Communication Breakdown: Multiple Networks Decline in AD Brains

A healthy brain switches between its different functional networks like a well-oiled machine, but as dementia takes over, communication becomes disorganized. Connections sputter, and once-sharp distinctions between networks blur, according to a paper in the June 27 Journal of Neuroscience. Researchers led by Beau Ances at Washington University, St. Louis, Missouri, used resting-state functional connectivity MRI to examine the integrity of several brain networks in healthy older adults and people with mild Alzheimer’s disease. Participants with AD showed weaker connectivity in five different brain systems than did their healthy peers, and the difference was greater in those with more advanced disease. How this functional data relates to the spread of AD pathology through the brain is not yet known.

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

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References

Webinar Citations

  1. “Network Epicenters” in Healthy Connectome Predict Dementia
  2. Together at Last, Top Five Biomarkers Model Stages of AD

News Citations

  1. Network Diagnostics: "Default-Mode" Brain Areas Identify Early AD
  2. Functional Imaging Gives Early Glimpse of AD
  3. Cortical Hubs Found Capped With Amyloid
  4. Traveling Tau—A New Paradigm for Tau- and Other Proteinopathies?
  5. Aβ the Bad Apple? Seeding and Propagating Amyloidosis
  6. Insidious Spread of Aβ: More Support for Synaptic Transmission
  7. Network News: Images of AD Brains Reveal Widespread Snafus
  8. Brain Aβ Patterns Linked to Brain Energy Metabolism
  9. Do Overactive Brain Networks Broadcast Alzheimer’s Pathology?

Paper Citations

  1. Apostolova LG, Steiner CA, Akopyan GG, Dutton RA, Hayashi KM, Toga AW, Cummings JL, Thompson PM. Three-dimensional gray matter atrophy mapping in mild cognitive impairment and mild Alzheimer disease. Arch Neurol. 2007 Oct;64(10):1489-95. PubMed.
  2. Apostolova LG, Thompson PM. Mapping progressive brain structural changes in early Alzheimer's disease and mild cognitive impairment. Neuropsychologia. 2008;46(6):1597-612. PubMed.
  3. Greicius MD, Srivastava G, Reiss AL, Menon V. Default-mode network activity distinguishes Alzheimer's disease from healthy aging: evidence from functional MRI. Proc Natl Acad Sci U S A. 2004 Mar 30;101(13):4637-42. PubMed.
  4. Sorg C, Riedl V, Mühlau M, Calhoun VD, Eichele T, Läer L, Drzezga A, Förstl H, Kurz A, Zimmer C, Wohlschläger AM. Selective changes of resting-state networks in individuals at risk for Alzheimer's disease. Proc Natl Acad Sci U S A. 2007 Nov 20;104(47):18760-5. PubMed.
  5. 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. PubMed.
  6. Bero AW, Yan P, Roh JH, Cirrito JR, Stewart FR, Raichle ME, Lee JM, Holtzman DM. Neuronal activity regulates the regional vulnerability to amyloid-β deposition. Nat Neurosci. 2011 Jun;14(6):750-6. Epub 2011 May 1 PubMed.

Further Reading

Primary Papers

  1. 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. PubMed.

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