In-vivo MRI of noradrenergic and dopaminergic nuclei predicts future cognition and Alzheimers disease progression

Abstract

Noradrenergic and dopaminergic nuclei modulate cognition, and post-mortem data indicate they are affected early in the neurodegenerative cascade of Alzheimers disease. We derived in-vivo locus coeruleus (LC) and substantia nigra-ventral tegmental area (SN-VTA) MRI integrity measures from 739 ADNI participants, examined MRI-histology correspondence in individuals with both in-vivo imaging and post-mortem data, and tested whether these measures reflect early MRI-indexed degeneration predicting later cognitive decline. LC and SN-VTA contrast predicted cognitive and behavioral function 10 years later, despite only weak associations with current function. LC- and SN-VTA-associated brain-wide atrophy patterns aligned with PET-derived norepinephrine-transporter and dopamine-receptor maps, respectively. A one-standard-deviation decrease in baseline LC contrast was associated with 84% higher five-year odds of MCI-to-AD progression, and predictive effects of the catecholaminergic nuclei were mediated by their corresponding atrophy patterns. The SN-VTA pattern was associated with less amyloid PET-related memory decline. Together, these findings establish LC and SN-VTA MRI contrast as markers of early neurodegeneration that forecast cognitive decline years before clinical onset.