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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; pfdr < 0.05). FW was significantly higher in those with AD compared to CN in all the examined regions (mean Cohen d = 1.41; pfdr < 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 r2 = 0.10; pfdr < 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.
Glossary
- AD=
- Alzheimer disease;
- ADRC=
- Alzheimer's Disease Research Center;
- ANCOVA=
- analysis of covariance;
- CDR-SB=
- Clinical Dementia Rating–Sum of Boxes;
- CN=
- cognitively normal;
- dMRI=
- diffusion MRI;
- DTI=
- diffusion tensor imaging;
- EMCI=
- early MCI;
- FAt=
- FW-corrected fractional anisotropy;
- frPSI=
- Failure to Recover from Proactive Semantic Inference;
- FSL=
- FMRIB Software Library;
- FW=
- free water;
- LASSI-L=
- Loewenstein-Acevedo Scale for Semantic Interference and Learning;
- LMCI=
- late MCI;
- MCI=
- mild cognitive impairment;
- MMSE=
- Mini-Mental State Examination;
- MNI=
- Montreal Neurological Institute;
- MoCA=
- Montreal Cognitive Assessment;
- ROI=
- region of interest;
- SUVR=
- standardized uptake value ratio
Footnotes
Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
- Received April 22, 2021.
- Accepted in final form November 30, 2021.
- © 2021 American Academy of Neurology
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