Plasma Total-Tau and Neurofilament Light Chain as Diagnostic Biomarkers of Alzheimer’s Disease Dementia and Mild Cognitive Impairment in Adults with Down Syndrome

Article type: Research Article

Authors: Petersen, Melissa E.^{a; *} | Rafii, Michael S.^b | Zhang, Fan^a | Hall, James^c | Julovich, David^c | Ances, Beau M.^d | Schupf, Nicole^{e; f; g; h} | Krinsky-McHale, Sharon J.ⁱ | Mapstone, Mark^j | Silverman, Wayne^k | Lott, Ira^k | Klunk, William^l | Head, Elizabeth^m | Christian, Bradⁿ | Foroud, Tatiana^o | Lai, Florence^p | Diana Rosas, H.^q | Zaman, Shahid^{r; s} | Wang, Mei-Cheng^t | Tycko, Benjamin^u | Lee, Joseph H.^e | Handen, Benjamin^l | Hartley, Sigan^v | Fortea, Juan^{w; x} | O’Bryant, Sid^c | for the Alzheimer’s Biomarker Consortium –Down Syndrome (ABC-DS)

Affiliations: [a] University of North Texas Health Science Center, Department of Family Medicine and Institute for Translational Research, Fort Worth, TX, USA | [b] Alzheimer’s Therapeutic Research Institute (ATRI), Keck School of Medicine, University of Southern California, San Diego, CA, USA | [c] University of North Texas Health Science Center, Institute for Translational Research and Department of Pharmacology and Neuroscience, Fort Worth, TX, USA | [d] Washington University School of Medicine in St. Louis, Center for Advanced Medicine Neuroscience, St. Louis, MO, USA | [e] Columbia University Irving Medical Center, Taub Institute for Research on Alzheimer’s Disease and the Aging Brain/G.H. Sergievsky Center, New York, NY, USA | [f] Columbia University, Mailman School of Public Health, Department of Epidemiology, New York, NY, USA | [g] Columbia University Irving Medical Center, Department of Neurology, Neurological Institute, New York, NY, USA | [h] Columbia University Medical Center, Department of Psychiatry, New York, NY, USA | [i] NYS Institute for Basic Research in Developmental Disabilities, Department of Psychology, Staten Island, NY, USA | [j] University of California, Irvine, Department of Neurology, Irvine, CA, USA | [k] University of California, Irvine, School of Medicine, Department of Pediatrics, Orange, CA, USA | [l] University of Pittsburgh, Department of Psychiatry, Pittsburgh, PA, USA | [m] University of California, Irvine, Department of Pathology, Irvine, CA, USA | [n] University of Wisconsin Madison, Department of Medical Physics and Psychiatry, Madison, WI, USA | [o] Indiana University School of Medicine, Department of Medical & Molecular Genetics, Indianapolis, IN, USA | [p] Massachusetts General Hospital, Department of Neurology, Harvard Medical School, Charlestown, MA, USA | [q] Massachusetts General Hospital, Departments of Neurology and Radiology, Harvard Medical School, Charlestown, MA, USA | [r] University of Cambridge, School of Clinical Medicine, Department of Psychiatry, Cambridge, UK | [s] Cambridgeshire and Peterborough NHS Foundation Trust, Fulbourn Hospital, Cambridge, UK | [t] Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA | [u] Columbia University Irving Medical Center, Department of Pathology and Cell Biology, New York, NY, USA | [v] University of Wisconsin, School of Human Ecology and Waisman Center, Madison, WI, USA | [w] Barcelona Down Medical Center, Fundació Catalana de Síndrome de Down, Barcelona, Spain | [x] Sant Pau Memory Unit, Department of Neurology, Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau, Universitat Aut`onoma de Barcelona, Barcelona, Spain

Correspondence: [*] Correspondence to: Melissa Petersen, PhD, University of North Texas Health Science Center, Department of Family Medicine and Institute for Translational Research, 3500 Camp Bowie Blvd, Fort Worth, TX 76107, USA. E-mail: [email protected].

Abstract: Background:The need for diagnostic biomarkers of cognitive decline is particularly important among aging adults with Down syndrome (DS). Growing empirical support has identified the utility of plasma derived biomarkers among neurotypical adults with mild cognitive impairment (MCI) and Alzheimer’s disease (AD); however, the application of such biomarkers has been limited among the DS population. Objective:This study aimed to investigate the cross-sectional diagnostic performance of plasma neurofilament light chain (Nf-L) and total-tau, individually and in combination among a cohort of DS adults. Methods:Plasma samples were analyzed from n = 305 (n = 225 cognitively stable (CS); n = 44 MCI-DS; n = 36 DS–AD) participants enrolled in the Alzheimer’s Biomarker Consortium —Down Syndrome. Results:In distinguishing DS-AD participants from CS, Nf-L alone produced an AUC of 90%, total-tau alone reached 74%, and combined reached an AUC of 86%. When age and gender were included, AUC increased to 93%. Higher values of Nf-L, total-tau, and age were all shown to be associated with increased risk for DS-AD. When distinguishing MCI-DS participants from CS, Nf-L alone produced an AUC of 65%, while total-tau alone reached 56%. A combined model with Nf-L, total-tau, age, and gender produced an AUC of 87%. Both higher values in age and total-tau were found to increase risk for MCI-DS; Nf-L levels were not associated with increased risk for MCI-DS. Conclusion:Advanced assay techniques make total-tau and particularly Nf-L useful biomarkers of both AD pathology and clinical status in DS and have the potential to serve as outcome measures in clinical trials for future disease-modifying drugs.

Keywords: Neurofilament light chain, proteomics, sensitivity, specificity, total-tau, trisomy 21

DOI: 10.3233/JAD-201167

Journal: Journal of Alzheimer's Disease, vol. 79, no. 2, pp. 671-681, 2021