Volume and Connectivity of the Ventral Tegmental Area are Linked to Neurocognitive Signatures of Alzheimer’s Disease in Humans

Article type: Research Article

Authors: De Marco, Matteo^{; 1} | Venneri, Annalena^{; 1; *}

Affiliations: Department of Neuroscience, University of Sheffield, UK

Correspondence: [*] Correspondence to: Professor Annalena Venneri, Department of Neuroscience, Medical School, University of Sheffield, Beech Hill Road, Royal Hallamshire Hospital, Sheffield, S10 2RX, UK. Tel.: +44 0 114 2713430; Fax: +44 0 114 2713158; E-mail: [email protected].

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

Abstract: Background:There is an urgent need to identify the earliest biological changes within the neuropathological cascade of Alzheimer’s disease (AD) processes. Recent findings in a murine model of AD showed significant preclinical loss of dopaminergic neurons in the ventral tegmental area (VTA), accompanied by reduced hippocampal innervation and declining memory. It is unknown if these observations can be translated in humans. Objective:We tested the hypothesis that VTA volume is associated with the typical clinical markers of AD in a cohort of patients and healthy controls. Methods:Structural and resting state functional MRI scans, and neuropsychological scores were acquired for 51 healthy adults, 30 patients with a diagnosis of mild cognitive impairment, and 29 patients with a diagnosis of AD dementia. VTA volume was quantified together with other control nuclei. The association between nuclei volume, hippocampal size, memory performance, and linguistic-executive skills was tested. The effect of VTA functional connectivity was also tested. Results:VTA size, but not of control nuclei, yielded a strong association with both hippocampal size and memory competence (but not linguistic-executive performance), and this was particularly strong in healthy adults. In addition, functional connectivity between the VTA and hippocampus was significantly associated with both markers of AD. Conclusion:Diminished dopaminergic VTA activity may be crucial for the earliest pathological features of AD and might suggest new strategies for early treatment. Memory encoding processes may represent cognitive operations susceptible to VTA neurodegeneration.

Keywords: Alzheimer’s disease, cognitive dysfunction, dopaminergic neurons, early diagnosis, functional neuroimaging, gray matter, hippocampus, memory, mild cognitive impairment, neuroimaging, tegmentum mesencephali, ventral tegmental nucleus

DOI: 10.3233/JAD-171018

Journal: Journal of Alzheimer's Disease, vol. 63, no. 1, pp. 167-180, 2018