Autoantibodies against N-methyl-D-aspartate receptor (anti-NMDAR) and ribosomal-P (anti-P) antigens are potential pathogenic factors in the frequently observed diffuse brain dysfunctions in patients with systemic lupus erythematosus (SLE). Although studies have been conducted in this area, the role of anti-NMDAR antibodies in SLE cognitive dysfunction remains elusive. Moreover, the specific contribution of anti-P antibodies has not been reported yet. The present study attempts to clarify the contribution of anti-NMDAR and anti-P antibodies to cognitive dysfunction in SLE.
Methods
The Cambridge Neuropsychological Test Automated Battery (CANTAB) was used to assess a wide range of cognitive function areas in 133 Chilean women with SLE. ANCOVA models included autoantibodies, patient and disease features.
Results
Cognitive deficit was found in 20%. Higher SLEDAI-2K scores were associated with impairment in spatial memory and learning abilities, whereas both anti-NMDAR and anti-P antibodies contributed to deficits in attention and spatial planning abilities, which reflect fronto-parietal cortex dysfunctions.
Conclusions
These results reveal an association of active disease together with specific circulating autoantibodies, such as anti-NMDAR and anti-P, with cognitive dysfunction in SLE patients.
The American College of Rheumatology nomenclature and case definitions for neuropsychiatric lupus syndromes. Arthritis Rheum 1999; 42: 599–608.
2.
BertsiasGKBoumpasDT. Pathogenesis, diagnosis and management of neuropsychiatric SLE manifestations. Nat Rev Rheumatol2010; 6: 358–367.
3.
KozoraEHanlyJGLaptevaLFilleyCM. Cognitive dysfunction in systemic lupus erythematosus: Past, present, and future. Arthritis Rheum2008; 58: 3286–3298.
4.
RekvigOPPuttermanCCasuC. Autoantibodies in lupus: Culprits or passive bystanders?Autoimmun Rev2012; 11: 596–603.
5.
SciasciaSBertolacciniMLRoccatelloDKhamashtaMASannaG. Autoantibodies involved in neuropsychiatric manifestations associated with systemic lupus erythematosus: A systematic review. J Neurol2014; 261: 1706–1714.
6.
HanlyJG. Diagnosis and management of neuropsychiatric SLE. Nat Rev Rheumatol2014; 10: 338–347.
7.
CalderónJFloresPBabulM. Systemic lupus erythematosus impairs memory cognitive tests not affected by depression. Lupus2014; 23: 1042–1053.
8.
Bertsias GK, Cervera R, Boumpas D. Systemic lupus erythematosus: Pathogenesis and clinical features. In: Bijlsma JWJ (ed.) EULAR Textbook on rheumatic disease. 2nd ed. BMJ Publishing Group, Italy, 2012, pp.476–505.
9.
MikdashiJA. Ad Hoc Committee on Lupus Response Criteria: Cognition Sub-committee. Proposed response criteria for neurocognitive impairment in systemic lupus erythematosus clinical trials. Lupus2007; 16: 418–425.
10.
HanlyJGFiskJD. Diagnosis of cognitive impairment in adult and pediatric SLE. Nat Rev Rheumatol2011; 7: 564–565.
11.
KozoraEErkanDWestSG. Site differences in mild cognitive dysfunction (MCD) among patients with systemic lupus erythematosus (SLE). Lupus2013; 22: 73–80.
12.
DenburgSDDenburgJA. Cognitive dysfunction and antiphospholipid antibodies in systemic lupus erythematosus. Lupus2003; 12: 883–890.
13.
TomiettoPAnneseVD’AgostiniS. General and specific factors associated with severity of cognitive impairment in systemic lupus erythematosus. Arthritis Rheum2007; 57: 1461–1472.
14.
HanlyJGUrowitzMBSuL. Prospective analysis of neuropsychiatric events in an international disease inception cohort of patients with systemic lupus erythematosus. Ann Rheum Dis2010; 69: 529–535.
15.
BreyRLHollidaySLSakladAR. Neuropsychiatric syndromes in lupus: Prevalence using standardized definitions. Neurology2002; 58: 1214–1220.
16.
DiamondBHuertaPTMina-OsorioPKowalCVolpeBT. Losing your nerves? Maybe it's the antibodies. Nat Rev Immunol2009; 9: 449–456.
17.
MatusSBurgosPVBravo-ZehnderM. Antiribosomal-P autoantibodies from psychiatric lupus target a novel neuronal surface protein causing calcium influx and apoptosis. J Exp Med2007; 204: 3221–3234.
18.
DeGiorgioLAKonstantinovKNLeeSCHardinJAVolpeBTDiamondB. A subset of lupus anti-DNA antibodies cross-reacts with the NR2 glutamate receptor in systemic lupus erythematosus. Nat Med2001; 7: 1189–1193.
19.
DiamondB. Antibodies and the brain: Lessons from lupus. J Immun2010; 185: 2637–2640.
20.
LauvsnesMBOmdalR. Systemic lupus erythematosus, the brain, and anti-NR2 antibodies. J Neurol2012; 259: 622–629.
HusebyeESSthoegerZMDayanM. Autoantibodies to a NR2A peptide of the glutamate/NMDA receptor in sera of patients with systemic lupus erythematosus. Ann Rheum Dis2005; 64: 1210–1213.
23.
OmdalRBrokstadKWaterlooKKoldingsnesWJonssonRMellgrenSI. Neuropsychiatric disturbances in SLE are associated with antibodies against NMDA receptors. Eur J Neurol2005; 12: 392–398.
24.
LaptevaLNowakMYarboroCH. Anti-N-methyl-D-aspartate receptor antibodies, cognitive dysfunction, and depression in systemic lupus erythematosus. Arthritis Rheum2006; 54: 2505–2514.
25.
HanlyJGRobichaudJFiskJD. Anti-NR2 glutamate receptor antibodies and cognitive function in systemic lupus erythematosus. J Rheumatol2006; 33: 1553–1558.
26.
KozoraEWestSGMaierSF. Antibodies against N-methyl-D-aspartate receptors in patients with systemic lupus erythematosus without major neuropsychiatric syndromes. J Neurol Sci2010; 295: 87–91.
27.
HanlyJGUrowitzMBSuL. Autoantibodies as biomarkers for the prediction of neuropsychiatric events in systemic lupus erythematosus. Ann Rheum Dis2011; 70: 1726–1732.
28.
HarrisonMJRavdinLDLockshinMD. Relationship between serum NR2a antibodies and cognitive dysfunction in systemic lupus erythematosus. Arthritis Rheum2006; 54: 2515–2522.
29.
KowalCDegiorgioLALeeJY. Human lupus autoantibodies against NMDA receptors mediate cognitive impairment. Proc Natl Acad Sci U S A2006; 103: 19854–19859.
30.
HirohataSArinumaYTakayamaMYoshioT. Association of cerebrospinal fluid anti-ribosomal P protein antibodies with diffuse psychiatric/neuropsychological syndromes in systemic lupus erythematosus. Arthritis Res Ther2007; 9: R44–R44.
31.
BrianiCLucchettaMGhirardelloA. Neurolupus is associated with anti-ribosomal P protein antibodies: An inception cohort study. J Autoimmun2009; 32: 79–84.
32.
MassardoLBurgosPMartínezME. Antiribosomal P protein antibodies in Chilean SLE patients: No association with renal disease. Lupus2002; 11: 379–383.
33.
ReichlinM. Autoantibodies to the ribosomal P proteins in systemic lupus erythematosus. Clin Exp Med2006; 6: 49–52.
34.
KatzavASolodeevIBrodskyO. Induction of autoimmune depression in mice by anti-ribosomal P antibodies via the limbic system. Arthritis Rheum2007; 56: 938–948.
35.
BonfaEGolombekSJKaufmanLD. Association between lupus psychosis and anti-ribosomal P protein antibodies. N Engl J Med1987; 317: 265–271.
36.
KarassaFBAfeltraAAmbrozicA. Accuracy of anti-ribosomal P protein antibody testing for the diagnosis of neuropsychiatric systemic lupus erythematosus: An international meta-analysis. Arthritis Rheum2006; 54: 312–324.
37.
HanlyJGWalshNMFiskJD. Cognitive impairment and autoantibodies in systemic lupus erythematosus. Br J Rheumatol1993; 32: 291–296.
38.
McLaurinEYHollidaySLWilliamsPBreyRL. Predictors of cognitive dysfunction in patients with systemic lupus erythematosus. Neurology2005; 64: 297–303.
39.
RobbinsTWJamesMOwenAMSahakianBJMcInnesLRabbittP. Cambridge Neuropsychological Test Automated Battery (CANTAB): A factor analytic study of a large sample of normal elderly volunteers. Dementia1994; 5: 266–281.
40.
WildKHowiesonDWebbeFSeelyeAKayeJ. Status of computerized cognitive testing in aging: A systematic review. Alzheimers Dement2008; 4: 428–437.
41.
OwenAMRobertsACPolkeyCESahakianBJRobbinsTW. Extra-dimensional versus intra-dimensional set shifting performance following frontal lobe excisions, temporal lobe excisions or amygdalo-hippocampectomy in man. Neuropsychologia1991; 29: 993–1006.
42.
BarnettJHSahakianBJWernersU. Visuospatial learning and executive function are independently impaired in first-episode psychosis. Psychol Med2005; 35: 1031–1041.
43.
HochbergMC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum1997; 40: 1725–1725.
44.
InouyeSKvan DyckCHAlessiCABalkinSSiegalAPHorwitzRI. Clarifying confusion: The confusion assessment method. A new method for detection of delirium. Ann Intern Med1990; 113: 941–948.
45.
MioshiEDawsonKMitchellJArnoldRHodgesJR. The Addenbrooke’s Cognitive Examination Revised (ACE-R): A brief cognitive test battery for dementia screening. Int J Geriatr Psychiatry2006; 21: 1078–1085.
GladmanDDGoldsmithCHUrowitzMB. The Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) Damage Index for Systemic Lupus Erythematosus International Comparison. J Rheumatol2000; 27: 373–376.
48.
MiyakisSLockshinMDAtsumiT. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost2006; 4: 295–306.
49.
ZigmondASSnaithRP. The hospital anxiety and depression scale. Acta Psychiatr Scand1983; 67: 361–370.
50.
SheehanDVLecrubierYSheehanKH. The Mini-International Neuropsychiatric Interview (M.I.N.I.): The development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry1998; 59(Suppl 20): 22–33. quiz 4–57).
51.
Diagnostic and statistical manual of mental disorders-IV. 4th ed. Washington: American Psychiatric Association, 2004.
52.
ParkSBCoullJTMcShaneRH. Tryptophan depletion in normal volunteers produces selective impairments in learning and memory. Neuropharmacology1994; 33: 575–588.
53.
SahakianBJCoullJT. Tetrahydroaminoacridine (THA) in Alzheimer’s disease: An assessment of attentional and mnemonic function using CANTAB. Acta Neurol Scand Suppl1993; 149: 29–35.
54.
OwenAMSahakianBJSempleJPolkeyCERobbinsTW. Visuo-spatial short-term recognition memory and learning after temporal lobe excisions, frontal lobe excisions or amygdalo-hippocampectomy in man. Neuropsychologia1995; 33: 1–24.
55.
DiasRRobbinsTWRobertsAC. Dissociation in prefrontal cortex of affective and attentional shifts. Nature1996; 380: 69–72.
56.
ShalliceT. Specific impairments of planning. Philos Trans R Soc Lond B Biol Sci1982; 298: 199–209.
57.
ChaseHWClarkLSahakianBJBullmoreETRobbinsTW. Dissociable roles of prefrontal subregions in self-ordered working memory performance. Neuropsychologia2008; 46: 2650–2661.
58.
PetriMNaqibuddinMCarsonKA. Depression and cognitive impairment in newly diagnosed systemic lupus erythematosus. J Rheumatol2010; 37: 2032–2038.
59.
KozoraEFilleyCM. Cognitive dysfunction and white matter abnormalities in systemic lupus erythematosus. J Int Neuropsychol Soc2011; 17: 385–392.
60.
HuertaPTKowalCDeGiorgioLAVolpeBTDiamondB. Immunity and behavior: Antibodies alter emotion. Proc Natl Acad Sci U S A2006; 103: 678–683.
61.
Bravo-Zehnder M, Toledo EM, Segovia-Miranda F, et al. Anti-ribosomal protein autoantibodies from neuropsychiatric lupus impair memory. Arthritis Rheum 2014; in revision.
62.
ErkanDKozoraELockshinMD. Cognitive dysfunction and white matter abnormalities in antiphospholipid syndrome. Pathophysiology2011; 18: 93–102.
63.
MaeshimaEYamadaYYukawaSNomotoH. Higher cortical dysfunction, antiphospholipid antibodies and neuroradiological examinations in systemic lupus erythematosus. Intern Med1992; 31: 1169–1174.
64.
LeritzEBrandtJMinorMReis-JensenFPetriM. “Subcortical” cognitive impairment in patients with systemic lupus erythematosus. J Int Neuropsychol Soc2000; 6: 821–825.
65.
ContiFAlessandriCPerriconeC. Neurocognitive dysfunction in systemic lupus erythematosus: Association with antiphospholipid antibodies, disease activity and chronic damage. PLoS One2012; 7: e33824–e33824.
66.
CarlomagnoSMigliaresiSAmbrosoneLSanninoMSangesGDi IorioG. Cognitive impairment in systemic lupus erythematosus: A follow-up study. J Neurol2000; 247: 273–279.
67.
WaterlooKOmdalRSjoholmH. Neuropsychological dysfunction in systemic lupus erythematosus is not associated with changes in cerebral blood flow. J Neurol2001; 248: 595–602.
68.
WaterlooKOmdalRHusbyGMellgrenSI. Neuropsychological function in systemic lupus erythematosus: A five-year longitudinal study. Rheumatology (Oxford)2002; 41: 411–415.
