Chronic neuroinflammation has been implicated in Alzheimer’s disease (AD) pathology.
Objective:
To investigate the association between cytokine and anti-amyloid-β (Aβ) autoantibody levels and the degree of brain atrophy and cognitive impairment in AD patients.
Methods:
Cerebrospinal fluid (CSF) levels of C-C motif chemokine ligand 2 (CCL2), C-X-C motif chemokine ligand 8, C-X-C motif chemokine ligand 10, interleukin 6, and anti-Aβ autoantibody were evaluated in 69 AD patients. Serum levels of CCL2 and anti-Aβ autoantibody were also examined. The degree of brain atrophy was assessed using the voxel-based specific regional analysis system for AD, which targets the volumes of interest (VOI) in medial temporal structures. Cognitive function was evaluated by neuropsychological testing, including the Mini-Mental State Examination (MMSE) and Frontal Assessment Battery (FAB).
Results:
CSF CCL2 levels correlated significantly with the severity (p = 0.023) and the extent (p = 0.022) of VOI atrophy, and with the extent of gray matter atrophy (p = 0.039) in AD patients. CSF anti-Aβ autoantibody levels were inversely correlated with the severity of VOI atrophy (p = 0.020), the extent of VOI atrophy (p = 0.015), and the ratio of VOI/GM atrophy (r = –0.358, p = 0.004). CSF CCL2 levels were also inversely correlated with MMSE (p = 0.0497) and FAB scores (p = 0.016).
Conclusions:
CSF CCL2 levels are associated with the degree of medial temporal lobe and gray matter atrophy, and cognitive decline in AD.
CagninA, GerhardA, BanatiRB (2002) In vivo imaging of neuroinflammation. Eur Neuropsychopharmacol12, 581–586.
6.
ParachikovaA, AgadjanyanMG, CribbsDH, Blurton-JonesM, PerreauV, RogersJ, BeachTG, CotmanCW (2006) Inflammatory changes parallel the early stages of Alzheimer disease. Neurobiol Aging28, 1821–1833.
7.
SokolovaA, HillMD, RahimiF, WardenLA, HallidayGM, ShepherdCE (2009) Monocyte chemoattractant protein-1 plays a dominant role inthe chronic inflammation observed in Alzheimer’s disease. Brain Pathol19, 392–398.
8.
SmitsHA, RijsmusA, van LoonJH, WatJW, VerhoefJ, BovenLA, NottetHS (2002) Amyloid-beta-induced chemokine production in primary human macrophages and astrocytes. J Neuroimmunol127, 160–168.
9.
ItoS, SawadaM, HanedaM, IshidaY, IsobeK (2006) Amyloid-betapeptides induce several chemokine mRNA expressions in the primarymicroglia and Ra2 cell line via the PI3K/Akt and/or ERK pathway. Neurosci Res56, 294–299.
ElKhoury J, LusterAD (2008) Mechanisms of microglia accumulation in Alzheimer’s disease: Therapeutic implications. Trends Pharmacol Sci29, 626–632.
12.
HickmanSE, El KhouryJ (2010) Mechanisms of mononuclearphagocyte recruitment in Alzheimer’s disease. CNS NeurolDisord Drug Targets9, 168–173.
13.
El KhouryJ, ToftM, HickmanSE, MeansTK, TeradaK, GeulaC, LusterAD (2007) CCR2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease. Nat Med13, 432–438.
14.
American Psychiatric Association (2013) Diagnostic and statistical manual of mental disorders, 5th edn. American Psychiatric Association, Washington, DC.
15.
FolsteinMF, FolsteinSE, McHughPR (1975) Mini-mental state: A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res12, 189–198.
16.
DuboisB, SlachevskyA, LitvanI, PillonB (2000) The FAB: A Frontal Assessment Battery at bedside. Neurology55, 1621–1626.
17.
LesherEL, BerryhillJS (1994) Validation of the Geriatric Depression Scale-Short Form among inpatients. J Clin Psychol50, 256–260.
18.
HughesCP, BergL, DanzigerWL, CobenLA, MartinRL (1982) A new clinical scale for the staging of dementia. Br J Psychiatry140, 566–572.
19.
HirataY, MatsudaH, NemotoK, OhnishiT, HiraoK, YamashitaF, AsadaT, IwabuchiS, SamejimaH (2005) Voxel-based morphometry to discriminate early Alzheimer’s disease from controls. Neurosci Lett382, 269–274.
20.
MatsudaH, MizumuraS, NemotoK, YamashitaF, ImabayashiE, SatoN, AsadaT (2012) Automatic voxel-based morphometry of structural MRI by SPM8 plus diffeomorphic anatomic registration through exponentiated lie algebra improves the diagnosis of probable Alzheimer Disease. AJNR Am J Neuroradiol33, 1109–1114.
21.
MatsudaH (2016) MRI morphometry in Alzheimer’s disease. Ageing Res Rev30, 17–24.
22.
KimuraA, TakemuraM, SaitoK, YoshikuraN, HayashiY, InuzukaT (2017) Association between naturally occurring anti-amyloid β autoantibodies and medial temporal lobe atrophy in Alzheimer’s disease. J Neurol Neurosurg Psychiatry88, 126–131.
23.
WestinK, BuchhaveP, NielsenH, MinthonL, JanciauskieneS, HanssonO (2012) CCL2 is associated with a faster rate of cognitive decline during early stages of Alzheimer’s disease. PLoS One7, e30525.
24.
YamamotoM, HoribaM, BuescherJL, HuangD, GendelmanHE, RansohoffRM, IkezuT (2005) Overexpression of monocyte chemotactic protein-1/CCL2 in beta-amyloid precursor protein transgenic mice show accelerated diffuse beta-amyloid deposition. Am J Pathol166, 1475–1485.
NaertG, RivestS (2011) CC chemokine receptor 2 deficiency aggravates cognitive impairments and amyloid pathology in a transgenic mouse model of Alzheimer’s disease. J Neurosci31, 6208–6220.
27.
KiyotaT, GendelmanHE, WeirRA, HigginsEE, ZhangG, JainM (2013) CCL2 affects β-amyloidosis and progressive neurocognitive dysfunction in a mouse model of Alzheimer’s disease. Neurobiol Aging34, 1060–1068.
DodelR, BalakrishnanK, KeyvaniK, DeusterO, NeffF, Andrei-SelmerLC, RöskamS, StüerC, Al-AbedY, NoelkerC, Balzer-GeldsetzerM, OertelW, DuY, BacherM (2011) Naturally occurring autoantibodies against beta-amyloid: Investigating their role in transgenic animal and in vitro models of Alzheimer’s disease. J Neurosci31, 5847–5854.
30.
DodelR, HampelH, DepboyluC, LinS, GaoF, SchockS, JäckelS, WeiX, BuergerK, HöftC, HemmerB, MöllerHJ, FarlowM, OertelWH, SommerN, DuY (2002) Human antibodies against amyloid beta peptide: A potential treatment for Alzheimer’s disease. Ann Neurol52, 253–256.
31.
GuH, ZhongZ, JiangW, DuE, DodelR, FarlowMR, ZhengW, DuY (2014) The role of choroid plexus in IVIG-induced beta-amyloid clearance. Neuroscience270, 168–176.
32.
KaurC, RathnasamyG, LingEA (2016) The choroid plexus in healthy and diseased brain. J Neuropathol Exp Neurol75, 198–213.
33.
BalusuS, BrkicM, LibertC, VandenbrouckeRE (2016) The choroid plexus-cerebrospinal fluid interface in Alzheimer’s disease: More than just a barrier. Neural Regen Res11, 534–547.
34.
BagyinszkyE, GiauVV, ShimK, SukK, AnSSA, KimS (2017) Role of inflammatory molecules in the Alzheimer’s disease progression and diagnosis. J Neurol Sci376, 242–254.
