Microstructural assessment of the locus coeruleus-entorhinal cortex pathway and association with ATN markers in cognitive impairment

INTRODUCTION: Whether Alzheimer's disease pathology involves white matter pathways connecting the locus coeruleus (LC) to the entorhinal cortex (EC) is unclear. In this cross-sectional observational study, we investigated the microstructural integrity of the LC–EC pathway in relation to amyloid, tau, and neurodegeneration (ATN) biomarkers along the cognitive spectrum from normal cognition to dementia. METHODS: One hundred twenty-four participants underwent clinical assessment, diffusion-weighted imaging, structural magnetic resonance imaging (N), amyloid (A), and tau (T) positron emission tomography. Diffusivity indices were assessed in the LC–EC tract using a probabilistic atlas, and linear models were used to assess associations with ATN markers and cognition. RESULTS: Differences in LC–EC microstructural parameters were observed in participants with Braak stage > I versus Braak 0 (p < 0.020), N+ versus N− (p < 0.001), and cognitively impaired versus unimpaired (p < 0.019). LC–EC mean diffusivity was associated with Mini-Mental State Examination score even after accounting for ATN markers (p = 0.015). DISCUSSION: Our results suggest that LC–EC diffusivity provides complementary information over ATN biomarkers in explaining cognitive impairment. Highlights: Locus coeruleus–entorhinal cortex (LC–EC) tract microstructure is associated with tau and especially neurodegeneration markers. LC–EC tract microstructure is more sensitive to tau pathology and neurodegeneration than tracts commonly affected in Alzheimer's disease. LC–EC diffusivity measures provide complementary information over amyloid, tau, and neurodegeneration (ATN) biomarkers.

INTRODUCTION: Whether Alzheimer's disease pathology involves white matter pathways connecting the locus coeruleus (LC) to the entorhinal cortex (EC) is unclear. In this cross-sectional observational study, we investigated the microstructural integrity of the LC–EC pathway in relation to amyloid, tau, and neurodegeneration (ATN) biomarkers along the cognitive spectrum from normal cognition to dementia. METHODS: One hundred twenty-four participants underwent clinical assessment, diffusion-weighted imaging, structural magnetic resonance imaging (N), amyloid (A), and tau (T) positron emission tomography. Diffusivity indices were assessed in the LC–EC tract using a probabilistic atlas, and linear models were used to assess associations with ATN markers and cognition. RESULTS: Differences in LC–EC microstructural parameters were observed in participants with Braak stage > I versus Braak 0 (p < 0.020), N+ versus N− (p < 0.001), and cognitively impaired versus unimpaired (p < 0.019). LC–EC mean diffusivity was associated with Mini-Mental State Examination score even after accounting for ATN markers (p = 0.015). DISCUSSION: Our results suggest that LC–EC diffusivity provides complementary information over ATN biomarkers in explaining cognitive impairment. Highlights: Locus coeruleus–entorhinal cortex (LC–EC) tract microstructure is associated with tau and especially neurodegeneration markers. LC–EC tract microstructure is more sensitive to tau pathology and neurodegeneration than tracts commonly affected in Alzheimer's disease. LC–EC diffusivity measures provide complementary information over amyloid, tau, and neurodegeneration (ATN) biomarkers.