Elevated locus coeruleus metabolism provides resilience against cognitive decline in preclinical Alzheimer's disease

Abstract

Introduction: Alterations in locus coeruleus' (LC) metabolic turnover are associated with Alzheimer's disease (AD)-pathology and cognitive impairment. However, the evolution of these changes across disease stages and their functional relevance remains unknown.

Methods: We examined associations of [¹⁸F]-fluorodeoxyglucose positron emission tomography (FDG-PET) -derived LC metabolism with clinical diagnostic status, cerebrospinal fluid (CSF) -based AD biomarkers of AD pathology, and cognitive decline in Alzheimer's Disease Neuroimaging Initiative (ADNI) participants (n = 604).

Results: FDG-PET-derived LC metabolism was elevated in the earliest preclinical stages and lower in later disease stages. Higher LC metabolism was associated with attenuated memory decline in preclinical stages, particularly in those with low CSF Aβ_42, but not in AD patients with cognitive impairment.

Discussion: Higher locus coeruleus [¹⁸F]-FDG-PET-derived signal in the early preclinical stages of AD can confer cognitive resilience and may reflect increased metabolic activity, whereas later stages are characterized by lower LC FDG-PET-derived signal, possibly due to neurodegeneration.

Highlights: LC FDG-PET signal is lower in Alzheimer's disease (AD) patients. LC FDG-PET signal is higher in the preclinical stage of AD. We observed less memory decline in those with higher LC FDG-PET signal. Higher LC FDG-PET signal conferred cognitive resilience in preclinical AD.

Keywords: Alzheimer's Disease; CSF; FDG‐PET; MRI; PET; biomarkers; cognitive decline; disease staging; locus coeruleus; neuromodulatory subcortical systems; preclinical.

FIGURE 1

Processing pipeline to obtain deblurred and joint‐entropy prior penalty corrected LC FDG‐PET signal. (A) The primary analyses were performed using an LC template mask, based on the Keren template, which was dilated and smoothed with an ellipsoid Gaussian kernel to account for the low spatial resolution of PET scans and obtain a continuous mask. Sensitivity analyses were performed using an in‐house developed LC mask based on 7 Tesla MT‐TFL images. The processing consisted of the co‐registration of the FreeSurfer‐processed T1 anatomical images to an MNI template to facilitate the transformation of the MNI‐based LC templates to native space. The FDG‐PET images and LC templates were registered to native anatomic MRI space on an individual basis. The average signal from the LC was extracted after applying the MRI‐PET joint entropy deblurring algorithm for the dilated Keren and 7T MT‐TFL‐based masks. FDG‐PET images were referenced to either the CW matter or the pons (excluding the LC). CW, cerebellar white; FDG‐PET, [18F]fluoredeoxyglucose positron emission tomography; LC, locus coeruleus; MNI, Montreal Neurological Institute; MRI, magnetic resonance imaging; MT‐TFL, magnetization transfer‐weighted turbo flash.

FIGURE 2

Associations between LC FDG‐PET signal, sample characteristics, and diagnostic and disease stage groups. (A) A scatterplot with a regression line shows the relationship between the LC FDG‐PET signal and age. FDG‐PET‐derived LC glucose metabolism was associated with age, with a lower LC signal in older individuals (B) Boxplot showing the relationship of LC FDG‐PET signal and sex. LC FDG‐PET signal was higher in females than in males. (C) Boxplot showing LC FDG‐PET signal per diagnostic group. The AD group showed significantly lower LC metabolism compared to the control group. (D) Boxplot showing LC FDG‐PET signal per disease stage group. The preclinical group showed significantly higher LC FDG‐PET signal compared to both the control and the prodromal/AD groups. (E) Boxplot splitting the preclinical group and prodromal/AD group according to biomarker status, showing the increase in LC FDG‐PET signal is primarily driven by the early preclinical (CN A+T‐) group. (F) A scatterplot with a regression line (entire sample) shows the association between FDG‐PET‐derived LC signal and mPACC scores, with lower LC signal corresponding to worse mPACC scores. A+T‐, amyloid positive and tau negative; A+T+, amyloid and tau positive; AD, Alzheimer's disease; A‐T‐, amyloid and tau negative; CN, cognitively normal; FDG‐PET, [18F]fluorodeoxyglucose positron emission tomography; LC, locus coeruleus; MCI, mild cognitive impairment; mPACC, modified Preclinical Alzheimer's Cognitive Composite; SUVr, standardized uptake values referenced to the cerebellar white.

FIGURE 3

Relationships of LC FDG‐PET signal and CSF‐based biomarkers and memory function. (A) Scatterplot with a regression line and 95% confidence interval shows that lower CSF‐based Aβ₄₂ levels corresponded to higher LC FDG‐PET signal in the diagnostic control group. (B) Scatterplot with a regression line and 95% confidence intervals show that higher CSF‐based p‐tau₁₈₁ levels corresponded to higher LC FDG‐PET signal in the AD group. (C) Interaction plot with regression lines and 95% confidence intervals showing that the association of LC FDG‐PET signal and CSF‐based p‐tau varies with different levels of CSF‐based Aβ in those with AD. Johnson–Neyman analysis indicated that the relationship between LC FDG‐PET signal and CSF‐based p‐tau₁₈₁ levels is significant for CSF‐based Aβ₄₂ levels between 576 and 1099 pg/mL, indicated by the gray shaded area and the black arrow. All values in this plot correspond to amyloid positivity, with the orange line marking the threshold. (D) Interaction plot with data points, regression lines, and 95% confidence intervals demonstrating that lower LC FDG‐PET signal was associated with faster composite memory function decline in the entire sample. (E) Interaction plot with data points, regression lines, and 95% confidence intervals for the early preclinical group (CN A+T‐) shows that memory performance over time was preserved for those with higher LC FDG‐PET signal at baseline but declined for those with lower LC FDG‐PET signal. (F) Three‐way interaction plot with regression lines and 95% confidence intervals for the association of LC FDG‐PET signal and composite memory scores over time at specific Aβ levels in the early preclinical group (CN A+T‐). Memory decline was steeper in those with lower LC FDG‐PET signal, in particular in those with high amyloid burden, whereas high LC FDG‐PET signal appears to have a protective effect on memory, even in the presence of high amyloid burden. AB, CSF‐based Aβ₄₂; AD, Alzheimer's disease; CN, cognitively normal; CSF, cerebrospinal fluid; FDG‐PET, [18F]fluorodeoxyglucose positron emission tomography; LC, locus coeruleus; SUVr, standardized uptake values referenced to the cerebellar white.