Association of Cognitive Impairment With Free Water in the Nucleus Basalis of Meynert and Locus Coeruleus to Transentorhinal Cortex Tract

Abstract

Objective:Determine the relationship between diffusion microstructure and early changes in Alzheimer’s disease (AD) severity as assessed by clinical diagnosis, cognitive performance, dementia severity, and plasma concentrations of neurofilament light chain.Methods:Diffusion MRI scans were collected on cognitively normal participants (CN), patients with early mild cognitive impairment (EMCI), late mild cognitive impairment (LMCI), and AD. Free water (FW) and FW-corrected fractional anisotropy were calculated in the locus coeruleus to transentorhinal cortex tract, four magnocellular regions of the basal forebrain (e.g. nucleus basalis of Meynert), entorhinal cortex, and hippocampus. All patients underwent a battery of cognitive assessments; neurofilament light chain levels were measured in plasma samples.Results:FW was significantly higher in EMCI compared to CN in the locus coeruleus to transentorhinal cortex tract, nucleus basalis of Meynert, and hippocampus (mean Cohen d = 0.54; pfdr<0.05). FW was significantly higher in AD compared to CN in all the examined regions (mean Cohen d = 1.41; pfdr<0.01). Additionally, FW in the hippocampus, entorhinal cortex, nucleus basalis of Meynert, and locus coeruleus to transentorhinal cortex tract positively correlated with all five cognitive impairment metrics, and neurofilament light chain levels (mean r2 = 0.10; pfdr<0.05).Conclusions:These results show that higher FW is associated with greater clinical diagnosis severity, cognitive impairment, and neurofilament light chain. They also suggest that FW elevation occurs in the locus coeruleus to transentorhinal cortex tract, nucleus basalis of Meynert, and hippocampus in the transition from CN to EMCI, while other basal forebrain regions and the entorhinal cortex are not affected until a later stage of AD. FW is a clinically relevant and non-invasive early marker of structural changes related to cognitive impairment.