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1.  Functional connectivity tracks clinical deterioration in Alzheimer’s disease 
Neurobiology of Aging  2011;33(4):828.e19-828.e30.
While resting state functional connectivity has been shown to decrease in patients with mild/moderate Alzheimer’s disease, it is not yet known how functional connectivity changes in patients as the disease progresses. Furthermore, it has been noted that the default mode network is not as homogenous as previously assumed and several fractionations of the network have been proposed. Here, we separately investigated the modulation of three default mode sub-networks, as identified with group ICA, by comparing Alzheimer’s disease patients to healthy controls and by assessing connectivity changes over time. Our results showed decreased connectivity at baseline in patients versus controls in the posterior default mode network, and increased connectivity in the anterior and ventral default mode networks. At follow-up, functional connectivity decreased across all default mode systems in patients. Our results suggest that earlier in the disease, regions of the posterior default mode network start to disengage whereas regions within the anterior and ventral networks enhance their connectivity. However, as the disease progresses connectivity within all systems eventually deteriorates.
PMCID: PMC3218226  PMID: 21840627
Alzheimer’s disease; functional connectivity; resting state fMRI; disease progression; default mode network; fractionation
2.  Gender Modulates the APOE ε4 Effect in Healthy Older Adults: Convergent Evidence from Functional Brain Connectivity and Spinal Fluid Tau Levels 
The Journal of Neuroscience  2012;32(24):8254-8262.
We examined whether the effect of APOE genotype on functional brain connectivity is modulated by gender in healthy older human adults. Our results confirm significantly decreased connectivity in the default mode network in healthy older APOE ε4 carriers compared to ε3 homozygotes. More importantly, further testing revealed a significant interaction between APOE genotype and gender in the precuneus, a major default mode hub. Female ε4 carriers showed significantly reduced default mode connectivity compared to either female ε3 homozygotes or male ε4 carriers, whereas male ε4 carriers differed minimally from male ε3 homozygotes. An additional analysis in an independent sample of healthy elderly using an independent marker of Alzheimer’s disease, i.e. spinal fluid levels of tau, provided corresponding evidence for this gender by APOE interaction. Taken together, these results converge with previous work showing a higher prevalence of the ε4 allele among women with Alzheimer’s disease and, critically, demonstrate that this interaction between APOE genotype and gender is detectable in the preclinical period.
PMCID: PMC3394933  PMID: 22699906
3.  Resting-state fMRI as a biomarker for Alzheimer's disease? 
Previous work indicates that resting-state functional magnetic resonance imaging (fMRI) is sensitive to functional brain changes related to Alzheimer's disease (AD) pathology across the clinical spectrum. Cross-sectional studies have found functional connectivity differences in the brain's default mode network in aging, mild cognitive impairment, and AD. In addition, two recent longitudinal studies have shown that functional connectivity changes track AD progression. This earlier work suggests that resting-state fMRI may be a promising biomarker for AD. However, some key issues still need to be addressed before resting-state fMRI can be successfully applied clinically. In a previous issue of Alzheimer's Research & Therapy, Vemuri and colleagues discuss the use of resting-state fMRI in the study of AD. In this commentary, I will highlight and expand upon some of their main conclusions.
PMCID: PMC3334541  PMID: 22423634
4.  Loss of ‘Small-World’ Networks in Alzheimer's Disease: Graph Analysis of fMRI Resting-State Functional Connectivity 
PLoS ONE  2010;5(11):e13788.
Local network connectivity disruptions in Alzheimer's disease patients have been found using graph analysis in BOLD fMRI. Other studies using MEG and cortical thickness measures, however, show more global long distance connectivity changes, both in functional and structural imaging data. The form and role of functional connectivity changes thus remains ambiguous. The current study shows more conclusive data on connectivity changes in early AD using graph analysis on resting-state condition fMRI data.
Methodology/Principal Findings
18 mild AD patients and 21 healthy age-matched control subjects without memory complaints were investigated in resting-state condition with MRI at 1.5 Tesla. Functional coupling between brain regions was calculated on the basis of pair-wise synchronizations between regional time-series. Local (cluster coefficient) and global (path length) network measures were quantitatively defined. Compared to controls, the characteristic path length of AD functional networks is closer to the theoretical values of random networks, while no significant differences were found in cluster coefficient. The whole-brain average synchronization does not differ between Alzheimer and healthy control groups. Post-hoc analysis of the regional synchronization reveals increased AD synchronization involving the frontal cortices and generalized decreases located at the parietal and occipital regions. This effectively translates in a global reduction of functional long-distance links between frontal and caudal brain regions.
We present evidence of AD-induced changes in global brain functional connectivity specifically affecting long-distance connectivity. This finding is highly relevant for it supports the anterior-posterior disconnection theory and its role in AD. Our results can be interpreted as reflecting the randomization of the brain functional networks in AD, further suggesting a loss of global information integration in disease.
PMCID: PMC2967467  PMID: 21072180
5.  Glucocorticoids Decrease Hippocampal and Prefrontal Activation during Declarative Memory Retrieval in Young Men 
Brain Imaging and Behavior  2007;1(1-2):31-41.
Glucocorticoids (GCs, cortisol in human) are associated with impairments in declarative memory retrieval. Brain regions hypothesized to mediate these effects are the hippocampus and prefrontal cortex (PFC). Our aim was to use fMRI in localizing the effects of GCs during declarative memory retrieval. Therefore, we tested memory retrieval in 21 young healthy males in a randomized placebo-controlled crossover design. Participants encoded word lists containing neutral and emotional words 1 h prior to ingestion of 20 mg hydrocortisone. Memory retrieval was tested using an old/new recognition paradigm in a rapid event-related design. It was found that hydrocortisone decreased brain activity in both the hippocampus and PFC during successful retrieval of neutral words. These observations are consistent with previous animal and human studies suggesting that glucocorticoids modulate both hippocampal and prefrontal brain regions that are crucially involved in memory processing.
Electronic Supplementary Material
The online version of this article (doi:10.1007/s11682-007-9003-2) contains supplementary material, which is available to authorized users.
PMCID: PMC2780685  PMID: 19946603
fMRI; Glucocorticoids; Hippocampus; Memory retrieval; PFC

Results 1-5 (5)