Universität zu Köln

Richter, Nils ORCID: 0000-0002-3377-5684, Beckers, Nora, Onur, Oezguer A., Dietlein, Markus, Tittgemeyer, Marc, Kracht, Lutz, Neumaier, Bernd, Fink, Gereon R. ORCID: 0000-0002-8230-1856 and Kukolja, Juraj (2018). Effect of cholinergic treatment depends on cholinergic integrity in early Alzheimer's disease. Brain, 141. S. 903 - 916. OXFORD: OXFORD UNIV PRESS. ISSN 1460-2156

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Abstract

In early Alzheimer's disease, which initially presents with progressive loss of short-term memory, neurodegeneration especially affects cholinergic neurons of the basal forebrain. Pharmacotherapy of Alzheimer's disease therefore often targets the cholinergic system. In contrast, cholinergic pharmacotherapy of mild cognitive impairment is debated since its efficacy to date remains controversial. We here investigated the relationship between cholinergic treatment effects and the integrity of the cholinergic system in mild cognitive impairment due to Alzheimer's disease. Fourteen patients with high likelihood of mild cognitive impairment due to Alzheimer's disease and 16 age-matched cognitively normal adults performed an episodic memory task during functional magnetic resonance imaging under three conditions: (i) without pharmacotherapy; (ii) with placebo; and (iii) with a single dose of rivastigmine (3 mg). Cortical acetylcholinesterase activity was measured using PET with the tracer 11 C-N-methyl-4-piperidyl acetate (MP4A). Cortical acetylcholinesterase activity was significantly decreased in patients relative to controls, especially in the lateral temporal lobes. Without pharmacotherapy, mild cognitive impairment was associated with less memory-related neural activation in the fusiform gyrus and impaired deactivation in the posterior cingulate cortex, relative to controls. These differences were attenuated under cholinergic stimulation with rivastigmine: patients showed increased neural activation in the right fusiform gyrus but enhanced deactivation of the posterior cingulate cortex under rivastigmine, compared to placebo. Conversely, controls showed reduced activation of the fusiform gyrus and reduced deactivation of the posterior cingulate under rivastigmine, compared to placebo. In both groups, the change in neural activation in response to rivastigmine was negatively associated with local acetylcholinesterase activity. At the behavioural level, an analysis of covariance revealed a significant group x treatment interaction in episodic memory performance when accounting for hippocampal grey matter atrophy and function. Our results indicate that rivastigmine differentially affects memory-related neural activity in patients with mild cognitive impairment and cognitively normal, age-matched adults, depending on acetylcholinesterase activity as a marker for the integrity of the cortical cholinergic system. Furthermore, hippocampal integrity showed an independent association with the response of memory performance to acetylcholinesterase inhibition.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Richter, Nils UNSPECIFIED orcid.org/0000-0002-3377-5684 UNSPECIFIED Beckers, Nora UNSPECIFIED UNSPECIFIED UNSPECIFIED Onur, Oezguer A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Dietlein, Markus UNSPECIFIED UNSPECIFIED UNSPECIFIED Tittgemeyer, Marc UNSPECIFIED UNSPECIFIED UNSPECIFIED Kracht, Lutz UNSPECIFIED UNSPECIFIED UNSPECIFIED Neumaier, Bernd UNSPECIFIED UNSPECIFIED UNSPECIFIED Fink, Gereon R. UNSPECIFIED orcid.org/0000-0002-8230-1856 UNSPECIFIED Kukolja, Juraj UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-193181
DOI:	10.1093/brain/awx356
Journal or Publication Title:	Brain
Volume:	141
Page Range:	S. 903 - 916
Date:	2018
Publisher:	OXFORD UNIV PRESS
Place of Publication:	OXFORD
ISSN:	1460-2156
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language MILD COGNITIVE IMPAIRMENT; ACETYLCHOLINE ESTERASE-ACTIVITY; EVENT-RELATED FMRI; IN-VIVO; EPISODIC MEMORY; CHOLINESTERASE-INHIBITORS; BRAIN ACTIVATION; BASAL FOREBRAIN; NEURAL ACTIVITY; MODULATION Multiple languages Clinical Neurology; Neurosciences Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/19318