21 Mar 2014

Growing evidence suggests that a breakdown in the brain’s communications networks underlies the clinical symptoms of dementia. In the March 19 Neuron, researchers led by Gaël Chételat at Inserm-EPHE-Université of Caen, France, and first author Renaud La Joie, now at the University of California, Berkeley, further refine this idea, showing that networks play a more important role than regional atrophy in determining how dementia affects people’s behavior. The hippocampus, a key mediator of memory formation, shrinks in both Alzheimer’s disease and semantic dementia, but only people with the former develop memory problems. Using functional brain imaging, Chételat and colleagues found that the hippocampus anchors distinct brain networks with different jobs. Memory functions depend on the hippocampus’ connections with posterior brain regions affected in AD, and not on links to the anterior areas vulnerable in semantic dementia, the researchers report. “[The data] help us understand how two different diseases can impair the same region, and at the same time have very distinct cognitive deficits,” La Joie told Alzforum.

“I was very excited by the findings,” said Charan Ranganath at the University of California, Davis. He was not involved in the work, but had previously hypothesized that different networks might be affected in Alzheimer’s and semantic dementia (see Ranganath and Ritchey, 2012). “The data are consistent with the emerging idea that different dementing disorders progress along particular networks in the brain,” he told Alzforum.

Work by William Seeley and colleagues at the University of California, San Francisco, along with Michael Greicius at Stanford University, California, first showed that the patterns of atrophy in different neurodegenerative diseases matched up with functional brain networks (see Apr 2009 news story). This finding supports a model in which pathologic proteins spread through the brain by creeping along neuronal connections (see Apr 2012 webinar; Zhou et al., 2012). The transfer of toxic forms of Aβ and tau, among others, has been directly shown in animal models (see Nov 2010 news story; Feb 2012 news story). These studies have intensified interest in studying connectivity, and have led some researchers to dub AD a “network disease” (see Jul 2012 news story; Jul 2013 news story; Aug 2013 news story). 

Chételat and colleagues wondered if differing network connections could explain the paradox of why hippocampal atrophy does not lead to memory problems in semantic dementia. This disease causes language problems, in which patients can no longer name objects or understand words. La Joie imaged 18 patients with AD and 13 with semantic dementia, as well as 38 healthy controls, using fluorodeoxyglucose positron emission tomography (FDG-PET). FDG-PET detects brain regions with sluggish glucose metabolism, an early sign of faltering brain function. La Joie and colleagues found four regions that were selectively depressed in semantic dementia (the right and left anterior temporal cortex, subgenual cortex, and right anterior cingulate cortex), and two that were depressed only in Alzheimer’s (the precuneus and right angular gyrus). Next, the authors used resting-state functional MRI in 58 healthy volunteers to find other brain areas with synchronized activity to these six regions. This analysis revealed that all six regions communicated with the hippocampus, identifying this structure as a common hub in both diseases.

Why then does only Alzheimer’s disease cause memory loss? Previous studies found that in semantic dementia, the anterior hippocampus shrinks more than the posterior (see Chan et al., 2001; La Joie et al., 2013). The authors therefore looked for regions that synchronized specifically with these subregions in healthy volunteers. The anterior hippocampus linked to anterior brain regions, several of which matched the areas of low metabolism in semantic dementia patients. Likewise, the posterior hippocampus connected to posterior regions affected in AD. In the healthy volunteers, stronger connectivity within this posterior network correlated with better scores on tests of episodic memory, while anterior connections did not affect memory. The results suggest that only the posterior network contributes to memory abilities.

In ongoing work, Chételat and colleagues are directly measuring connectivity in patients with Alzheimer’s and semantic dementia to see if the identified networks in fact break down in these diseases. Intriguingly, the anterior and posterior networks overlap with the anterior and posterior portions, respectively, of the default mode network (DMN). The DMN activates during introspection and is an early site of Aβ deposition (see Mar 2004 news story; Feb 2009 news story). It is unclear why different dementias would hit separate portions of this network. La Joie speculated that semantic dementia might start in local anterior networks and travel from there into the anterior DMN and hippocampus.

Ashish Raj at Weill Cornell Medical College, New York, wrote to Alzforum, “The observation that the hippocampus mediates the spread of pathology in two types of dementia is a novel one, since earlier studies seemed to suggest that syndromic categories of dementia do not greatly overlap topographically.” He added that the data reinforce the idea that the same underlying disease propagation process can produce very different clinical symptoms, depending on the exact route the pathology takes through the brain. Future studies should trace anatomic connections between these regions more finely to see if pathogenic proteins directly travel along these paths, he suggested.—Madolyn Bowman Rogers

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References

News Citations

1. Network Connections: Missing Links in Neurodegeneration? 17 Apr 2009
2. Insidious Spread of Aβ: More Support for Synaptic Transmission 5 Nov 2010
3. Mice Tell Tale of Tau Transmission, Alzheimer’s Progression 3 Feb 2012
4. Communication Breakdown: Multiple Networks Decline in AD Brains 11 Jul 2012
5. Atrophy of Distinct Brain Networks May Explain Alzheimer’s Variants 12 Jul 2013
6. Brain Connectivity Reveals Preclinical Alzheimer’s Disease 29 Aug 2013
7. Network Diagnostics: "Default-Mode" Brain Areas Identify Early AD 19 Mar 2004
8. Cortical Hubs Found Capped With Amyloid 13 Feb 2009

Webinar Citations

1. “Network Epicenters” in Healthy Connectome Predict Dementia 16 Apr 2012

Paper Citations

1. Ranganath C, Ritchey M. Two cortical systems for memory-guided behaviour. Nat Rev Neurosci. 2012 Oct;13(10):713-26. PubMed.
2. Zhou J, Gennatas ED, Kramer JH, Miller BL, Seeley WW. Predicting regional neurodegeneration from the healthy brain functional connectome. Neuron. 2012 Mar 22;73(6):1216-27. PubMed.
3. Chan D, Fox NC, Scahill RI, Crum WR, Whitwell JL, Leschziner G, Rossor AM, Stevens JM, Cipolotti L, Rossor MN. Patterns of temporal lobe atrophy in semantic dementia and Alzheimer's disease. Ann Neurol. 2001 Apr;49(4):433-42. PubMed.
4. La Joie R, Perrotin A, De la Sayette V, Egret S, Doeuvre L, Belliard S, Eustache F, Desgranges B, Chételat G. Hippocampal subfield volumetry in mild cognitive impairment, Alzheimer's disease and semantic dementia. Neuroimage Clin. 2013;3:155-62. PubMed.

Further Reading

Papers

1. La Joie R, Landeau B, Perrotin A, Bejanin A, Egret S, Pélerin A, Mézenge F, Belliard S, de La Sayette V, Eustache F, Desgranges B, Chételat G. Intrinsic connectivity identifies the hippocampus as a main crossroad between Alzheimer's and semantic dementia-targeted networks. Neuron. 2014 Mar 19;81(6):1417-28. PubMed.

News

1. Dimmed Network Connections May Explain Metabolic Shortfall 10 Aug 2012
2. The Human Connectome Project: Deciphering the Brain’s Wiring 23 Oct 2012
3. Risk Genes Influence Brain Connectivity in Preclinical FTD 20 Dec 2013
4. Brain Aβ Patterns Linked to Brain Energy Metabolism 17 Sep 2010