Neutrophil activation in Alzheimer's disease and mild cognitive impairment: A systematic review and meta-analysis of protein markers in blood and cerebrospinal fluid

Che-Yuan Wu; Kritleen K Bawa; Michael Ouk; Nathan Leung; Di Yu; Krista L Lanctôt; Nathan Herrmann; Maureen Pakosh; Walter Swardfager

doi:10.1016/j.arr.2020.101130

Neutrophil activation in Alzheimer's disease and mild cognitive impairment: A systematic review and meta-analysis of protein markers in blood and cerebrospinal fluid

Ageing Res Rev. 2020 Sep:62:101130. doi: 10.1016/j.arr.2020.101130. Epub 2020 Jul 23.

Authors

Che-Yuan Wu¹, Kritleen K Bawa¹, Michael Ouk¹, Nathan Leung², Di Yu¹, Krista L Lanctôt³, Nathan Herrmann⁴, Maureen Pakosh⁵, Walter Swardfager⁶

Affiliations

¹ Department of Pharmacology & Toxicology, University of Toronto, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada; Hurvitz Brain Sciences Program, Sunnybrook Research Institute, 2075 Bayview Avenue, Toronto, ON, M4N 3M5, Canada.
² Department of Pharmacology & Toxicology, University of Toronto, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada.
³ Department of Pharmacology & Toxicology, University of Toronto, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada; Hurvitz Brain Sciences Program, Sunnybrook Research Institute, 2075 Bayview Avenue, Toronto, ON, M4N 3M5, Canada; Department of Psychiatry, Faculty of Medicine, University of Toronto, 250 College Street, 8th Floor, Toronto, ON, M5T 1R8, Canada; KITE UHN Toronto Rehabilitation Institute, 347 Rumsey Rd, East York, ON, M4G 2V6, Canada; Heart and Stroke Foundation Canadian Partnership for Stroke Recovery, Sunnybrook Research Institute, 2075 Bayview Avenue, Toronto, ON, M4N 3M5, Canada.
⁴ Hurvitz Brain Sciences Program, Sunnybrook Research Institute, 2075 Bayview Avenue, Toronto, ON, M4N 3M5, Canada; Department of Psychiatry, Faculty of Medicine, University of Toronto, 250 College Street, 8th Floor, Toronto, ON, M5T 1R8, Canada.
⁵ KITE UHN Toronto Rehabilitation Institute, 347 Rumsey Rd, East York, ON, M4G 2V6, Canada.
⁶ Department of Pharmacology & Toxicology, University of Toronto, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada; Hurvitz Brain Sciences Program, Sunnybrook Research Institute, 2075 Bayview Avenue, Toronto, ON, M4N 3M5, Canada; KITE UHN Toronto Rehabilitation Institute, 347 Rumsey Rd, East York, ON, M4G 2V6, Canada; Heart and Stroke Foundation Canadian Partnership for Stroke Recovery, Sunnybrook Research Institute, 2075 Bayview Avenue, Toronto, ON, M4N 3M5, Canada. Electronic address: w.swardfager@utoronto.ca.

PMID: 32712109
DOI: 10.1016/j.arr.2020.101130

Abstract

Inflammation is involved in the pathophysiology of Alzheimer's disease (AD), with multiple inflammatory processes implicated in its risk and progression. This review included original peer-reviewed studies measuring the cerebrospinal fluid or peripheral blood concentrations of protein markers specifically related to neutrophil activity in healthy controls (HC) and in patients with AD or mild cognitive impairment (MCI). A total of 35 studies (N_HC = 3095, N_AD = 2596, N_MCI = 1203) were included. Random-effects meta-analyses were used to estimate between-groups standardized mean differences (SMD) and 95 % confidence intervals. In blood, concentrations of myeloperoxidase (MPO; N_AD/N_HC = 271/209, SMD = 0.41 [0.20, 0.62]; I² = 15.7 %) and neutrophil gelatinase associated lipocalin (NGAL; N_AD/N_HC = 273/185, SMD = 0.30 [0.11, 0.49]; I² < 0.005 %) were significantly higher in AD relative to HC. Peripheral blood concentrations of NGAL were also higher in MCI compared to HC (N_MCI/N_HC = 489/145, SMD = 0.39 [0.11, 0.67]; I² = 38.6 %). None of the protein markers exhibited a significant difference between HC, MCI, or AD groups in the cerebrospinal fluid. The evidence suggests that peripheral neutrophil activation, as indicated by blood concentrations of NGAL and MPO, may be a pathological feature of cognitive impairment due to AD, evident at stages of MCI and AD dementia.

Keywords: Alzheimer’s disease (AD); Lipocalin 2; Mild cognitive impairment (MCI); Myeloperoxidase (MPO); Neutrophil; Neutrophil gelatinase associated lipocalin (NGAL).

Publication types

Meta-Analysis
Research Support, Non-U.S. Gov't
Systematic Review

MeSH terms

Alzheimer Disease* / diagnosis
Biomarkers
Cognitive Dysfunction* / diagnosis
Disease Progression
Humans
Neutrophil Activation

Substances

Biomarkers

Grants and funding

PJT-159711/CIHR/Canada