Differential involvement of neurotransmitter pathways in AD, bvFTD and MCI: Whole-brain MRI analysis
Ricardo Félix Morais, José Maria Sousa, Cemal Koba, L. de Andrés, Tiago Jesus, Inês Baldeiras, Tiago Gil Oliveira, Isabel Santana
Abstract
BACKGROUND AND OBJECTIVES: Neurodegenerative diseases, including Alzheimer's disease (AD), mild cognitive impairment (MCI), and frontotemporal dementia (FTD), are a growing public health challenge, with dementia incidence projected to triple in the coming decades. AD is associated with memory impairment, bvFTD with behavioral dysfunction, and MCI as a transitional stage between normal cognition and dementia. While structural brain changes have been widely studied, the role of neurotransmitter pathways remains underexplored. This study aims to correlate gray matter atrophy in AD, bvFTD, and MCI with neurotransmitter pathways to identify distinctive neurochemical impairments. METHODS: We included 214 participants (89 CE, 74 bvFTD, 51 MCI) from a single-center cohort. MRI from 3 T scanners was segmented via FreeSurfer. Neurotransmitter maps were sourced from JuSpace. We performed volumetric and whole-brain correlation analyses to evaluate relationships between brain regional volumes (BRVs) and neurotransmitter pathways. Group differences were assessed with Kruskal-Wallis tests followed by post-hoc analyses. RESULTS: Volumetric analysis showed expected atrophy patterns in each group. Correlation analysis indicated distinct neurotransmitter involvement: AD showed significant atrophy correlations with dopamine D2 and GABA A receptor distribution; bvFTD had significant negative correlations with the mu-opioid receptor; MCI exhibited early serotonergic dysregulation. CONCLUSIONS: We identified distinct atrophy patterns linked to specific neurotransmitter systems, each showing unique neurochemical profiles. In AD, precuneus and inferior parietal lobules atrophy aligns with dopaminergic and GABAergic receptors, potentially impacting memory and executive functions. In bvFTD, medial orbitofrontal and temporal atrophy, is linked to mu-opioid receptor impairment, possibly contributing to behavioral symptoms. In MCI, early serotonergic dysregulation involving SERT occurs before detectable atrophy.