Locus coeruleus integrity exhibits distinct anatomic vulnerabilities to regional tau and amyloid accumulation: parallel and intersecting mechanisms? Article Swipe
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· 2023
· Open Access
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· DOI: https://doi.org/10.1002/alz.072201
· OA: W4390196275
Background The locus coeruleus (LC) is one of the first regions to accumulate tau in Alzheimer’s disease (AD). As the disease progresses, tau in the LC has been related to increasing allocortical tau. Recent autopsy work reported that LC neurodegeneration correlated with parietal amyloid, suggesting that the LC may impact both Ab and tau, but with regionally varying contributions. We investigated whether cross‐sectional and longitudinal relationships between in vivo LC integrity and regional tau or Ab are uniquely determined by one pathology or exhibit shared vulnerabilities. Method 213 individuals from the Harvard Aging Brain Study (mean age:71.6 years, 58% female; 11% cognitively impaired; Figure 1) who underwent 3T LC‐MRI, Ab‐ and tau‐PET imaging were included. Of these, 62 individuals received a second MRI and PET session. For the LC, we extracted the 5 highest normalized intensity voxels. PET‐data was referenced to cerebellar gray and partial volume corrected. Linear regressions associated LC integrity to tau or Ab and variance contributions were quantified. Mixed effects models examined LC changes to changes in tau or Ab. Mediation analyses examined whether local Ab mediated relationships between LC integrity and local tau. Analyses were adjusted for age, sex and multiple comparisons using FDR‐correction. Result LC integrity was negatively associated with medial‐lateral temporal tau, and widespread Ab. Multivariable analyses demonstrated that LC integrity associated uniquely with tau in medial temporal lobe (MTL) regions and with Ab in frontoparietal regions. LC integrity was associated with both tau and Ab in inferior temporal (IT) and posterior cingulate cortices, and mediation analyses showed that LC integrity – tau associations in these regions were Ab‐mediated (Figure 2). Longitudinal analyses revealed stronger local associations between LC integrity and tau changes, compared to Ab. LC integrity changes were uniquely associated with tau changes in MTL, but longitudinal LC integrity‐IT tau correlations were mediated by local Ab (Figure 3). Conclusion The LC may have anatomically distinct cortical tau and Ab‐pathways in AD, with MTL correlations being almost uniquely tau‐related, frontoparietal associations uniquely Ab‐related and lateral temporal regions showing Ab‐mediated tau accumulation. Potential underlying mechanisms can include synaptic plasticity alterations, glial activation or neuronal hyperactivation.
