Elevated cerebrospinal fluid chitinase‐3 protein like‐1 (YKL‐40) is associated with decreased glucose metabolism in amyloid‐positive participants.

Abstract

AbstractBackgroundThe diverse role played by astrocytes in neurodegeneration remains elusive. Astrocytes elicit a substantial impact on the fluorodeoxyglucose (FDG)‐positron emission tomography (PET) signal, an imaging modality that is used as a surrogate marker for neuronal loss. The association between astrocyte activation and FDG‐PET uptake has been evaluated with astrocyte‐targeting PET. Measuring reactive astrocytosis with fluid biomarkers may be a simpler and affordable way of studying astrocytes and their association with FDG‐PET. The cerebrospinal fluid (CSF) biomarker chitinase‐3 protein like‐1 (YKL‐40), a marker of reactive astrocytosis is elevated in the CSF of AD patients, although its role is unclear. Here, we examined the relationship between CSF YKL‐40 and PET imaging markers across the AD continuum.Method421 participants, including 89 patients with AD, 234 patients with mild cognitive impairment (MCI), and 98 cognitively normal control (CN) participants were selected from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database based on the availability of coinciding amyloid (Aβ)‐PET, FDG‐PET and structural magnetic resonance imaging (MRI), and CSF YKL‐40. The relationships between CSF YKL‐40 and PET imaging markers were explored using both a region of interest (ROI) and a voxel‐wise approach.ResultAD patients demonstrated elevated CSF YKL‐40 compared to CN (p<0.001) and MCI (p<0.001) participants. CSF YKL‐40 was also significantly elevated in Aβ positive participants (p<0.001). ROI analysis revealed negative associations between CSF YKL‐40 and FDG‐PET uptake throughout the cortex in Aβ positive participants but limited to the cingulate cortex in Aβ negative participants. At a voxel‐level, Aβ‐PET uptake was positively associated with CSF YKL‐40 in Aβ positive participants. Meanwhile, a negative association was observed between CSF YKL‐40 and FDG‐PET across the brain in Aβ positive participants, a relationship lost in Aβ negative participants.ConclusionCSF YKL‐40 levels likely become elevated as AD progresses due to gradual amyloid deposition. Contrary to previous findings, reactive astrocytosis, as measured here with CSF YKL‐40, was associated with a reduction in glucose metabolism in amyloid positive participants, possibly due to the damaged caused to neurons by the AD pathology.