Donepezil Effects on Hippocampal and Prefrontal Functional Connectivity in Alzheimer's Disease: Preliminary Report
Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA. Journal of Alzheimer's disease: JAD
(Impact Factor: 4.15).
08/2012; 31:S221-6. DOI: 10.3233/JAD-2012-120709
We used functional connectivity magnetic resonance imaging (fcMRI) to investigate changes in interhemispheric brain connectivity in 11 patients with mild Alzheimer's disease (AD) following eight weeks of treatment with the cholinesterase inhibitor donepezil. We examined functional connectivity between four homologous temporal, frontal, and occipital regions. These regions were selected to represent sites of AD neuropathology, sites of donepezil-related brain activation change in prior studies, and sites that are minimally affected by the pathologic changes of AD. Based on previous findings of selective, localized frontal responses to donepezil, we predicted that frontal connectivity would be most strongly impacted by treatment. Of the areas examined, we found that treatment had a significant effect only on functional connectivity between right and left dorsolateral prefrontal cortices. Implications for understanding the impact of donepezil treatment on brain functioning and behavior in patients with AD are discussed. This preliminary report suggests that fcMRI may provide a useful index of treatment outcome in diseases affecting brain connectivity. Future research should investigate these treatment-related changes in larger samples of patients and age-matched controls.
Available from: Daniel Keeser
- "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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Donepezil is a highly selective acetylcholinesterase inhibitor and one of the only four drugs currently approved for treatment of Alzheimer's dementia. Providing high bioavailability and a very long half-time, donepezil is regarded as effective and well tolerable in Alzheimer's disease patients, even in difficult clinical conditions such as hepatic or renal impairment. It moderately improves cognitive and global functioning scores in patients with mild to moderate Alzheimer's disease over the course of 6 - 12 months, with open-label extension studies suggesting effects of even longer duration.
We summarized relevant pharmacokinetic, pharmacodynamic, clinical trial and neuroimaging data of donepezil. A literature search was performed in the PubMed database; articles published until October 2013 have been considered for this review. Moreover, references from original work and reviews have been searched for further relevant literature.
Donepezil is one of the most frequently prescribed anti-dementia drugs. The recent additional approval of the 23 mg formulation will expand its use in patients with moderate to severe Alzheimer's disease. After numerous Phase III study failures of novel disease-modifying drugs for Alzheimer's disease, donepezil is likely going to stay a first-line therapeutic option in Alzheimer's disease in the upcoming years.
Available from: Roberta Lizio
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ABSTRACT: Alzheimer's disease (AD) induces a widespread pathological extracellular accumulation of beta-amyloid (Aβ) peptides that affects cortical networks underpinning cognitive functions. This is related to abnormal functional and effective brain connectivity as revealed by graph markers of resting-state eyes-closed electroencephalographic (EEG) rhythms. Here we revised EEG studies in mild cognitive impairment and AD subjects showing that these markers are promising network disease endpoints for basic research and AD drug discovery.
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