In vivo MRI Structural and PET Metabolic Connectivity Study of Dopamine Pathways in Alzheimer’s Disease

Article type: Research Article

Authors: Iaccarino, Leonardo^{a; b; c; 1} | Sala, Arianna^{a; b; 1} | Caminiti, Silvia Paola^{a; b; 1} | Presotto, Luca^{b; d} | Perani, Daniela^{a; b; d; *} | for the Alzheimer’s Disease Neuroimaging Initiative²

Affiliations: [a] Vita-Salute San Raffaele University, Milan, Italy | [b] In vivo Human Molecular and Structural Neuroimaging Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy | [c] Memory and Aging Center, Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA | [d] Nuclear Medicine Unit, San Raffaele Hospital, Milan, Italy

Correspondence: [*] Correspondence to: Prof. Daniela Perani, MD, Vita-Salute San Raffaele University, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Nuclear Medicine Unit, IRCCS San Raffaele Hospital, Via Olgettina 60, Milan, Italy. Tel.: +39 02 264 2224; perani.daniela@hsr.it.

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

Note: [2] Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (http://adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf

Abstract: Background:Alzheimer’s disease (AD) is characterized by an involvement of brain dopamine (DA) circuitry, the presence of which has been associated with emergence of both neuropsychiatric symptoms and cognitive deficits. Objective:In order to investigate whether and how the DA pathways are involved in the pathophysiology of AD, we assessed by in vivo neuroimaging the structural and metabolic alterations of subcortical and cortical DA pathways and targets. Methods:We included 54 healthy control participants, 53 amyloid-positive subjects with mild cognitive impairment due to AD (MCI-AD), and 60 amyloid-positive patients with probable dementia due to AD (ADD), all with structural 3T MRI and 18F-FDG-PET scans. We assessed MRI-based gray matter reductions in the MCI-AD and ADD groups within an anatomical a priori-defined Nigrostriatal and Mesocorticolimbic DA pathways, followed by 18F-FDG-PET metabolic connectivity analyses to evaluate network-level metabolic connectivity changes. Results:We found significant tissue loss in the Mesocorticolimbic over the Nigrostriatal pathway. Atrophy was evident in the ventral striatum, orbitofrontal cortex, and medial temporal lobe structures, and already plateaued in the MCI-AD stage. Degree of atrophy in Mesocorticolimbic regions positively correlated with the severity of depression, anxiety, and apathy in MCI-AD and ADD subgroups. Additionally, we observed significant alterations of metabolic connectivity between the ventral striatum and fronto-cingulate regions in ADD, but not in MCI-AD. There were no metabolic connectivity changes within the Nigrostriatal pathway. Conclusion:Our cross-sectional data support a clinically-meaningful, yet stage-dependent, involvement of the Mesocorticolimbic system in AD. Longitudinal and clinical correlation studies are needed to further establish the relevance of DA system involvement in AD.

Keywords: Alzheimer’s disease, connectivity, dementia, dopamine systems, mild cognitive impairment, ventro-tegmental area

DOI: 10.3233/JAD-190954

Journal: Journal of Alzheimer's Disease, vol. 75, no. 3, pp. 1003-1016, 2020