Neurology | March 6, 2023

Ferreira P, Ferrari-Souza JP, Tissot C, Bellaver B, Leffa D, Lussier F, Povala G, Therriault J, Benedet AL, Ashton NJ, Cohen AD, Lopez OL, Tudorascu D, Klunk WE, Soucy JP, Gauthier S, Villemagne V, Zetterberg H, Blennow K, Rosa-Neto P, Zimmer ER, Karikari TK, Pascoal T

Neurology. 2023 

https://doi.org/10.1212/WNL.0000000000207115

Abstract

Objective: To test the utility of longitudinal changes in plasma phosphorylated tau 181 (p-tau181) and neurofilament light chain (NfL) as surrogate markers for clinical trials targeting cognitively unimpaired (CU) populations.

Methods: We estimated the sample size needed to test a 25% drug effect with 80% of power at a 0.05 level on reducing changes in plasma markers in CU participants from ADNI database.

Results: We included 257 CU individuals [45.5% males; mean age = 73 (6) years; 32% amyloid-beta (Aβ) positive]. Changes in plasma NfL were associated with age, while changes in plasma p-tau181 with progression to amnestic mild cognitive impairment. Clinical trials using p-tau181 and NfL would require 85% and 63% smaller sample sizes, respectively, for a 24-month than a 12-month follow-up. A population enrichment strategy using intermediate levels of Aβ positron emission tomography (Centiloid 20-40) further reduced the sample size of 24-month clinical trial using p-tau181 (73%) and NfL (59%) as a surrogate.

Discussion: Plasma p-tau181/NfL can potentially be used to monitor large-scale population interventions in CU individuals. The enrollment of CU with intermediate Aβ levels constitutes the alternative with the largest effect size and most cost-effective for trials testing drug effect on changes in plasma p-tau181 and NfL.