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The neuropathological profile of mild cognitive impairment (MCI): a systematic review

Abstract

Whether mild cognitive impairment (MCI) has a distinct neuropathological profile that reflects an intermediate state between no cognitive impairment and dementia is not clear. Identifying which biological events occur at the earliest stage of progressive disease and which are secondary to the neuropathological process is important for understating pathological pathways and for targeted disease prevention. Many studies have now reported on the neurobiology of this intermediate stage. In this systematic review, we synthesize current evidence on the neuropathological profile of MCI. A total of 162 studies were identified with varied definition of MCI, settings ranging from population to specialist clinics and a wide range of objectives. From these studies, it is clear that MCI is neuropathologically complex and cannot be understood within a single framework. Pathological changes identified include plaque and tangle formation, vascular pathologies, neurochemical deficits, cellular injury, inflammation, oxidative stress, mitochondrial changes, changes in genomic activity, synaptic dysfunction, disturbed protein metabolism and disrupted metabolic homeostasis. Determining which factors primarily drive neurodegeneration and dementia and which are secondary features of disease progression still requires further research. Standardization of the definition of MCI and reporting of pathology would greatly assist in building an integrated picture of the clinical and neuropathological profile of MCI.

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Acknowledgements

Duncan Harris and David J Llewellyn are supported by the NIHR Peninsula Collaboration for Leadership in Applied Health Research and Care (PenCLAHRC). BCMS is funded by the Joint European Post-Doctoral Programme: The European Research Area in Ageing (ERA-AGE) Network FLARE Programme.

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Correspondence to B C M Stephan.

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APPENDIX 1: ABBREVIATIONS

APPENDIX 1: ABBREVIATIONS

α7nAChR, alpha7 nicotinic acetylcholine receptor

ΔTau, cleavage of tau at Asp421

3-NT, 3-nitrotyrosine

3Rtau, three-repeat tau

4-NE, 4-hydroxynonenals

4Rtau, four-repeat tau

5-OH-cytosine, 5-hydroxycytosine

8-OH-adenine, 8-hydroxyadenine

8-OHdG, 8-hydroxy-2-deoxy guanosine

8-OH-guanine, 8-hydroxyguanine

8-OHG, 8-hydroxyguanosine

A–Z

Aβ, amyloid beta-peptide

ABCA1, ATP Binding Cassette Transporter A1

AChE, acetylcholinesterase

AD, Alzheimer's disease

Adv-AD, advanced AD

AGD, argyrophilic grain disease

aMCI, amnestic mild cognitive impairment

AMY, amygdala

APOE E, apolipoprotein E

APP, amyloid precursor protein

ASYMAD, asymptomatic Alzheimer's disease (no cognitive decline but AD pathology)

ATP, adenosine triphosphate

BACE1, beta-site amyloid precursor protein-cleaving enzyme 1

Bax, Bcl-2-associated X protein

b/w, between

Bcl-2, B-cell lymphoma 2

Bcl-xL, antiapoptotic member of the Bcl-2 family

BER, base-excision repair

BDNF, brain-derived neurotrophic factor

BVR-A, biliverdin reductase A

CAII, carbonic anhydrase II

CAA, cerebral amyloid angiopathy

CAT, Catalase

CBF, cholinergic basal forebrain

CDK, cyclin-dependent kinases

cDNA, complementary DNA

CDR, Clinical Dementia Rating Score

Cer, ceramides

CER, cerebellum

CERAD, Consortium to Establish a Registry for Alzheimer's Disease

ChAT, choline acetyltransferase

ChAT-ir, ChAT-like immunoreactive

CI-CVD, cognitive impairment with lacunes

CIND, Cognitive Impairment no Dementia

CN, calcineurin

COX-2, cyclooxygenase-2

CRF, corticotptrophin-releasing factor

Csp, caspase

Cu,Zn-SOD, superoxide dismutases enzyme with copper and zinc

Cyt-c, cytochrome c

Def-AD, Definite AD

DEM, dementia

Diff., difference

Dihydro DEH, dihydrolipoyl DEH

DP, diffuse plaques

DRB, drebrin

DRP-2, dihydropyrminidase like-2

DWMD, deep white matter demyelination

EAAT2, excitatory amino acid transporter 2

E-AD, early AD

EC, entorhinal cortex

EfTu, elongation factor Tu

ENO1, enolase

EpoR, erythropoietin receptor

ERK1/2, extracellular signal-regulated kinases-1/2

ERK, extracellular-regulated kinase

F(2)-IsoP, F(2)-isoprostane

F(4)-NP, F(4)-neuroprostane

FBA-C, fructose bisphospate aldolase C

FC, frontal cortex

FRAP, ferric reducing ability of plasma

G-6-PD, glucose-6-phosphate

G6PDH, glucose-6-phosphate dehydrogenase

GA, Golgi apparatus

GalC, galactocerebroside(s)

GAPDH, glyceraldehyde-3-phosphate dehydrogenase

GFAP, glial fibrillary acidic protein

GLUL, glutamine synthetase

GPx, glutathione peroxidase

GR, glutathione reductase

GRP-78, glucose-regulated protein 78

Grp., group

GSH, glutathione

GSSG, oxidized form glutathione disulfide

GST, glutathione-S-transferase

GSTM3, glutathione-S-transferases Mu

HHE, protein-bound 4-hydroxhexenal

HIPP, hippocampus

HLA-DR, human leukocyte antigen DR-1

HNE, 4-hydroxy-2-nonenal

HO-1, heme oxygenase-1

HPG, parahippocampal gyrus

HS, hippocampal sclerosis

HSP, heat-shock protein

IL-6, interleukin-6

iNOS, inducible nitric oxide synthase

IPL, inferior parietal lobe

L-AD, late stage AD

LB, Lewy body

LBD, Lewy body dementia

LC, locus coeruleus

LOAD, late onset AD

LRP1, lipoprotein receptor-1

MAPKI, mitogen-activated protein kinase I

MAP2KI, mitogen-activated protein kinase kinase I

MAPs, microtubule-associated proteins

MBP, myelin basic protein

MCI, mild cognitive impairment

MCI-LB, pre-clinical Lewy body dementia state

MDH, mdh2 encoded malate dehydrogenase

Mi-AD, mild AD

miRNA (miR-107), micro RNA miR-107

MLA, [3H]methyllycaconitine

MMSE, Mini Mental State Examination

mAChRs, muscarinic AChRs

MMPs, matrix metalloproteinases

MMP-9, extracellular collagenase metalloproteinase-9

Mo-AD, moderate AD

mRNA, messenger ribonucleic acid (RNA)

MRP3, multidrug resistant protein

mtDNA, mitochondrial deoxyribonucleic acid (DNA)

nAChR, nicotinic acetylcholine receptor

NADPH, carbonyl reductase

NB, nucleus basalis

NCI, no cognitive impairment

nDNA, nuclear deoxyribonucleic acid (DNA)

NFAT, nuclear factor of activated T-cells

NFT, intraneuronal fibrillary tangles

NGF, nerve growth factor

NIA-Reagan, National Institute on Aging-Reagan Institute criteria

nMCI, non-amnestic mild cognitive impairment

nNOS, neuronal nitric oxide synthase

NOX, nicotinamide adenosine dinucleotide phosphate oxidase

NP, neuritic plaque

NPrG, 1-N2-propanodeoxyguanosine

NR2A, N-methyl-D-aspartate receptor subunit 2A

OGG-1, oxoguanine glycosylase 1

p75NRT, p75 neurotrophin

PARP, poly (ADP-ribose) polymerase

Pc, parietal cortex

PC, choline glycerophospholipid

PCAD, Pre-clinical Alzheimer's disease

PCNA, proliferating cell nuclear antigen

PD, Parkinson's disease

PE, ethanolamine plasmalogen

PEBP1, phosphatidylethanolamine binding protein 1

PGC-1α, peroxisome proliferator-activated receptor gamma coactivator-1alpha

PHF, paired helical filaments

PHG, parahippocampal gyrus

Pin1, peptidyl-prolyl cis/trans isomerase

PK-M1, pyruvate kinase M1-type

PKM2, pyruvate kinase M2

PM1, carbonylation of phosphoglycerate mutase 1

PMS, postmitochondrial supernatant

Po-AD, possible AD

PPARG, peroxisome proliferator-activated receptor gamma

PR VI, peroxiredoxin 6

Pr-AD, probable AD

proBDNF, precursor of brain-derived neurotrophic factor

proNGF, pro-form of nerve growth factor

PSD-95, postsynaptic density-95

PtdSer, phosphatidylserine

pTyr-BVR-A, phosphorylation for Tyr residues of biliverdin reductass-A

PVD, periventricular demyelination

rMCI, revised MCI

RNS, reactive nitrogen species

ROS, reactive oxygen species

rRNA, ribosomal RNA

S-AD, severe AD

SBP1, synaptic binding protein I

Sds22, protein phosphatase-related protein Sds-22

SFC, superior frontal cortex

Sig., Significant

SIRT1, sirtuin 1

SIVD, subcortical ischemic vascular dementia

SLI, somatostatin-like immunoreactivity

SMTG, superior middle temporal gyri

SNAP25, synaptosomal-associated protein 25

SOD, superoxide dismutase

Sp-ir, spinophilin immunoreactivity

ST, sulfatides

STC, superior temporal cortex

STs, sulfated galactosylceramides

STS, superior temporal sulcus

SYN, synaptophysin

SYT, synaptotagmin

TauΔCsp-6, tau cleaved by caspase 6

TBARS, thiobarbituric acid reactive substances

TGF, transforming growth factor

TGF-β, transforming growth factor beta pathway

Trk, tyrosine kinase

tRNA, transfer ribonucleic acid (RNA)

tTG, tissue transglutaminase

UCHL1, ubiquitin carboxy-terminal hydrolase

VAChT, vesicular acetylcholine transporter

VAMP2, vesicle-associated membrane protein 2

Zn, zinc

ZnT-1, Zn transporter protein-1

ZnT-4, Zn transporter protein-4

ZnT-6, Zn transporter protein-6

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Stephan, B., Hunter, S., Harris, D. et al. The neuropathological profile of mild cognitive impairment (MCI): a systematic review. Mol Psychiatry 17, 1056–1076 (2012). https://doi.org/10.1038/mp.2011.147

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