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. 2021 May;17(5):822-830.
doi: 10.1002/alz.12233. Epub 2020 Nov 23.

ATN incorporating cerebrospinal fluid neurofilament light chain detects frontotemporal lobar degeneration

Katheryn A Q Cousins  1 , Jeffrey S Phillips  1 , David J Irwin  1 , Edward B Lee  2 , David A Wolk  2 , Leslie M Shaw  2 , Henrik Zetterberg  3   4   5   6 , Kaj Blennow  3   4 , Sarah E Burke  1 , Nikolas G Kinney  1 , Garrett S Gibbons  2 , Corey T McMillan  1 , John Q Trojanowski  2 , Murray Grossman  1
Affiliations

ATN incorporating cerebrospinal fluid neurofilament light chain detects frontotemporal lobar degeneration

Katheryn A Q Cousins et al. Alzheimers Dement. 2021 May.

Abstract

Introduction: The ATN framework provides an in vivo diagnosis of Alzheimer's disease (AD) using cerebrospinal fluid (CSF) biomarkers of pathologic amyloid plaques (A), tangles (T), and neurodegeneration (N). ATN is rarely evaluated in pathologically confirmed patients and its poor sensitivity to suspected non-Alzheimer's pathophysiologies (SNAP), including frontotemporal lobar degeneration (FTLD), leads to misdiagnoses. We compared accuracy of ATN (ATNTAU ) using CSF total tau (t-tau) to a modified strategy (ATNNfL ) using CSF neurofilament light chain (NfL) in an autopsy cohort.

Methods: ATNTAU and ATNNfL were trained in an independent sample and validated in autopsy-confirmed AD (n = 67) and FTLD (n = 27).

Results: ATNNfL more accurately identified FTLD as SNAP (sensitivity = 0.93, specificity = 0.94) than ATNTAU (sensitivity = 0.44, specificity = 0.97), even in cases with co-occurring AD and FTLD. ATNNfL misclassified fewer AD and FTLD as "Normal" (2%) than ATNTAU (14%).

Discussion: ATNNfL is a promising diagnostic strategy that may accurately identify both AD and FTLD, even when pathologies co-occur.

Keywords: ATN; Alzheimer's disease; biomarkers; cerebrospinal fluid; frontotemporal degeneration; neurofilament light chain; suspected non-Alzheimer's pathophysiology; total tau.

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Conflict of interest statement

CONFLICTS OF INTEREST

Henrik Zetterberg has served at scientific advisory boards for Denali, Roche Diagnostics, Wave, Samumed, and CogRx; has given lectures in symposia sponsored by Fujirebio, Alzecure, and Biogen; and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. Kaj

Blennow has served as a consultant, at advisory boards, or at data monitoring committees for Abcam, Axon, Biogen, Julius Clinical, Lilly, MagQu, Novartis, Roche Diagnostics, and Siemens Healthineers, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. Corey T. McMillan receives research funding from Biogen, Inc and provides consulting services for Invicro and Axon Advisors on behalf of Translational Bioinformatics, LLC. He also receives an honorarium as Associate Editor of NeuroImage: Clinical. All other authors have no conflicts of interest to report.

Figures

FIGURE 1
FIGURE 1
Boxplots of N measures in independent training sample of controls and familial patients. Comparisons across controls and familial patients of (Panel A) cerebrospinal fluid (CSF) total tau (t-tau) and (Panel B) CSF neurofilament light chain (NfL). Horizontal black lines indicate sample-specific optimal cut-points. Subjects above the line are considered N+; subjects below are N−. Color indicates mutation status (blue shades indicate familial frontotemporal lobar degeneration, red shades indicate familial Alzheimer’s disease, gray indicates not available [NA] for controls)
FIGURE 2
FIGURE 2
Boxplots of total tau (t-tau) and neurofilament light chain (NfL) in autopsy-confirmed Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD). Comparisons across pathology groups of (Panel A) cerebrospinal fluid (CSF) t-tau and (Panel B) CSF NfL. Shape indicates N status (−/+). Horizontal black lines indicate optimal cut-points. Patients above the line are considered N+; patients below are N−. Color indicates pathological subtype: AD (light red; negligible copathology), AD+FTLD (royal blue), ADmixed (dark red), FTLD (light blue), FTLD+AD (royal blue), FTLDmixed (dark blue)
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