Age and Anterior Basal Forebrain Volume Predict the Cholinergic Deficit in Patients with Mild Cognitive Impairment due to Alzheimer’s Disease

Article type: Research Article

Authors: Richter, Nils^{a; b; c; *} | David, Lara-Sophia^b | Grothe, Michel J.^{d; e} | Teipel, Stefan^{d; f} | Dietlein, Markus^g | Tittgemeyer, Marc^c | Neumaier, Bernd^{c; h; i} | Fink, Gereon R.^{a; b} | Onur, Oezguer A.^{a; b; 1} | Kukolja, Juraj^{a; b; j; k; 1}

Affiliations: [a] Cognitive Neuroscience, Institute of Neuroscience and Medicine (INM-3), Research Center Jülich, Jülich, Germany | [b] Department of Neurology, Medical Faculty and University Hospital of Cologne, Cologne, Germany | [c] Max-Planck-Institute for Metabolism Research, Cologne, Cologne, Germany | [d] German Center for Neurodegenerative Diseases (DZNE), Rostock, Germany | [e] Unidad de Trastornos del Movimiento, Servicio de Neurología y Neurofisiología Clínica, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain | [f] Department of Psychosomatic Medicine, University of Rostock, Rostock, Germany | [g] Department of Nuclear Medicine, Medical Faculty and University Hospital of Cologne, Cologne, Germany | [h] Nuclear Chemistry, Institute of Neuroscience and Medicine (INM-5), Research Center Jülich, Jülich, Germany | [i] Institute for Radiochemistry and Experimental Molecular Imaging, Medical Faculty and University Hospital of Cologne, Cologne, Germany | [j] Department of Neurology and Clinical Neurophysiology, Helios University Hospital Wuppertal, Wuppertal, Germany | [k] Faculty of Health, Witten/Herdecke University, Witten, Germany

Correspondence: [*] Correspondence to: Nils Richter, Cognitive Neuroscience, Institute of Neuroscience and Medicine (INM-3), Research Center Jülich, 52425 Jülich, Germany. Tel.: +49 (0) 221 478 97493; Fax: +49 (0)221 478 86384; E-mail: [email protected].

Note: [1] These authors contributed equally to this work.

Abstract: Background:Early and severe neuronal loss in the cholinergic basal forebrain is observed in Alzheimer’s disease (AD). To date, cholinomimetics play a central role in the symptomatic treatment of AD dementia. Although basic research indicates that a cholinergic deficit is present in AD before dementia, the efficacy of cholinomimetics in mild cognitive impairment (MCI) remains controversial. Predictors of cholinergic impairment could guide individualized therapy. Objective:To investigate if the extent of the cholinergic deficit, measured using positron emission tomography (PET) and the tracer 11C-N-methyl-4-piperidyl acetate (MP4A), could be predicted from the volume of cholinergic basal forebrain nuclei in non-demented AD patients. Methods:Seventeen patients with a high likelihood of MCI due to AD and 18 age-matched cognitively healthy adults underwent MRI-scanning. Basal forebrain volume was assessed using voxel-based morphometry and a cytoarchitectonic atlas of cholinergic nuclei. Cortical acetylcholinesterase (AChE) activity was measured using MP4A-PET. Results:Cortical AChE activity and nucleus basalis of Meynert (Ch4 area) volume were significantly decreased in MCI. The extent of the cholinergic deficit varied considerably across patients. Greater volumes of anterior basal forebrain nuclei (Ch1/2 area) and younger age (Spearman’s rho (17)  = –0.596, 95% -CI [–0.905, –0.119] and 0.593, 95% -CI [0.092, 0.863])) were associated with a greater cholinergic deficit. Conclusion:Data suggest that less atrophy of the Ch1/2 area and younger age are associated with a more significant cholinergic deficit in MCI due to AD. Further investigations are warranted to determine if the individual response to cholinomimetics can be inferred from these measures.

Keywords: Acetylcholinesterase, aging, MP4A, nucleus basalis of Meynert, positron emission tomography

DOI: 10.3233/JAD-210261

Journal: Journal of Alzheimer's Disease, vol. 86, no. 1, pp. 425-440, 2022