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. 2013 Jul 9;110(28):11606-11.
doi: 10.1073/pnas.1221536110. Epub 2013 Jun 24.

Intrinsic connectivity networks in healthy subjects explain clinical variability in Alzheimer's disease

Manja Lehmann  1 , Cindee M Madison, Pia M Ghosh, William W Seeley, Elizabeth Mormino, Michael D Greicius, Maria Luisa Gorno-Tempini, Joel H Kramer, Bruce L Miller, William J Jagust, Gil D Rabinovici
Affiliations

Intrinsic connectivity networks in healthy subjects explain clinical variability in Alzheimer's disease

Manja Lehmann et al. Proc Natl Acad Sci U S A. .

Abstract

Although previous studies have emphasized the vulnerability of the default mode network (DMN) in Alzheimer's disease (AD), little is known about the involvement of other functional networks and their relationship to clinical phenotype. To test whether clinicoanatomic heterogeneity in AD is driven by the involvement of specific networks, network connectivity was assessed in healthy subjects by seeding regions commonly and specifically atrophied in three clinical AD variants: early-onset AD (age at onset, <65 y; memory and executive deficits), logopenic variant primary progressive aphasia (language deficits), and posterior cortical atrophy (visuospatial deficits). Four-millimeter seed regions of interest were used to obtain intrinsic connectivity maps in 131 healthy controls (age, 65.5 ± 3.5 y). Atrophy patterns in independent cohorts of AD variant patients and their correspondence to connectivity networks in controls were also assessed. The connectivity maps of commonly atrophied regions of interest support posterior DMN and precuneus network involvement across AD variants, whereas seeding regions specifically atrophied in each AD variant revealed distinct, syndrome-specific connectivity patterns. Goodness-of-fit analysis of each connectivity map with network templates showed the highest correspondence between the early-onset AD seed connectivity map and anterior salience and right executive-control networks, the logopenic aphasia seed connectivity map and the language network, and the posterior cortical atrophy seed connectivity map and the higher visual network. Connectivity maps derived from controls matched regions commonly and specifically atrophied in the patients. Our findings indicate that the posterior DMN and precuneus network are commonly affected in AD variants, whereas syndrome-specific neurodegenerative patterns are driven by the involvement of specific networks outside the DMN.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Task-free intrinsic connectivity network maps in healthy individuals produced by seeding three regions that were commonly atrophied in AD variants, as well as the overlap of the three connectivity maps. Shown are statistical P maps after correction for multiple comparisons (FWE, P < 0.05). Bottom panel also shows the overlap of each connectivity map as well as the overlap region between the three maps with the best-fitting network templates, as revealed by GOF analysis.
Fig. 2.
Fig. 2.
Task-free intrinsic connectivity network maps in healthy individuals produced by seeding three regions that were specifically atrophied in AD variants. Shown are statistical P maps after correction for multiple comparisons (FWE, P < 0.05).
Fig. 3.
Fig. 3.
Overlap of seed-based connectivity networks of specifically atrophied ROIs with best-fitting functional network templates. The EOAD seed connectivity map showed two strong fits: the anterior salience network showed the best fit with the left hemisphere connectivity map, and the right executive-control network showed the best fit with the right connectivity map. The lvPPA seed and PCA seed connectivity maps showed the best fit with the language and higher visual networks, respectively.
Fig. 4.
Fig. 4.
Patterns of gray matter atrophy in each patient group compared with controls (Left, false discovery rate-corrected P < 0.05), and specifically in each patient group compared with the other two (Right, uncorrected P < 0.01).
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