Winston Thomas Chu1, Wei-En Wang1, Laszlo Zaborszky1, Todd Eliot Golde1, Steven DeKosky1, Ranjan Duara1, David A Loewenstein1, Malek Adjouadi1, Stephen A Coombes1, David E Vaillancourt2. 1. From the J. Crayton Pruitt Family Department of Biomedical Engineering (W.T.C., D.E.V.), Department of Applied Physiology and Kinesiology (W.T.C., W.-e.W., S.A.C., D.E.V.), Department of Neuroscience (T.E.G.); Center for Translational Research in Neurodegenerative Diseases (T.E.G.), Department of Neurology (S.D., D.E.V.), and McKnight Brain Institute (S.D., D.E.V.), University of Florida, Gainesville; Center for Molecular and Behavioral Neuroscience (L.Z.), Rutgers University, Newark, NJ; Wein Center for Alzheimer's Disease and Memory Disorders (R.D., D.A.L.), Mount Sinai Medical Center, Miami Beach; Center for Cognitive Neuroscience and Aging (D.A.L.) and Department of Psychiatry and Behavioral Sciences (D.A.L.), University of Miami Miller School of Medicine; and Center for Advanced Technology and Education (M.A.), Florida International University, Miami. 2. From the J. Crayton Pruitt Family Department of Biomedical Engineering (W.T.C., D.E.V.), Department of Applied Physiology and Kinesiology (W.T.C., W.-e.W., S.A.C., D.E.V.), Department of Neuroscience (T.E.G.); Center for Translational Research in Neurodegenerative Diseases (T.E.G.), Department of Neurology (S.D., D.E.V.), and McKnight Brain Institute (S.D., D.E.V.), University of Florida, Gainesville; Center for Molecular and Behavioral Neuroscience (L.Z.), Rutgers University, Newark, NJ; Wein Center for Alzheimer's Disease and Memory Disorders (R.D., D.A.L.), Mount Sinai Medical Center, Miami Beach; Center for Cognitive Neuroscience and Aging (D.A.L.) and Department of Psychiatry and Behavioral Sciences (D.A.L.), University of Miami Miller School of Medicine; and Center for Advanced Technology and Education (M.A.), Florida International University, Miami. vcourt@ufl.edu.
Abstract
BACKGROUND AND OBJECTIVES: The goal of this work was to determine the relationship between diffusion microstructure and early changes in Alzheimer 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) and patients with early mild cognitive impairment (EMCI), late mild cognitive impairment, and AD. Free water (FW) and FW-corrected fractional anisotropy were calculated in the locus coeruleus to transentorhinal cortex tract, 4 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 patients with EMCI compared to CN in the locus coeruleus to transentorhinal cortex tract, nucleus basalis of Meynert, and hippocampus (mean Cohen d = 0.54; p fdr < 0.05). FW was significantly higher in those with AD compared to CN in all the examined regions (mean Cohen d = 1.41; p fdr < 0.01). In addition, FW in the hippocampus, entorhinal cortex, nucleus basalis of Meynert, and locus coeruleus to transentorhinal cortex tract positively correlated with all 5 cognitive impairment metrics and neurofilament light chain levels (mean r 2 = 0.10; p fdr < 0.05). DISCUSSION: 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 noninvasive early marker of structural changes related to cognitive impairment.
BACKGROUND AND OBJECTIVES: The goal of this work was to determine the relationship between diffusion microstructure and early changes in Alzheimer 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) and patients with early mild cognitive impairment (EMCI), late mild cognitive impairment, and AD. Free water (FW) and FW-corrected fractional anisotropy were calculated in the locus coeruleus to transentorhinal cortex tract, 4 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 patients with EMCI compared to CN in the locus coeruleus to transentorhinal cortex tract, nucleus basalis of Meynert, and hippocampus (mean Cohen d = 0.54; p fdr < 0.05). FW was significantly higher in those with AD compared to CN in all the examined regions (mean Cohen d = 1.41; p fdr < 0.01). In addition, FW in the hippocampus, entorhinal cortex, nucleus basalis of Meynert, and locus coeruleus to transentorhinal cortex tract positively correlated with all 5 cognitive impairment metrics and neurofilament light chain levels (mean r 2 = 0.10; p fdr < 0.05). DISCUSSION: 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 noninvasive early marker of structural changes related to cognitive impairment.
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