ARF related news story on Sorg et al., 2007). These regions are also the first to get gummed up with β amyloid (see ARF related news story), which may invade linked regions by traveling through the brain’s wiring (see ARF related news story; ARF news story; ARF news story). But few studies have looked beyond the DMN for AD effects on functional connectivity.

To get a broader view, first author Mathew Brier examined five brain systems. These included the DMN and its opposite number, the dorsal attention network, which is active when a person is concentrating. In addition, the authors looked at the control network (involved in executive planning), the salience network (which plays a role in picking out relevant features from the environment), and the sensory-motor network. The participants in this cross-sectional study had an average age of 77. Almost 400 of them were cognitively healthy, with a clinical dementia rating (CDR) of zero; close to another 100 participants had very mild AD (CDR of 0.5), and 33 people had mild AD (CDR of 1). The authors found that for all systems except the salience network, activity within the network was less coordinated in people with higher CDR scores. The salience network showed higher connectivity at CDR 0.5, but plunged at CDR 1. Intriguingly, distinctions between some networks also collapsed in AD brains. Normally, the DMN turns off when the dorsal attention network switches on, and vice versa, but at more advanced disease stages, these patterns became muddier, the authors report. Coordination also faded between the DMN and the sensory-motor region, and the sensory-motor and control networks. “By looking at multiple networks and connections between networks, we get a more complete picture of what is going on in the disease,” Ances told Alzforum.

What this data cannot show is how this communication failure relates to AD pathology, Ances said. One possibility is that as Aβ and tau spread, they clog the circuitry and cause connections to falter. However, it is also possible that the signaling disconnection itself drives the disease, he noted. In future work, Ances plans to correlate the functional connectivity data with cerebrospinal fluid biomarkers such as tau and Aβ42 to try to place loss of connectivity into current models of biomarker progression (see ARF Webinar). If connections fail only after Aβ and tau pathology have become widespread, it would suggest that these molecules could be the culprits, Ances said.

Raj suggested that another implication of the current study is that perhaps the DMN is not so different from other brain networks. A number of studies have focused on distinctive features of the DMN, such as its metabolism or activity, to help explain why this region succumbs first to AD (see, e.g., ARF related news story on Buckner et al., 2005; ARF news story; and ARF related news story on Bero et al., 2011). However, since multiple brain networks appear to experience the same kind of connectivity losses as the DMN, maybe it has nothing to do with metabolism, Raj said. He suggested that this network may show the earliest symptoms merely because of its location in the brain. “These findings point to the need to re-evaluate the notion that some regions are selectively vulnerable,” Raj said.—Madolyn Bowman Rogers.

Reference:
Brier MR, Thomas JB, Snyder AZ, Benzinger TL, Zhang D, Raichle ME, Holtzman DM, Morris JC, Ances BM. Loss of intranetwork and internetwork resting state functional connections with Alzheimer’s disease progression. J Neurosci. 2012 Jun 27;32(26):8890-9. Abstract