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

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.

SUBMITTER: Lehmann M

PROVIDER: S-EPMC3710820 | biostudies-other | 2013 Jul

REPOSITORIES: biostudies-other

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

Lehmann Manja M Madison Cindee M CM Ghosh Pia M PM Seeley William W WW Mormino Elizabeth E Greicius Michael D MD Gorno-Tempini Maria Luisa ML Kramer Joel H JH Miller Bruce L BL Jagust William J WJ Rabinovici Gil D GD

Proceedings of the National Academy of Sciences of the United States of America 20130624 28

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 a ...[more]

PMID: 23798398

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Project description:There is striking overlap between the spatial distribution of amyloid-? pathology in patients with Alzheimer's disease and the spatial distribution of high intrinsic functional connectivity in healthy persons. This overlap suggests a mechanistic link between amyloid-? and intrinsic connectivity, and indeed there is evidence in patients for the detrimental effects of amyloid-? plaque accumulation on intrinsic connectivity in areas of high connectivity in heteromodal hubs, and particularly in the default mode network. However, the observed spatial extent of amyloid-? exceeds these tightly circumscribed areas, suggesting that previous studies may have underestimated the negative impact of amyloid-? on intrinsic connectivity. We hypothesized that the known positive baseline correlation between patterns of amyloid-? and intrinsic connectivity may mask the larger extent of the negative effects of amyloid-? on connectivity. Crucially, a test of this hypothesis requires the within-patient comparison of intrinsic connectivity and amyloid-? distributions. Here we compared spatial patterns of amyloid-?-plaques (measured by Pittsburgh compound B positron emission tomography) and intrinsic functional connectivity (measured by resting-state functional magnetic resonance imaging) in patients with prodromal Alzheimer's disease via spatial correlations in intrinsic networks covering fronto-parietal heteromodal cortices. At the global network level, we found that amyloid-? and intrinsic connectivity patterns were positively correlated in the default mode and several fronto-parietal attention networks, confirming that amyloid-? aggregates in areas of high intrinsic connectivity on a within-network basis. Further, we saw an internetwork gradient of the magnitude of correlation that depended on network plaque-load. After accounting for this globally positive correlation, local amyloid-?-plaque concentration in regions of high connectivity co-varied negatively with intrinsic connectivity, indicating that amyloid-? pathology adversely reduces connectivity anywhere in an affected network as a function of local amyloid-?-plaque concentration. The local negative association between amyloid-? and intrinsic connectivity was much more pronounced than conventional group comparisons of intrinsic connectivity would suggest. Our findings indicate that the negative impact of amyloid-? on intrinsic connectivity in heteromodal networks is underestimated by conventional analyses. Moreover, our results provide first within-patient evidence for correspondent patterns of amyloid-? and intrinsic connectivity, with the distribution of amyloid-? pathology following functional connectivity gradients within and across intrinsic networks.

Dataset Information

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

Publications

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

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