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. 2021 Sep 24;13(1):160.
doi: 10.1186/s13195-021-00899-0.

Cerebrospinal fluid levels of the neurotrophic factor neuroleukin are increased in early Alzheimer's disease, but not in cerebral amyloid angiopathy

Anna M De Kort  1 , H Bea Kuiperij  1 , Daniel Alcolea  2   3 , Iris Kersten  1 , Alexandra A M Versleijen  4 , Steven M Greenberg  5 , Erik Stoops  6 , Floris H B M Schreuder  1 , Catharina J M Klijn  1 , Alberto Lleó  2   3 , Jurgen A H R Claassen  7 , Marcel M Verbeek  8   9
Affiliations

Cerebrospinal fluid levels of the neurotrophic factor neuroleukin are increased in early Alzheimer's disease, but not in cerebral amyloid angiopathy

Anna M De Kort et al. Alzheimers Res Ther. .

Erratum in

Abstract

Background: Neuroleukin (NLK) is a protein with neurotrophic properties and is present in a proportion of senile plaques and amyloid laden vessels. It has been suggested that NLK is part of a neuroprotective response to amyloid β-induced cell death. The aim of our study was to investigate the value of cerebrospinal fluid (CSF) NLK levels as a biomarker of vascular amyloid deposition in patients with cerebral amyloid angiopathy (CAA) and in patients with amnestic mild cognitive impairment (aMCI) and Alzheimer's disease (AD).

Methods: CSF NLK levels were quantified by ELISA in CAA patients (n = 25) and controls (n = 27) and in two independent samples of aMCI patients, AD patients, and controls: (1) From the Radboud University Medical Center (Nijmegen), we included n = 19 aMCI patients, n = 40 AD patients, and n = 32 controls. (2) From the Hospital of Sant Pau (Barcelona), we included n = 33 aMCI patients, n = 17 AD patients, and n = 50 controls.

Results: CSF NLK levels were similar in CAA patients and controls (p = 0.95). However, we found an elevated CSF concentration of NLK in aMCI (p < 0.0001) and AD patients (p < 0.0001) compared to controls in both samples sets. In addition, we found a correlation of CSF NLK with CSF YKL-40 (age-adjusted-spearman-rank-coefficient = 0.82, p < 0.0001) in aMCI/AD patients, a well-known glial marker of neuro-inflammation.

Conclusions: We found that CSF NLK levels are elevated in aMCI and AD patients compared to controls, but are not increased in CAA patients. CSF NLK levels may be related to an increased neuroinflammatory state in early stages of AD, given its association with YKL-40.

Keywords: Alzheimer’s disease; Amyloid; Biomarkers; Cerebral amyloid angiopathy; Cerebrospinal fluid; Neuro-inflammation; Neuroleukin.

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Conflict of interest statement

E. Stoops is a full-time paid employee and shareholder of ADx NeuroSciences. All other authors report no declaration of interest.

Figures

Fig. 1
Fig. 1
CSF NLK levels in the sporadic CAA patients and controls (A) and in the aMCI/AD patients and controls (B–E), with and without stratification for AT(N) status. Box and scatterplots in all panels (depicting median, interquartile range and range). A NLK levels in CAA patients and controls. The NLK levels were similar (p = 0.95). B CSF NLK levels in aMCI patients, AD patients, and controls from Nijmegen. These levels were increased in aMCI (p = 0.001) and AD patients (p < 0.0001) compared to controls. C NLK levels in A+T+(N+) aMCI/AD patients and A−T−(N−) controls from Nijmegen. NLK levels were significantly higher in A+T+(N+) aMCI/AD patients (p < 0.0001). D CSF NLK levels in aMCI patients, AD patients, and controls from Barcelona. Levels were significantly higher in aMCI patients (p < 0.0001) and AD patients (p < 0.0001) compared to controls. E NLK levels in A+T+(N+) aMCI/AD patients and A−T−(N−) controls from Barcelona. NLK levels were significantly higher in A+T+(N+) aMCI/AD patients (p < 0.0001). Abbreviations: AD, Alzheimer’s disease; CAA, cerebral amyloid angiopathy; CSF, cerebrospinal fluid; aMCI, amnestic mild cognitive impairment; ns, non-significant. **p < 0.01, ***p < 0.001
Fig. 2
Fig. 2
A ROC analysis showed moderately high accuracy levels for discrimination of aMCI from control in the Nijmegen aMCI patients and controls (gray line) and the Barcelona aMCI patients and controls. B ROC analysis showed consistently high accuracy levels for discrimination of AD from control in the Nijmegen AD patients and controls (gray line) and the Barcelona AD patients and controls. Abbreviations: AD, Alzheimer’s disease; AUC area under the curve. The Barcelona cohort serves as a validation cohort
Fig. 3
Fig. 3
Scatter plot of the correlation between CSF NLK levels and YKL-40 levels in a subset (n = 47) of the Barcelona aMCI/AD patients and controls. NLK and YKL-40-levels significantly correlated in the combined aMCI/AD and controls (rSP = 0.51, p < 0.0001, gray line) and in the aMCI/AD patients separately (rSP = 0.79, p < 0.0001, black dots and black line), but not in the controls (rSP = 0.033, p = 0.87, white dots, dotted line). Abbreviations: AD, Alzheimer’s dementia; rSP, Spearman rank coefficient; aMCI, amnestic mild cognitive impairment; NLK, neuroleukin; YKL-40, chitinase-3 like-protein 1
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References

    1. Mattson MP. Pathways towards and away from Alzheimer’s disease. Nature. 2004;430(7000):631–639. doi: 10.1038/nature02621. - DOI - PMC - PubMed
    1. McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR, Jr, Kawas CH, et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011;7(3):263–269. doi: 10.1016/j.jalz.2011.03.005. - DOI - PMC - PubMed
    1. Petersen RC. Mild cognitive impairment as a diagnostic entity. J Intern Med. 2004;256(3):183–194. doi: 10.1111/j.1365-2796.2004.01388.x. - DOI - PubMed
    1. Jack CR, Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB, et al. NIA-AA Research Framework: Toward a biological definition of Alzheimer's disease. Alzheimers Dement. 2018;14(4):535–562. doi: 10.1016/j.jalz.2018.02.018. - DOI - PMC - PubMed
    1. Boyle PA, Yu L, Nag S, Leurgans S, Wilson RS, Bennett DA, Schneider JA. Cerebral amyloid angiopathy and cognitive outcomes in community-based older persons. Neurology. 2015;85(22):1930–1936. doi: 10.1212/WNL.0000000000002175. - DOI - PMC - PubMed

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