Table 2 Baseline and annual rates of change in plasma neurofilament light (v¹ NfL, and δNfL) and their association with cognitive performance at v¹ and change over time: overall and race-specific mixed-effects linear regression models: HANDLS 2004–2013^a.

From: Plasma neurofilament light as a potential biomarker for cognitive decline in a longitudinal study of middle-aged urban adults

	NfL, pg/mL, (v₁ Log_e transformed, z-scored)		δNfL, pg/mL (annualized change between v¹ and v², Log^e transformed, z-score)
	Model 1	Model 2	Model 1	Model 2
	γ ± SE	γ ± SE	γ ± SE	γ ± SE
Overall	(N = 625, k = 1.9−2.0)	(N = 625, k = 1.9−2.0)	(N = 625, k = 1.9−2.0)	(N = 625, k = 1.9−2.0)
Outcome = Cognitive performance test score
Normalized MMSE
Exposure, γ_0a	+1.024 ± 0.667^b	+0.688 ± 0.607^b	+0.719 ± 0.574	+1.009 ± 0.508**
Exposure × TIME, γ_1a	−0.254 ± 0.158^c	−0.208 ± 0.161^c	−0.004 ± 0.144	−0.086 ± 0.143
CVLT-List A
Exposure, γ_0a	+0.404 ± 0.310	+0.486 ± 0.302	−0.208 ± 0.264	−0.177 ± 0.249
Exposure × TIME, γ_1a	−0.078 ± 0.067	−0.051 ± 0.070	+0.061 ± 0.060	+0.035 ± 0.060
CVLT-DFR
Exposure, γ_0a	+0.164 ± 0.144	+0.226 ± 0.143	−0.127 ± 0.122	−0.139 ± 0.118
Exposure × TIME, γ_1a	−0.038 ± 0.031	−0.029 ± 0.032	+0.051 ± 0.027*	+0.045 ± 0.028
BVRT
Exposure, γ_0a	−0.072 ± 0.223	−0.211 ± 0.216	−0.038 ± 0.192	−0.042 ± 0.181
Exposure × TIME, γ_1a	+0.059 ± 0.048	+0.058 ± 0.051	+0.005 ± 0.044	+0.015 ± 0.044
BTA
Exposure, γ_0a	+0.164 ± 0.105	+0.100 ± 0.105	+0.073 ± 0.088	+0.102 ± 0.086
Exposure × TIME, γ_1a	−0.036 ± 0.025	-0.037 ± 0.026	−0.013 ± 0.022	−0.016 ± 0.022
AF
Exposure, γ_0a	−0.107 ± 0.253	−0.176 ± 0.250	+0.094 ± 0.218	+0.097 ± 0.210
Exposure × TIME, γ_1a	+0.007 ± 0.046	+0.006 ± 0.048	−0.071 ± 0.041*	−0.077 ± 0.042*
DS-F
Exposure, γ_0a	+0.104 ± 0.103	+0.046 ± 0.098	−0.021 ± 0.089	0.0077 ± 0.083
Exposure × TIME, γ_1a	−0.015 ± 0.018	−0.018 ± 0.019	−0.010 ± 0.016	−0.011 ± 0.017
DS-B
Exposure, γ_0a	+0.056 ± 0.097^b	+0.009 ± 0.091	+0.066 ± 0.084	+0.094 ± 0.076
Exposure × TIME, γ_1a	−0.023 ± 0.020	−0.025 ± 0.020	+0.005 ± 0.018	+0.000 ± 0.018
CDT
Exposure, γ_0a	+0.057 ± 0.056^b	+0.040 ± 0.057^b	−0.005 ± 0.048	−0.005 ± 0.048
Exposure × TIME, γ_1a	−0.011 ± 0.015^c	−0.010 ± 0.016^c	−0.003 ± 0.014 ^c	+0.001 ± 0.014 ^c
Log_e(TRAILS A)
Exposure, γ_0a	+0.032 ± 0.016*	+0.025 ± 0.017	+0.013 ± 0.014	+0.014 ± 0.014
Exposure × TIME, γ_1a	−0.001 ± 0.004	−0.001 ± 0.004	+0.002 ± 0.004	+0.0021 ± 0.004
Log_e(TRAILS B)
Exposure, γ_0a	+0.026 ± 0.029	+0.023 ± 0.028	+0.014 ± 0.025	+0.010 ± 0.024
Exposure × TIME, γ_1a	−0.004 ± 0.006	−0.004 ± 0.006	+0.001 ± 0.006	+0.002 ± 0.006
Whites	(N = 273, k = 1.9−2.0)	(N = 273, k = 1.9−2.0)	(N = 273, k = 1.9−2.0)	(N = 273, k = 1.9−2.0)
Outcome = Cognitive performance test score
Normalized MMSE
Exposure, γ_0a	+2.334 ± 0.988**	+1.616 ± 0.836*	+0.279 ± 0.880	+0.581 ± 0.731
Exposure × TIME, γ_1a	−0.661 ± 0.252***	−0.565 ± 0.246**	+0.060 ± 0.239	+0.005 ± 0.230
CVLT-List A
Exposure, γ_0a	+0.311 ± 0.458	+0.194 ± 0.433	−0.518 ± 0.395	−0.369 ± 0.370
Exposure × TIME, γ_1a	−0.025 ± 0.116	+0.026 ± 0.120	+0.099 ± 0.106	+0.071 ± 0.108
CVLT-DFR
Exposure, γ_0a	+0.238 ± 0.214	+0.190 ± 0.208	−0.299 ± 0.184	−0.290 ± 0.178
Exposure × TIME, γ_1a	−0.032 ± 0.049	−0.008 ± 0.050	+0.092 ± 0.045**	+0.086 ± 0.045*
BVRT
Exposure, γ_0a	-0.217 ± 0.319	-0.206 ± 0.294	+0.147 ± 0.283	+0.008 ± 0.257
Exposure × TIME, γ_1a	+0.076 ± 0.067	+0.066 ± 0.069	−0.058 ± 0.063	−0.027 ± 0.063
BTA
Exposure, γ_0a	+0.375 ± 0.160**	+0.273 ± 0.158*	−0.010 ± 0.135	+0.013 ± 0.130
Exposure × TIME, γ_1a	−0.072 ± 0.040*	−0.055 ± 0.040	−0.002 ± 0.036	−0.003 ± 0.035
AF
Exposure, γ_0a	−0.282 ± 0.379	−0.442 ± 0.363	+0.048 ± 0.335	−0.004 ± 0.321
Exposure × TIME, γ_1a	+0.004 ± 0.075	−0.005 ± 0.077	−0.075 ± 0.070	−0.063 ± 0.071
DS-F
Exposure, γ_0a	0.122 ± 0.154	+0.030 ± 0.136	+0.118 ± 0.136	+0.108 ± 0.118
Exposure × TIME, γ_1a	−0.021 ± 0.030	−0.025 ± 0.030	+0.012 ± 0.028	+0.016 ± 0.028
DS-B
Exposure, γ_0a	+0.217 ± 0.153	+0.103 ± 0.137	+0.167 ± 0.136	+0.207 ± 0.119*
Exposure × TIME, γ_1a	−0.048 ± 0.033	−0.044 ± 0.034	+0.031 ± 0.031	+0.022 ± 0.031
CDT
Exposure, γ_0a	−0.075 ± 0.079	−0.066 ± 0.078	+0.085 ± 0.070	+0.091 ± 0.068
Exposure × TIME, γ_1a	+0.036 ± 0.023	+0.035 ± 0.024	−0.041 ± 0.022*	−0.043 ± 0.022*
Log_e(TRAILS A)
Exposure, γ_0a	+0.034 ± 0.021	+0.038 ± 0.020*	+0.004 ± 0.019	+0.004 ± 0.018
Exposure × TIME, γ_1a	−0.002 ± 0.005	−0.001 ± 0.005	+0.002 ± 0.004	+0.001 ± 0.005
Log_e(TRAILS B)
Exposure, γ_0a	+0.000 ± 0.041	+0.018 ± 0.037	+0.029 ± 0.036	+0.019 ± 0.032
Exposure × TIME, γ_1a	−0.002 ± 0.009	−0.004 ± 0.009	+0.002 ± 0.008	+0.002 ± 0.008
African American	(N = 352, k = 1.9)	(N = 352, k = 1.9)	(N = 352, k = 1.9)	(N = 352, k = 1.9)
Outcome = Cognitive performance test score
Normalized MMSE
Exposure, γ_0a	−0.183 ± 0.910	−0.075 ± 0.870	+1.153 ± 0.756	+1.305 ± 0.705*
Exposure × TIME, γ_1a	+0.047 ± 0.203	+0.025 ± 0.210	−0.053 ± 0.180	−0.102 ± 0.182
CVLT-List A
Exposure, γ_0a	+0.336 ± 0.413	+0.562 ± 0.412	+0.097 ± 0.343	+0.053 ± 0.332
Exposure × TIME, γ_1a	−0.099 ± 0.080	−0.108 ± 0.084	+0.040 ± 0.068	+0.023 ± 0.070
CVLT-DFR
Exposure, γ_0a	+0.066 ± 0.193	+0.216 ± 0.197	+0.039 ± 0.160	−0.009 ± 0.158
Exposure × TIME, γ_1a	−0.046 ± 0.040	−0.052 ± 0.042	+0.022 ± 0.034	+0.017 ± 0.035
BVRT
Exposure, γ_0a	+0.158 ± 0.317	−0.117 ± 0.314	−0.228 ± 0.264	−0.139 ± 0.255
Exposure × TIME, γ_1a	+0.025 ± 0.069	+0.034 ± 0.072	+0.046 ± 0.060	+0.043 ± 0.061
BTA
Exposure, γ_0a	+0.020 ± 0.140	+0.005 ± 0.141	+0.157 ± 0.116	+0.173 ± 0.115
Exposure × TIME, γ_1a	−0.023 ± 0.032	−0.036 ± 0.034	−0.025 ± 0.028	−0.022 ± 0.028
AF
Exposure, γ_0a	−0.110 ± 0.336	−0.062 ± 0.337	+0.193 ± 0.280	+0.182 ± 0.275
Exposure × TIME, γ_1a	+0.007 ± 0.059	+0.016 ± 0.061	−0.075 ± 0.051	−0.098 ± 0.052*
DS-F
Exposure, γ_0a	+0.081 ± 0.139	+0.043 ± 0.137	−0.130 ± 0.116	−0.085 ± 0.112
Exposure × TIME, γ_1a	−0.011 ± 0.024	−0.013 ± 0.025	−0.023 ± 0.021	−0.025 ± 0.021
DS-B
Exposure, γ_0a	−0.086 ± 0.126	−0.082 ± 0.118	−0.020 ± 0.103	−0.021 ± 0.096
Exposure × TIME, γ_1a	−0.004 ± 0.024	−0.007 ± 0.025	−0.008 ± 0.021	−0.007 ± 0.022
CDT
Exposure, γ_0a	+0.156 ± 0.079*	+0.134 ± 0.081	−0.072 ± 0.066	−0.070 ± 0.066
Exposure × TIME, γ_1a	−0.046 ± 0.021**	−0.043 ± 0.021**	+0.022 ± 0.0180	+0.026 ± 0.018
Log_e(TRAILS A)
Exposure, γ_0a	+0.025 ± 0.025	+0.008 ± 0.025	+0.020 ± 0.021	+0.027 ± 0.020
Exposure × TIME, γ_1a	−0.001 ± 0.006	−0.001 ± 0.006	+0.003 ± 0.005	+0.003 ± 0.005
Log_e(TRAILS B)
Exposure, γ_0a	+0.039 ± 0.042	+0.019 ± 0.042	−0.001 ± 0.035	−0.001 ± 0.034
Exposure × TIME, γ_1a	−0.004 ± 0.009	−0.003 ± 0.009	+0.001 ± 0.007	+0.003 ± 0.007

Abbreviations: AF Animal Fluency; BTA Brief Test of Attention; BVRT Benton Visual Retention Test; CDT Clock Drawing Test; CES-D Center for Epidemiologic Studies-Depression; CVLT-DFR California Verbal Learning Test-Delayed Free Recall; CVLT-List A California Verbal Learning Test-List A; DS-B Digits Span-Backward; DS-F Digits Span-Forward; HANDLS Healthy Aging in Neighborhoods of Diversity across the Life Span; HEI-2010 Healthy Eating Index, 2010 version; k number of observations/participant; MMSE Mini-Mental State Examination; SD standard deviation; SE standard error; NfL neurofilament light; TRAILS A Trailmaking test, part A; TRAILS B Trailmaking test, part B; WRAT-3 Wide Range Achievement Test, 3rd revision; X mean.
*p < 0.10; **p < 0.05; ***p < 0.010; ****p < 0.001, test for null hypothesis of γ = 0. Bolded values passed correction for multiple testing; underlined values passed q < 0.05 correction for multiple testing in Model 1.
^aModels 1A.1−1K.2 included each of NfL (Log_e transformed, z-scored) or δNfL (annualized change in Log_e transformed NfL, z-scored), separately as the main predictor for v1 cognitive performance and cognitive change over time (11 test scores), using a series of mixed-effects linear regression models, carried out in the overall population, and stratified by race. These models adjusted only for age, sex, race, poverty status, and the inverse mills ratio. Models 2A.1−2K.2 followed a similar approach but adjusted further for selected socio-demographic, lifestyle, and health-related factors, namely educational attainment, the WRAT-3 score, current drug use, current tobacco use, body mass index, self-rated health, co-morbidity index, HEI-2010, total energy intake, and the CES-D total score. 1 SD of baseline Log_e(NfL) is estimated at 0.51; mean = 1.98. dNfL values are annualized changes in Log_e transformed NfL between v₁ and v₂, z-scored. 1 SD of annualized change in Log_e(NfL) is estimated at 0.101; mean = 0.044.
^bp < 0.05 for Race × NfL/δNfL in models that are unstratified by race to which this three-way interaction was included.
^cp < 0.05 for Race × NfL/δNfL × TIME in models that are unstratified by race to which this two-way interaction was included.

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Table 2 Baseline and annual rates of change in plasma neurofilament light (v¹ NfL, and δNfL) and their association with cognitive performance at v¹ and change over time: overall and race-specific mixed-effects linear regression models: HANDLS 2004–2013^a.

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