Neurofilament light chain concentration mediates the association between regional medial temporal lobe structure and memory in adults with Down syndrome

Natalie DiProspero; Mithra Sathishkumar; John Janecek; Anna Smith; Liv McMillan; Melissa Petersen; Nicholas Tustison; David B Keator; Eric Doran; Christy L Hom; Dana Nguyen; Howard Andrews; Sharon Krinsky-McHale; Adam M Brickman; H Diana Rosas; Florence Lai; Elizabeth Head; Mark Mapstone; Wayne Silverman; Ira T Lott; Sid O'Bryant; Michael A Yassa

doi:10.1002/dad2.12542

Neurofilament light chain concentration mediates the association between regional medial temporal lobe structure and memory in adults with Down syndrome

Alzheimers Dement (Amst). 2024 Feb 12;16(1):e12542. doi: 10.1002/dad2.12542. eCollection 2024 Jan-Mar.

Authors

Natalie DiProspero^{1

2}, Mithra Sathishkumar^{1

2}, John Janecek^{1

2}, Anna Smith^{1

2}, Liv McMillan^{1

2}, Melissa Petersen³, Nicholas Tustison^{1

4}, David B Keator⁵, Eric Doran⁶, Christy L Hom⁶, Dana Nguyen⁶, Howard Andrews⁷, Sharon Krinsky-McHale⁸, Adam M Brickman^{8

9}, H Diana Rosas¹⁰, Florence Lai¹⁰, Elizabeth Head^{2

11}, Mark Mapstone^{2

12}, Wayne Silverman⁶, Ira T Lott⁶, Sid O'Bryant³, Michael A Yassa^{1

2

5

12}

Affiliations

¹ Department of Neurobiology and Behavior School of Biological Sciences University of California Irvine California USA.
² Center for the Neurobiology of Learning and Memory University of California Irvine California USA.
³ Institute for Translational Research University of North Texas Health Science Center Fort Worth Texas USA.
⁴ Department of Radiology University of Virginia Charlottesville Virginia USA.
⁵ Department of Psychiatry and Behavioral Sciences School of Medicine University of California Irvine California USA.
⁶ Department of Pediatrics School of Medicine University of California Irvine California USA.
⁷ Department of Psychiatry College of Physicians and Surgeons Columbia University New York New York USA.
⁸ Department of Neurology College of Physicians and Surgeons Columbia University New York New York USA.
⁹ Taub Institute for Research on Alzheimer's Disease and the Aging Brain College of Physicians and Surgeons Columbia University New York New York USA.
¹⁰ Department of Neurology Massachusetts General Hospital Boston Massachusetts USA.
¹¹ Department of Pathology School of Medicine University of California Irvine California USA.
¹² Department of Neurology School of Medicine University of California Irvine California USA.

Abstract

Introduction: Virtually all people with Down syndrome (DS) develop neuropathology associated with Alzheimer's disease (AD). Atrophy of the hippocampus and entorhinal cortex (EC), as well as elevated plasma concentrations of neurofilament light chain (NfL) protein, are markers of neurodegeneration associated with late-onset AD. We hypothesized that hippocampus and EC gray matter loss and increased plasma NfL concentrations are associated with memory in adults with DS.

Methods: T1-weighted structural magnetic resonance imaging (MRI) data were collected from 101 participants with DS. Hippocampus and EC volume, as well as EC subregional cortical thickness, were derived. In a subset of participants, plasma NfL concentrations and modified Cued Recall Test scores were obtained. Partial correlation and mediation were used to test relationships between medial temporal lobe (MTL) atrophy, plasma NfL, and episodic memory.

Results: Hippocampus volume, left anterolateral EC (alEC) thickness, and plasma NfL were correlated with each other and were associated with memory. Plasma NfL mediated the relationship between left alEC thickness and memory as well as hippocampus volume and memory.

Discussion: The relationship between MTL gray matter and memory is mediated by plasma NfL levels, suggesting a link between neurodegenerative processes underlying axonal injury and frank gray matter loss in key structures supporting episodic memory in people with DS.

Keywords: Alzheimer's disease; Down syndrome; anterolateral entorhinal cortex; cognitive decline; dementia; episodic memory; hippocampus; medial temporal lobe; mild cognitive impairment.