Myeloperoxidase (MPO), a neutrophil-derived pro-inflammatory protein, co-localizes with amyloid-β (Aβ) plaques in Alzheimer’s disease (AD). Anti-dementia treatment may facilitate efflux of Aβ and associated plaque proteins from the brain to the peripheral circulation, therefore providing potential biomarkers for the monitoring of donor response to drug treatment.
Objective:
We investigated the diagnostic utility of MPO as a biomarker of AD, and how anti-dementia treatment alters plasma MPO concentration.
Methods:
Thirty-two AD patients were recruited, and plasma collected pre-drug administration (baseline), and 1- and 6-months post-treatment. All patients received cholinesterase inhibitors (ChEIs). At baseline and 6 months, patients underwent neuropsychological assessment. Forty-nine elderly healthy individuals with normal cognitive status served as controls. Plasma MPO concentration was measured by ELISA.
Results:
AD drug naïve patients had similar plasma MPO concentration to their control counterparts (p > 0.05). Baseline MPO levels positively correlated with Neuropsychiatric Inventory score (r = 0.5080; p = 0.011) and carer distress (r = 0.5022; p = 0.012). Following 1-month ChEI treatment, 84.4% of AD patients exhibited increased plasma MPO levels (p < 0.001), which decreased at 6 months (p < 0.001). MPO concentration at 1 month was greatest in AD patients whose memory deteriorated during the study period (p = 0.028), and for AD patients with deterioration in Cornell assessment score (p = 0.044).
Conclusion:
Whereas baseline MPO levels did not differentiate between healthy and AD populations, baseline MPO positively correlated with initial Neuropsychiatric Inventory evaluation. Post-treatment, transient MPO upregulation in ChEI-treated patients may reflect worse therapeutic outcome. Further studies are required to assess the potential of plasma MPO as an AD therapeutic biomarker.
CombarrosO, InfanteJ, LlorcaJ, PenaN, Fernandez-ViaderoC, BercianoJ (2002) The myeloperoxidase gene in Alzheimer’s disease: A case-control study and meta-analysis. Neurosci Lett326, 33–36.
2.
GreenPS, MendezAJ, JacobJS, CrowleyJR, GrowdonW, HymanBT, HeineckeJW (2004) Neuronal expression of myeloperoxidase is increased in Alzheimer’s disease. J Neurochem90, 724–733.
3.
GellhaarS, SunnemarkD, ErikssonH, OlsonL, GalterD (2017) Myeloperoxidase-immunoreactive cells are significantly increased in brain areas affected by neurodegeneration in Parkinson’s and Alzheimer’s disease. Cell Tissue Res369, 445–454.
4.
KellerJN, SchmittFA, ScheffSW, DingQ, ChenQ, ButterfieldDA, MarkesberyWR (2005) Evidence of increased oxidative damage in subjects with mild cognitive impairment. Neurology64, 1152–1156.
5.
MakiRA, TyurinVA, LyonRC, HamiltonRL, DeKoskyST, KaganVE, ReynoldsWF (2009) Aberrant expression of myeloperoxidase in astrocytes promotes phospholipid oxidation and memory deficits in a mouse model of Alzheimer disease. J Biol Chem284, 3158–3169.
PopeSK, KritchevskySB, AmbrosoneC, YaffeK, TylavskyF, SimonsickEM, RosanoC, StewartS, HarrisT (2006) Myeloperoxidase polymorphism and cognitive decline in older adults in the Health, Aging, and Body Composition Study. Am J Epidemiol163, 1084–1090.
8.
Leininger-MullerB, HoyA, HerbethB, PfisterM, SerotJM, Stavljenic-RukavinaM, MassanaL, PassmoreP, SiestG, VisvikisS (2003) Myeloperoxidase G-463A polymorphism and Alzheimer’s disease in the ApoEurope study. Neurosci Lett349, 95–98.
9.
ReynoldsWF, RheesJ, MaciejewskiD, PaladinoT, SieburgH, MakiRA, MasliahE (1999) Myeloperoxidase polymorphism is associated with gender specific risk for Alzheimer’s disease. Exp Neurol155, 31–41.
10.
CrawfordFC, FreemanMJ, SchinkaJA, MorrisMD, AbdullahLI, RichardsD, SevushS, DuaraR, MullanMJ (2001) Association between Alzheimer’s disease and a functional polymorphism in the Myeloperoxidase gene. Exp Neurol167, 456–459.
11.
SchreitmüllerBLC, StranskyE, StellosK (2013) Increased myeloperoxidase (MPO) plasma levels in patients with Alzheimer’s disease. Alzheimers Dement9, P235.
12.
HoyA, Leininger-MullerB, KutterD, SiestG, VisvikisS (2002) Growing significance of myeloperoxidase in non-infectious diseases. Clin Chem Lab Med40, 2–8.
13.
LoriaV, DatoI, GrazianiF, BiasucciLM (2008) Myeloperoxidase: A new biomarker of inflammation in ischemic heart disease and acute coronary syndromes. Mediators Inflamm2008, 135625.
DuronE, HanonO (2008) Vascular risk factors, cognitive decline, and dementia. Vasc Health Risk Manag4, 363–381.
16.
MoriF, LaiCC, FusiF, GiacobiniE (1995) Cholinesterase inhibitors increase secretion of APPs in rat brain cortex. Neuroreport6, 633–636.
17.
NitschRM, SlackBE, WurtmanRJ, GrowdonJH (1992) Release of Alzheimer amyloid precursor derivatives stimulated by activation of muscarinic acetylcholine receptors. Science258, 304–307.
18.
HuppertFA, BrayneC, GillC, PaykelES, BeardsallL (1995) CAMCOG–a concise neuropsychological test to assist dementia diagnosis: Socio-demographic determinants in an elderly population sample. Br J Clin Psychol34, 529–541.
19.
WalkerMP, AyreGA, CummingsJL, WesnesK, McKeithIG, O’BrienJT, BallardCG (2000) The Clinician Assessment of Fluctuation and the One Day Fluctuation Assessment Scale. Two methods to assess fluctuating confusion in dementia. Br J Psychiatry177, 252–256.
20.
AlexopoulosGS, AbramsRC, YoungRC, ShamoianCA (1988) Cornell Scale for Depression in Dementia. Biol Psychiatry23, 271–284.
21.
CummingsJL, MegaM, GrayK, Rosenberg-ThompsonS, CarusiDA, GornbeinJ (1994) The Neuropsychiatric Inventory: Comprehensive assessment of psychopathology in dementia. Neurology44, 2308–2314.
22.
ColantonioDA, DunkinsonC, BovenkampDE, Van EykJE (2005) Effective removal of albumin from serum. Proteomics5, 3831–3835.
23.
AndreasenN, SjogrenM, BlennowK (2003) CSF markers for Alzheimer’s disease: Total tau, phospho-tau and Abeta42. World J Biol Psychiatry4, 147–155.
24.
Mukaetova-LadinskaEB, MonteithR, PerryEK (2010) Cerebrospinal fluid biomarkers for dementia with Lewy bodies. Int J Alzheimers Dis2010, 536538.
25.
AlbertMS, DeKoskyST, DicksonD, DuboisB, FeldmanHH, FoxNC, GamstA, HoltzmanDM, JagustWJ, PetersenRC, SnyderPJ, CarrilloMC, ThiesB, PhelpsCH (2011) The diagnosis of mild cognitive impairment due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement7, 270–279.
26.
WuCY, BawaKK, OukM, LeungN, YuD, LanctotKL, HerrmannN, PakoshM, SwardfagerW (2020) 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 Rev62, 101130.
StenvinkelP, Rodriguez-AyalaE, MassyZA, QureshiAR, BaranyP, FellstromB, HeimburgerO, LindholmB, AlvestrandA (2006) Statin treatment and diabetes affect myeloperoxidase activity in maintenance hemodialysis patients. Clin J Am Soc Nephrol1, 281–287.
29.
MasuokaN, LeiC, LiH, InamuraN, ShiotaniS, YanaiN, SatoK, SakuraiK, HisatsuneT (2021) Anserine, HClO-scavenger, protected against cognitive decline in individuals with mild cognitive impairment. Aging (Albany NY)13, 1729–1741.
30.
CalcianoMA, ZhouW, SnyderPJ, EinsteinR (2010) Drug treatment of Alzheimer’s disease patients leads to expression changes in peripheral blood cells. Alzheimers Dement6, 386–393.
31.
Mukaetova-LadinskaEB, HarringtonCR, XuerebJ, RothM, WischikCM (1995) Biochemical, neuropathological, and clinical correlations of neurofibrillary degeneration in Alzheimer’s disease. In Treating Alzheimer’s and Other Dementias: Clinical Application of Recent Research Advances, Bergener M, Finkel SI, eds. Springer, New York, pp. 57-80..
32.
TronconeL, LucianiM, CogginsM, WilkerEH, HoCY, CodispotiKE, FroschMP, KayedR, Del MonteF (2016) Abeta amyloid pathology affects the hearts of patients with Alzheimer’s disease: Mind the heart. J Am Coll Cardiol68, 2395–2407.
33.
LiuG, YaoL, LiuJ, JiangY, MaG, Genetic Environmental Risk for Alzheimer’s disease C, ChenZ, ZhaoB, LiK (2014) Cardiovascular disease contributes to Alzheimer’s disease: Evidence from large-scale genome-wide association studies. Neurobiol Aging35, 786–792.
LeeHJ, SeoHI, ChaHY, YangYJ, KwonSH, YangSJ (2018) Diabetes and Alzheimer’s disease: Mechanisms and nutritional aspects. Clin Nutr Res7, 229–240.
36.
PetersR, WarwickJ, AnsteyKJ, AndersonCS (2019) Blood pressure and dementia: What the SPRINT-MIND trial adds and what we still need to know. Neurology92, 1017–1018.
37.
UngvariZ, TothP, TarantiniS, ProdanCI, SorondF, MerkelyB, CsiszarA (2021) Hypertension-induced cognitive impairment: From pathophysiology to public health. Nat Rev Nephrol17, 639–654.
38.
WanamakerBL, SwigerKJ, BlumenthalRS, MartinSS (2015) Cholesterol, statins, and dementia: What the cardiologist should know. Clin Cardiol38, 243–250.
39.
XuC, TaoX, MaX, ZhaoR, CaoZ (2021) Cognitive dysfunction after heart disease: A manifestation of the heart-brain axis. Oxid Med Cell Longev2021, 4899688.
40.
McNeilCJ, MyintPK, SanduAL, PotterJF, StaffR, WhalleyLJ, MurrayAD (2018) Increased diastolic blood pressure is associated with MRI biomarkers of dementia-related brain pathology in normative ageing. Age Ageing47, 95–100.
