Cholinergic and serotonergic modulation of resting state functional brain connectivity in Alzheimer's disease

Bernadet L Klaassens,Joop M.A Van Gerven,Erica S Klaassen,Jeroen Van Der Grond,Serge A.R.B Rombouts

doi:10.1016/j.neuroimage.2019.05.044

Bernadet L Klaassens, Joop M.A Van Gerven + Show 3 more

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https://doi.org/10.1016/j.neuroimage.2019.05.044

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Abstract

Disruption of cholinergic and serotonergic neurotransmitter systems is associated with cognitive, emotional and behavioural symptoms of Alzheimer's disease (AD). To investigate the responsiveness of these systems in AD we measured the effects of a single-dose of the selective serotonin reuptake inhibitor citalopram and acetylcholinesterase inhibitor galantamine in 12 patients with AD and 12 age-matched controls on functional brain connectivity with resting state functional magnetic resonance imaging. In this randomized, double blind, placebo-controlled crossover study, functional magnetic resonance images were repeatedly obtained before and after dosing, resulting in a dataset of 432 scans. Connectivity maps of ten functional networks were extracted using a dual regression method and drug vs. placebo effects were compared between groups with a multivariate analysis with signals coming from cerebrospinal fluid and white matter as covariates at the subject level, and baseline and heart rate measurements as confound regressors in the higher-level analysis (at p < 0.05, corrected). A galantamine induced difference between groups was observed for the cerebellar network. Connectivity within the cerebellar network and between this network and the thalamus decreased after galantamine vs. placebo in AD patients, but not in controls. For citalopram, voxelwise network connectivity did not show significant group × treatment interaction effects. However, we found default mode network connectivity with the precuneus and posterior cingulate cortex to be increased in AD patients, which could not be detected within the control group. Further, in contrast to the AD patients, control subjects showed a consistent reduction in mean connectivity with all networks after administration of citalopram. Since AD has previously been characterized by reduced connectivity between the default mode network and the precuneus and posterior cingulate cortex, the effects of citalopram on the default mode network suggest a restoring potential of selective serotonin reuptake inhibitors in AD. The results of this study also confirm a change in cerebellar connections in AD, which is possibly related to cholinergic decline.

Highlights

In Alzheimer's disease (AD), destruction of neural tissue leads to loss of cholinergic nuclei in the basal forebrain and depleted cholinergic innervation towards the cerebral cortex, thalamus and hippocampus (Mesulam and Geula, 1988; Muir, 1997; Schliebs and Arendt, 2011)
No significant group Â treatment interaction effects were observed for citalopram or galantamine
Comparing AD patients with age-matched controls, we found a significant group Â treatment interaction effect after administration of the Acetylcholinesterase inhibitors (AChEIs) galantamine on cerebellar network connectivity

Summary

Introduction

In Alzheimer's disease (AD), destruction of neural tissue leads to loss of cholinergic nuclei in the basal forebrain and depleted cholinergic innervation towards the cerebral cortex, thalamus and hippocampus (Mesulam and Geula, 1988; Muir, 1997; Schliebs and Arendt, 2011). Acetylcholinesterase inhibitors (AChEIs) prevent the breakdown of acetylcholine and are often used as drug treatment to improve the cognitive symptoms of AD (Pepeu and Giovannini, 2009; Soreq and Seidman, 2001). Single-dose administration of compounds that inhibit or excite synaptic activity can alter brain connectivity during rest, reflecting the responsiveness of neurotransmitter networks and related functions (Khalili-Mahani et al, 2015; Kleinloog et al, 2015; Niesters et al, 2014). This pharmacological ‘challenge’ technique is aimed at discovering the underlying neurobiological mechanisms behind drug action and neurotransmitter-related disease. The approach seems especially relevant for measuring deviant functional processes in AD, which is conceived as a disorder of both large-scale network disconnections (Delbeuck et al, 2003; Seeley et al, 2009) and decrements in neurotransmission

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