Diagnostic Fluid Biomarkers in Alzheimer’s Disease: Blood and Cerebrospinal Fluid

doi:10.21203/rs.3.rs-763031/v1

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Diagnostic Fluid Biomarkers in Alzheimer’s Disease: Blood and Cerebrospinal Fluid

https://doi.org/10.21203/rs.3.rs-763031/v1

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Background: Potential biomarkers for Alzheimer’s disease (AD) include amyloid β 1-42 (Aβ 1-42 ), t-Tau, p-Tau 181 , neurofilament light chain (NFL), and neuroimaging, but the feasibility of using these for the diagnosis and monitoring of AD has not been reported. Therefore, further development of these biomarkers is essential.

Methods: We measured NFL and Aβ 1-42 concentrations in CSF and plasma samples from 136 participants and performed correlation analysis to evaluate the utility of these biomarkers for early diagnosis and monitoring of disease progression in AD spectrum.

Results: With disease progression, concentrations of NFL increased, and those of Aβ 1-42 were decreases. The plasma and CSF values of NFL/Aβ 1-42 were strongly correlated ( r = 0.558). In addition, the plasma value of NFL/Aβ 1-42 was strong correlated with hippocampal volume/ICV ( r = 0.409). In the early stage of AD, the plasma_NFL/Aβ 1-42 was associated with higher diagnostic accuracy than were the individual biomarkers. Moreover, in preclinical AD, plasma_NFL/Aβ 1-42 changed more rapidly than did either the t-Tau or the p-Tau 181 values measured in the CSF.

Conclusions: Taken together, our findings highlight the utility of plasma_NFL/Aβ 1-42 as a biomarker for early diagnosis and monitoring of disease progression in AD spectrum.

Molecular Biology

Neurology

Cellular & Molecular Neuroscience

Alzheimer's disease

plasma biomarkers

NFL

Aβ1-42

diagnosis

Table 1. Patient demographics (n=136)

Characteristics	Total	CN (n=51)		aMCI (n=54)		AD dementia (n=31)
Characteristics	Total	Aβ -	Aβ + (Preclinical AD)	Aβ -	Aβ + (Prodromal AD)	Aβ +
N	136	28	23	22	32	31
Age, mean (SD), y	136	69.4 (6.3)	73.9 (2.5)*	69.1 (8.6)	72.7 (8.0)*^†	65.2 (8.7)*^†
Education, mean (SD), y	132	9.3 (4.2)	11.2 (5.5)	10.4 (5.1)	9.6 (5.1)	6.4 (3.5)*^†
Female sex, No. (%)	136	17 (60.7)	10 (43.5)	6 (27.3)	16 (50.0)	21.0 (67.7)
K-MMSE score, mean (SD)	131	26.5 (2.3)	27.5 (1.9)	25.7 (3.1)	24.8 (2.8)*	18.9 (4.3)*^†
APOE ε4 carrier, No. (%)	133	3 (10.7)	16 (69.5)*	2 (9.1)	26 (81.3)*^†	24 (77.4)*^†
CSF biomarkers, mean (SD), pg/ml
NFL concentrations, pg/mL	136	655.7 (150.0)	989.2 (487.5)*	693.7 (281.7)	960.5 (398.3)*^†	970.4 (360.9)*^†
Aβ_1-42 concentrations, pg/mL	136	1089.3 (160.2)	516.4 (192.3)*	947.3 (161.5)	473.0 (147.1)*^†	399.1 (135.1)*^†
t-Tau concentrations, pg/mL	136	209.7 (54.6)	322.9 (122.1)*	206.8 (70.9)	475.7 (210.8)*^†	522.8 (217.1)*^†
p-Tau₁₈₁ concentrations, pg/mL	136	40.0 (8.8)	52.6 (19.4)*	38.2 (9.4)	72.2 (26.8)*^†	74.4 (27.0)*^†
Plasma biomarkers, mean (SD), pg/ml
NFL concentrations, pg/mL	136	16.7 (6.0)	20.9 (6.5)*	18.1 (9.1)	22.5 (9.3)*	21.8 (6.6)*
Aβ_1-42 concentrations, pg/mL	136	12.7 (3.9)	9.9 (3.0)*	12.4 (3.8)	9.5 (2.2) *^†	8.2 (2.4)*^†
Combination biomarkers, ratio
CSF_NFL/Aβ_1-42ratio	136	0.62 (0.17)	2.02 (1.0)*	0.74 (0.3)	2.29 (1.3)*^†	2.62 (1.18)*^†
Plasma_NFL/Aβ_1-42ratio	136	1.46 (0.65)	2.46 (1.3)*	1.46 (0.5)	2.46 (1.1)*^†	2.92 (1.19)*^†
Neuroimaging
Aβ-PET (SUVR score)	135	1.0 (0.06)	1.24 (0.13)*	0.97 (0.06)	1.30 (0.19)*^†	1.3886 (0.11)*^†
Hippocampal volume/ICV	134	0.0029 (0.00032)	0.0027 (0.00031)	0.0025 (0.00043)	0.0024 (0.00037)*	0.0021 (0.00038)*^†
Entorhinal cortex (mm)	134	3.4213 (0.32244)	3.3355 (2.28296)	3.3066 (0.47337)	3.0681 (0.38707)*	2.9610 (0.45533)*^†

Values are presented as means ± SD. Abbreviation: K-MMSE, Korean Mini-Mental State Examination; ICV, Intracranial volume; SUVR, Standardized uptake value ratio; CSF, Cerebrospinal fluid; Aβ_1-42, amyloid beta_1-42; t-Tau, total Tau protein, p-Tau, phosphorylated Tau protein; NFL, neurofilament light chain; CN, cognitive normal; aMCI, amnestic mild cognitive impairment; AD, Alzheimer’s disease. Statistically significant difference analysis using ANCOVA were adjusted sex and age. * Indicates a statistically significant difference between the indicated group and the amyloid-negative CN group. ^† Indicates a statically significant difference between amyloid-negative aMCI group.

Table 2. Correlations between CSF biomarkers, plasma biomarkers, and neuroimaging data

Molecules

CSF biomarkers

Plasma biomarkers

Combination biomarkers

Neuroimaging data

NFL

Aβ_1-42

t-Tau

p-Tau₁₈₁

NFL

Aβ_1-42

CSF_

NFL/Aβ_1-42

Plasma_

NFL/Aβ_1-42

Aβ-PET (SUVR)

Hippocampal volume/ICV

Entorhinal thickness

CSF NFL concentrations

- 0.259**

0.486*

0.502*

0.608*

- 0.110

0.710*

0.521*

0.334*

- 0.359**

- 0.194**

CSF Aβ_1-42

concentrations

- 0.410*

- 0.357*

- 0.242**

0.472*

- 0.736*

- 0.462*

- 0.701*

0.340*

0.245*

CSF t-Tau

concentrations

0.923*

0.265**

- 0.305*

0.491*

0.382*

0.617*

- 0.427*

- 0.378*

CSF p-Tau₁₈₁

concentrations

0.280**

- 0.304*

0.476*

0.364*

0.555*

- 0.392*

- 0.334*

Plasma NFL

concentrations

0.169**

0.493*

0.612*

0.218**

- 0.432*

- 0.221**

Plasma Aβ_1-42

concentrations

- 0.321*

- 0.503*

- 0.374*

0.086

0.031

CSF_NFL/Aβ_1-42

ratio

0.562*

0.580*

- 0.379*

- 0.213**

Plasma_NFL/Aβ_1-42

ratio

0.410*

- 0.409*

- 0.132

Aβ-PET

(SUVR score)

- 0.348*

- 0.307*

Hippocampal volume/ICV

0.622*

Entorhinal thickness

Data are presented as Pearson’s correlation coefficient (r). Bold values indicate significant associations (*, p < 0.001; **, p < 0.01). Abbreviations: Aβ, amyloid-beta protein; t-Tau, total Tau protein; p-Tau, phosphorylated Tau protein; NFL, neurofilament light chain; ICV, Intracranial volume; SUVR, standardized uptake value ratio; CSF, cerebrospinal fluid.

Table 3. Diagnostic accuracy and cut-off values for differentiating patients group

		CSF biomarker (pg/mL)				Plasma biomarker (pg/mL)		Combination (∆, delta ratio)		Neuroimaging data
		NFL	Aβ_1-42	t-Tau	p-Tau¹⁸¹	NFL	Aβ_1-42	CSF_ NFL/Aβ_1-42	Plasma_ NFL/Aβ_1-42	Aβ-PET (SUVR)	Hippocampal volume/ICV	Entorhinal cortex
CN (Aβ -) versus Pre-AD	Cutoff	> 696.2	< 817.3	> 241.5	> 43.6	> 17.3	< 10.45	> 0.89	> 1.7	> 1.0695	< 0.0028	< 3.3995
	Sen (%)	65.2	96.4	76.2	66.7	69.6	67.9	100.0	69.6	91.3	57.1	57.1
	Spe (%)	60.7	95.2	67.9	64.3	50.0	69.6	96.4	66.7	82.1	56.5	56.5
	AUC (95%CI)	0.731 (0.59-0.88)	0.994 (0.98-1.00)	0.776 (0.63-0.92)	0.711 (0.55-0.87)	0.668 (0.52-0.82)	0.741 (0.60-0.88)	1.000 (1.00-1.00)	0.791 (0.67-0.91)	0.974 (0.94-1.0)	0.624 (0.47-0.78)	0.598 (0.44-0.76)
	p value	0.005	< 0.001	0.003	0.010	0.041	0.003	< 0.001	< 0.001	< 0.001	0.130	0.233
CN (Aβ -) versus Pro-AD	Cut-off	> 735.7	< 745.6	> 276.9	> 48.8	> 19.0	< 9.3	> 0.94	> 2.05	> 1.1015	< 0.0026	< 3.2835
	Sen (%)	75.8	100.0	84.8	81.8	63.6	84.6	93.9	72.2	90.6	75.0	75.0
	Spe (%)	71.4	93.9	85.7	82.1	57.1	61.1	96.4	76.9	92.9	75.0	74.2
	AUC (95%CI)	0.781 (0.66-0.90)	1.000 (1.00-1.00)	0.922 (0.85-0.99)	0.890 (0.80-0.98)	0.696 (0.57-0.83)	0.748 (0.58-0.92)	0.988 (0.97-1.00)	0.865 (0.74-0.99)	0.951 (0.89-1.00)	0.826 (0.72-0.93)	0.793 (0.68-0.91)
	p value	< 0.001	< 0.001	< 0.001	< 0.001	0.009	0.02	< 0.001	0.001	< 0.001	< 0.001	< 0.001
CN (Aβ -) versus AD dementia	Cut-off	> 752.4	< 620.0	> 284.7	> 52.4	> 20.9	< 8.5	> 1.26	> 2.30	> 1.2075	< 0.0025	< 3.2675
	Sen (%)	71.0	100.0	87.1	83.9	64.5	84.6	96.8	93.8	100.0	85.7	75.0
	Spe (%)	75.0	93.5	89.3	89.3	67.9	75.0	100.0	92.3	100.0	83.3	73.3
	AUC (95%CI)	0.782 (0.67-0.90)	0.997 (0.99-1.00)	0.962 (0.92-1.00)	0.898 (0.81-0.97)	0.710 (0.58-0.84)	0.916 (0.82-1.00)	0.999 (0.99-1.00)	0.964 (0.90-1.00)	1.00 (1.00-1.00)	0.923 (0.85-0.99)	0.804 (0.69-0.92)
	p value	< 0.001	< 0.001	< 0.001	< 0.001	0.006	< 0.001	< 0.001	< 0.001	< 0.001	< 0.001	< 0.001
aMCI (Aβ -) versus Pro-AD	Cut-off	> 763.6	< 745.6	> 259.5	> 45.0	> 18.8	< 10.45	> 1.08	> 1.77	> 1.0545	< 0.0024	< 3.2530
	Sen (%)	66.7	95.5	87.9	84.8	63.6	77.3	84.8	75.0	90.6	54.5	68.2
	Spe (%)	68.2	93.9	86.4	86.4	63.6	68.8	86.4	72.7	90.9	53.1	67.7
	AUC (95%CI)	0.719 (0.58-0.86)	0.986 (0.96-1.00)	0.919 (0.84-0.99)	0.905 (0.82-0.99)	0.650 (0.49-0.81)	0.769 (0.62-0.92)	0.947 (0.90-0.99)	0.822 (0.71-0.93)	0.960 (0.90-1.00)	0.561 (0.40-0.72)	0.717 (0.56-0.87)
	p value	0.006	< 0.001	< 0.001	< 0.001	0.061	0.001	< 0.001	< 0.001	< 0.001	0.449	0.009

Statistically-derived optimal cut-off values were determined with the best balance between sensitivity (Sen) and specificity (Spe) values. Discrimination of prodromal AD and AD dementia groups from the cognitively normal group was performed using receiver operating characteristic (ROC) curve analysis and quantified by the area under the curve (AUC) using SPSS software version 24.0.

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Diagnostic Fluid Biomarkers in Alzheimer’s Disease: Blood and Cerebrospinal Fluid

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