Goveas JS, Xie C, Ward BD, Wu Z, Li W, Franczak M et al. Recovery of hippocampal network connectivity correlates with cognitive improvement in mild Alzheimer's disease patients treated with donepezil assessed by resting-state fMRI. J Magn Reson Imaging 34: 764-773

Department of Psychiatry and Behavioral Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
Journal of Magnetic Resonance Imaging (Impact Factor: 3.21). 10/2011; 34(4):764-73. DOI: 10.1002/jmri.22662
Source: PubMed


To identify the neural correlates of cognitive improvement in mild Alzheimer's disease (AD) subjects following 12 weeks of donepezil treatment.
Resting-state functional connectivity magnetic resonance imaging (R-fMRI) was used to measure the hippocampal functional connectivity (HFC) in 14 mild AD and 18 age-matched normal (CN) subjects. AD subjects were scanned at baseline and after donepezil treatment. CN subjects were scanned only at baseline as a reference to identify regions correlated or anticorrelated to the hippocampus. Before each scan, participants underwent cognitive, behavioral, and functional assessments.
After donepezil treatment, neural correlates of cognitive improvement measured by Mini-Mental State Examination scores were identified in the left parahippocampus, dorsolateral prefrontal cortex (DLPFC), and inferior frontal gyrus. Improvement in AD Assessment Scale-cognitive subscale scores correlated with the HFC changes in the left DLPFC and middle frontal gyrus. Stronger recovery in the network connectivity was associated with cognitive improvement.
R-fMRI may provide novel insights into the brain's responses to AD treatment in clinical pharmacological trials, and also may predict clinical response.

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Available from: Piero Antuono
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    • "Given this difference in methods, the comparability of our results with those previously reported on brain regions that are positively influenced by cholinergic enhancement is limited, in particular as studies using seed-based analyses have reported heterogeneous observations dependent upon the seed region selected for analysis. For instance, Goveas and colleagues reported an increase of functional connectivity in a hippocampal functional connectivity network particularly in the precentral gyrus but also in the left Parahippocampus and in the right posterior cingulate cortex (Goveas et al., 2011), Li and colleagues demonstrated an increase in cortical regions similar to DMN nodes including the ventral anterior cingulate cortex, the right Precuneus, and the left parahippocampal gyrus among others (Li et al., 2012), and Zaidel and co-workers reported an increase of interhemispheric functional connectivity only between dorsolateral prefrontal cortices (Zaidel et al., 2012). Despite the limitations in comparability, the findings presented in the current work are in line with these previous reports with respect to AChEI induced effects on the posterior cingulate cortex, the Precuneus, and the medial aspect of the temporal lobe. "
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    ABSTRACT: Acetylcholinesterase inhibitors (AChEIs) are efficacious for the treatment of mild to moderate forms of Alzheimer׳s dementia (AD). Default-mode network (DMN) connectivity is considered to be early impaired in AD. Long-term effects of AChEIs on the DMN in AD have not yet been investigated. Twenty-eight AD patients and 11 age-matched healthy volunteers (HC) participated in the prospective study. AD patients were randomly assigned to either a pharmacotherapy arm (Galantamine, AD G) or to a placebo arm (AD P+G) for the period of 6 months followed by open-label Galantamine therapy from month 7-12. All subjects underwent neuropsychological testing, resting-state functional and structural MRI at baseline and after 12 months, AD patients additionally in between after 6 months. Thirteen AD patients completed the treatment trial and underwent all functional MRI follow-up sequences of good quality. Functional connectivity significantly increased within the AD G group in the posterior cingulate cortex and in the Precuneus between baseline and 12 months follow-up (pcorr<0.05). Between-group analyses demonstrated that functional connectivity in the AD G group significantly increased in the posterior cingulate cortex as well as in the Precuneus compared to the HC group and in the anteromedial aspect of the temporal lobes compared to the AD P+G group, respectively, at 12 months follow-up (pcorr<0.05). Cognitive performance remained stable within groups over time indicating that resting-state fMRI may be sensitive for the detection of pharmacologically induced effects on brain function of AD patients.
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    • "Reduced integrity in the default mode network is also associated with amyloid beta and tau pathology before the clinical onset of AD (Wang et al., 2013). Several pharmacological intervention studies have employed the resting-state connectivity as a biomarker for testing the efficacy of the treatment (Goveas et al., 2011; Lorenzi et al., 2011; Li et al., 2012) [see Hampel et al., 2011 for a related discussion]. Future cognitive training studies need to adopt a similar approach to test the effect of cognitive training on default-mode network. "
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    ABSTRACT: Cognitive training is an emergent approach that has begun to receive increased attention in recent years as a non-pharmacological, cost-effective intervention for Alzheimer's disease (AD). There has been increasing behavioral evidence regarding training-related improvement in cognitive performance in early stages of AD. Although these studies provide important insight about the efficacy of cognitive training, neuroimaging studies are crucial to pinpoint changes in brain structure and function associated with training and to examine their overlap with pathology in AD. In this study, we reviewed the existing neuroimaging studies on cognitive training in persons at risk of developing AD to provide an overview of the overlap between neural networks rehabilitated by the current training methods and those affected in AD. The data suggest a consistent training-related increase in brain activity in medial temporal, prefrontal, and posterior default mode networks, as well as increase in gray matter structure in frontoparietal and entorhinal regions. This pattern differs from the observed pattern in healthy older adults that shows a combination of increased and decreased activity in response to training. Detailed investigation of the data suggests that training in persons at risk of developing AD mainly improves compensatory mechanisms and partly restores the affected functions. While current neuroimaging studies are quite helpful in identifying the mechanisms underlying cognitive training, the data calls for future multi-modal neuroimaging studies with focus on multi-domain cognitive training, network level connectivity, and individual differences in response to training.
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    • "Furthermore, several fMRI studies reported markedly reduced functional connectivity in hippocampus-related memory networks in early-stage AD [15], [16] as well as mild cognitive impairment [17]–[19]. One recent resting-state fMRI study found stronger recovery of hippocampal functional connectivity after donepezil treatment in AD patients [20], which indicates there is some plasticity in hippocampal connectivity. Therefore, we selected the hippocampus as the region of interest to conduct functional connectivity analysis and to explore the effects of acupuncture. "
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    ABSTRACT: Our objective is to clarify the effects of acupuncture on hippocampal connectivity in patients with Alzheimer disease (AD) using functional magnetic resonance imaging (fMRI). Twenty-eight right-handed subjects (14 AD patients and 14 healthy elders) participated in this study. Clinical and neuropsychological examinations were performed on all subjects. MRI was performed using a SIEMENS verio 3-Tesla scanner. The fMRI study used a single block experimental design. We first acquired baseline resting state data during the initial 3 minutes and then performed acupuncture stimulation on the Tai chong and He gu acupoints for 3 minutes. Last, we acquired fMRI data for another 10 minutes after the needle was withdrawn. The preprocessing and data analysis were performed using statistical parametric mapping (SPM5) software. Two-sample t-tests were performed using data from the two groups in different states. We found that during the resting state, several frontal and temporal regions showed decreased hippocampal connectivity in AD patients relative to control subjects. During the resting state following acupuncture, AD patients showed increased connectivity in most of these hippocampus related regions compared to the first resting state. In conclusion, we investigated the effect of acupuncture on AD patients by combing fMRI and traditional acupuncture. Our fMRI study confirmed that acupuncture at Tai chong and He gu can enhance the hippocampal connectivity in AD patients.
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