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

Neuropsychopharmacology. 2022 Apr;47(5):1128-1136. doi: 10.1038/s41386-022-01293-6. Epub 2022 Feb 17.

Abstract

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-β 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-β positron emission tomography (with [18F]MK6240 and [18F]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 [18F]MK6240. NPS were assessed with the Mild Behavioral Impairment Checklist (MBI-C). LC signal contrast was decreased in tau-positive participants (t186 = -4.00, p = 0.0001) and negatively correlated to Braak stage (Spearman ρ = -0.31, p = 0.00006). In tau-positive participants (n = 51), higher LC signal predicted NPS severity (ρ = 0.35, p = 0.019) independently of tau burden, amyloid-β 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 (ρ = 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Alzheimer Disease* / diagnostic imaging
  • Alzheimer Disease* / metabolism
  • Amyloid beta-Peptides / metabolism
  • Humans
  • Locus Coeruleus / diagnostic imaging
  • Locus Coeruleus / metabolism
  • Norepinephrine / metabolism
  • Positron-Emission Tomography
  • tau Proteins / metabolism

Substances

  • Amyloid beta-Peptides
  • tau Proteins
  • Norepinephrine