Background : The Locus Coeruleus (LC), a bilateral brainstem nucleus, is the principal source of Noradrenaline in the brain and undergoes functional and structural changes in ageing and neurodegenerative diseases (NDs). The most prevalent ND is Alzheimer’s Disease (AD), which is characterized by the accumulation of two pathological proteins in the brain, amyloid beta (Aβ) and hyperphosphorylated tau. The LC is one of the earliest regions to accumulate tau pathology during AD before spreading to innervated cortical areas. LC functional connectivity disruption may therefore constitute a crucial and early signature of AD pathology to study.
Research goal : The aim of the study was to assess the functional connectivity of the LC and major Resting State Networks (RSNs) in healthy young adults and older persons. More particularly in older Cognitively Unimpaired (oCU) participants with and without Subjective Cognitive Decline (SCD), and in Cognitively Impaired (CI) participants with Mild Cognitive Impairment (MCI) or Dementia.
Methods : We used gold-standard neuropsychological tests including the Mini-Mental State Examination, the Free and Cued Selective Reminding Tests (FCSRT) for Delayed and Immediate Recall (DR and IR respectively) for all participants except younger healthy adults. All the subjects underwent resting-state functional Magnetic Resonance Imaging (rs-fMRI) and T1-weighted MRI (T1 MRI) scan acquisition. The images were acquired at ultra-high field resolution on a 7T Siemens Magnetom MRI scanner and were preprocessed and analyzed using in-house pipelines for Seed-based Connectivity and Independent Component analyses (SCA and ICA respectively).
Results : Key differences in LC and RSNs functional connectivity were observed between groups. In younger subjects, LC was functionally connected with the frontal regions and the Cingulate Cortex, whereas in the oCU it showed connectivity with the Cerebellum and decreased connectivity with the Frontal Lobe compared to younger subjects. In the CI group, we did not detect any connection between the LC and frontal regions nor the cerebellum with but with temporal regions, including the Parahippocampal Gyrus. Major RSNs, including the Default Mode Network, the Salience Network, the Dorsal Attention Network and the Executive Control Network showed significantly decreased functional connectivity in oCU compared to younger healthy adults. The Default Mode Network was the only RSN that showed significantly decreased functional connectivity between CI and oCU.
Conclusion: Our analyses demonstrated that functional connectivity significantly declines in the elderly and the CI in RSNs except for the Sensorimotor and Visual networks. Overall, LC functional connectivity undergoes functional connectivity reconfiguration with age and cognitive impairment, with a different LC connectivity pattern across our cohort groups. The lack of connectivity with frontal regions within the CI group could mean a possible loss of function in these regions, while in the oCU group the increased connectivity with the cerebellum could be indicative of a possible compensation mechanism.
