Recovery of hippocampal network connectivity correlates with cognitive improvement in mild alzheimer's disease patients treated with donepezil assessed by resting‐state fMRI

Abstract

Purpose To identify the neural correlates of cognitive improvement in mild AD subjects, following 12 weeks of donepezil treatment. Materials and Methods Resting-state functional connectivity MRI (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. Results 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. Conclusion R-fMRI may provide novel insight into the brain's functional responses to AD treatment in clinical pharmacological trials, and also may predict clinical response.

Decreased Effective Connectivity from Cortices to the Right Parahippocampal Gyrus in Alzheimer's Disease Subjects

“…This is often severe, affecting work, lifelong hobbies, and social life. Resting-state functional magnetic resonance imaging (R-fMRI) has been used extensively to diagnose AD Greicius et al, 2004;Li et al, 2002) and assess treatment (Goveas et al, 2011;Li et al, 2012;Sole-Padulles et al, 2013). These studies were based on the cross-correlation coefficient between the spontaneous blood oxygen leveldependent (BOLD) signals in the brain.…”

Central effects of cholinesterase inhibitors in Alzheimer’s disease: insights from advanced neuroimaging

“…Resting-state activity changes will, in principle, reflect the downstream impact on brain networks of loss of synaptic function leading to neuronal death, and are likely to be sensitive to treatments that modulate synaptic function. Significant increases in functional connectivity of the hippocampal regions were found after 12 weeks of treatment with donepezil in a group of 14 patients with mild AD [52]. An enhancement of hippocampal functional connectivity with an extensive set of limbic and frontal structures was observed, including the parahippocampus, insula, lentiform nucleus, thalamus, posterior cingulate and middle and precentral frontal gyri.…”

Time related effects on functional brain connectivity after serotonergic and cholinergic neuromodulation

“…There is a tendency toward diminished DMN activity in normal aging, MCI and dementia, pointing to reduced integrity of structures that are vulnerable to atrophy, beta amyloid deposition and reduced glucose metabolism [Hafkemeijer et al, 2012]. Studies that are performed on the resting state fMRI response to cholinergic interventions are restricted to AD patients and mainly indicate an increase in connectivity with DMN areas [Goveas et al, 2011; Li et al, 2012; Solé‐Padullés et al, 2013]. In another study, no effect on the DMN was found in both APOE ε4 carriers and non‐carriers [Wang et al, 2014].…”

“…Yet, there is also proof of more extensive effects of SSRIs on brain connectivity [Klaassens et al, 2015; Schaefer et al, 2014]. In AD patients, cholinergic stimulation induces alterations in connectivity for DMN regions [Goveas et al, 2011; Li et al, 2012; Solé‐Padullés et al, 2013], as well as networks involved in attention, control, and salience processing [Wang et al, 2014]. …”