Axonal injury partially mediates associations between increased left ventricular mass index and white matter damage


Background and Purpose: Left ventricular (LV) mass index is a marker of subclinical LV wall remodeling that relates to white matter damage in aging, but the molecular pathways underlying this association are unknown. This study assessed if LV mass index related to cerebrospinal fluid (CSF) biomarkers of neuroinflammation (soluble triggering receptor expressed on myeloid cells 2 (sTREM2)), axonal injury (neurofilament light (NFL)), neurodegeneration (total tau (t-tau)), and amyloid-β (Aβ), and whether these biomarkers partially accounted for previously reported associations between increased LV mass index and white matter damage.

Methods: Vanderbilt Memory and Aging Project participants (n=142, 72±6 years) underwent cardiac magnetic resonance to obtain LV mass index (g/m2), lumbar puncture to obtain CSF biomarkers (pg/mL), and diffusion tensor imaging (DTI). Linear regressions related LV mass index to each biomarker. Voxel-wise analyses related LV mass index to DTI metrics. Follow-up models separately assessed LV mass index x diagnosis and LV mass index x apolipoprotein (APOE) ε4 status interaction terms. In models where LV mass index significantly related to a biomarker and white matter microstructure, we assessed if the biomarker mediated associations between LV mass index and white matter microstructure.

Results: Main effect models were null. LV mass index interacted with diagnosis (p=0.01) with higher LV mass index relating to increased NFL among individuals with mild cognitive impairment (MCI) and among APOE-ε4 carriers (p-values<0.04). NFL partially mediated up to 13% of the effect of increased LV mass index on white matter microstructural damage.

Conclusions: Subclinical cardiovascular remodeling is associated with neuroaxonal degeneration among individuals with MCI and among APOE-ε4 carriers. Further, neuroaxonal degeneration partially mediates associations between higher LV mass index and white matter microstructural damage. Findings highlight neuroaxonal degeneration, rather than amyloidosis or neuroinflammation, as a critical component of the pathway between structural cardiovascular remodeling and white matter damage.

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