12 July 2013. Some people with Alzheimer’s pathology in their brains develop atypical clinical symptoms, such as visual problems or difficulty in naming objects. Atrophy in specific functional networks in the brain corresponds to those symptoms, report researchers led by Manja Lehmann and Gil Rabinovici at the University of California, San Francisco, in the June 24 Proceedings of the National Academy of Sciences. The researchers compared patients with three rare forms of AD: early-onset AD (EOAD), posterior cortical atrophy (PCA), and logopenic variant primary progressive aphasia (LPA). In addition to having different areas of specific atrophy, these patients share common areas of brain degeneration, the researchers found. The commonly affected areas correspond to the default mode network (DMN), which is active when the brain is not engaged in a specific task. This network degenerates in typical, amnestic AD, as well.
That the atrophy occurs along functional networks supports the idea that different types of AD spread through connected brain regions. In the variants, however, it is not yet clear whether pathology advances from common areas into specific networks, or vice versa. Longitudinal studies will be needed to answer this question, Lehmann said.
Other researchers found the data intriguing. “We know there is a lot of heterogeneity in the spatial expression of these diseases. The fact that some brain areas are common anchors is informative,” said Ashish Raj at Weill Cornell Medical College, New York City. Beau Ances at Washington University, St. Louis, Missouri, told Alzforum, “They’ve shown that these disorders have specific signatures.” The data may help begin to unravel the mystery of why AD progresses differently in different people, he said.
Prior studies have shown that compared to controls, AD patients have weaker connectivity in the DMN (see ARF related news story), as well as in multiple other brain networks (see ARF related news story). Previously, William Seeley at UCSF and Michael Greicius at Stanford University, both co-authors on the new paper, found that different forms of dementia (such as frontotemporal dementia and corticobasal syndrome) affect distinct functional networks (see ARF related news story).
In the current work, the authors turned to rare variants of AD. EOAD is characterized by memory and executive deficits, PCA by visuospatial deficits (see ARF related news story), and LPA impairs people’s ability to name objects and repeat sentences (see Bonner et al., 2010). While other forms of progressive aphasia are marked more by tau pathology and are closely related to frontotemporal dementias, LPA and PCA have predominant Aβ pathology. In a previous structural MRI study, the authors found brain atrophy in each of these three conditions (see Migliaccio et al., 2009). In the present study, Lehmann and colleagues focused on regions that showed the greatest atrophy across all three disorders, as well as regions that were specifically shrunken in each. The authors wanted to find out what functional networks these atrophied regions participate in, as a first step toward seeing whether connectivity in these networks might be altered in disease states.
To first find the networks, the authors performed resting-state functional MRI in 131 healthy volunteers with an average age of 65, and looked for brain regions that synchronized activity with the areas of interest. Regions of common atrophy among EOAD, LPA, and PCA included the posterior cingulate cortex and precuneus. In the healthy volunteers, these areas matched up with the posterior DMN and precuneus networks. Meanwhile, regions specifically atrophied in early-onset AD corresponded to the anterior salience and right executive control networks in the volunteers. Those affected in LPA formed part of language networks, while in PCA, the higher visual network was involved. Perhaps not surprisingly, the functions of these networks predict the typical clinical symptoms of each disorder. The authors then assembled an independent cohort of patients, comprising 36 with early-onset AD, 18 with LPA, and 20 with PCA, and confirmed that they had the predicted patterns of atrophy corresponding to these same networks. In ongoing work, the authors are measuring connectivity in the AD patients to look for functional disruptions in these areas, Lehmann said.
One question the study cannot answer is whether degeneration begins in the DMN and spreads from there to specific networks, or whether it begins in distinct networks and advances into the common hub of the DMN. This question can only be addressed by studying the progression of the disease in early-stage patients over time. This is difficult because these rare syndromes are typically diagnosed late, Lehmann noted. Lehmann also plans to examine genetic and developmental risk factors in search of clues for why distinct forms of AD develop in different people. For example, prior dyslexia is more common in AD patients who develop language difficulties than in those who do not, suggesting that the language network might be selectively vulnerable in this population, Lehmann said.—Madolyn Bowman Rogers.
Lehmann M, Madison CM, Ghosh PM, Seeley WW, Mormino E, Greicius MD, Gorno-Tempini ML, Kramer JH, Miller BL, Jagust WJ, Rabinovici GD. Intrinsic connectivity networks in healthy subjects explain clinical variability in Alzheimer’s disease. Proc Natl Acad Sci USA. 2013 Jun 24. Abstract