Association of locus coeruleus integrity with Braak stage and neuropsychiatric symptom severity in Alzheimer's disease

The clinical and pathophysiological correlates of locus coeruleus (LC) degeneration in Alzheimer's disease (AD) could be clarified using a method to index LC integrity in vivo, neuromelanin-sensitive MRI (NM-MRI). We examined whether integrity of the LC-norepinephrine system, assessed with NM-MRI, is associated with stage of AD and with neuropsychiatric symptoms (NPS), independent of cortical pathophysiology (amyloid-beta and tau burden). Cognitively normal older adults (n = 118), and individuals with mild cognitive impairment (MCI, n = 44), and AD (n = 28) underwent MR imaging and tau and amyloid-beta positron emission tomography (with [F-18]MK6240 and [F-18]AZD4694, respectively). Integrity of the LC-norepinephrine system was assessed based on contrast-to-noise ratio of the LC on NM-MRI images. Braak stage of AD was derived from regional binding of [F-18]MK6240. NPS were assessed with the Mild Behavioral Impairment Checklist (MBI-C). LC signal contrast was decreased in tau-positive participants (t(186) = -4.00, p = 0.0001) and negatively correlated to Braak stage (Spearman rho = -0.31, p = 0.00006). In tau-positive participants (n = 51), higher LC signal predicted NPS severity (rho = 0.35, p = 0.019) independently of tau burden, amyloid-beta burden, and cortical gray matter volume. This relationship appeared to be driven by the impulse dyscontrol domain of NPS, which was highly correlated to LC signal (rho = 0.44, p = 0.0027). NM-MRI reveals loss of LC integrity that correlates to severity of AD. However, LC preservation in AD may also have negative consequences by conferring risk for impulse control symptoms. NM-MRI shows promise as a practical biomarker that could have utility in predicting the risk of NPS or guiding their treatment in AD.

Automated summary

This study used neuromelanin-sensitive MRI (NM-MRI) to evaluate the correlation between locus coeruleus (LC) degeneration and the severity of Alzheimer's disease (AD) as well as neuropsychiatric symptoms (NPS). The results showed that decreased LC integrity was associated with AD severity, but preserving LC in AD patients may increase the risk of impulse control symptoms. NM-MRI holds promise as a practical biomarker for predicting NPS risk or guiding AD treatment.