University of Edinburgh Research Explorer



Title:Fatigue and cognitive function in systemic lupus erythematosus: associations with white matter microstructural damage. A diffusion tensor MRI study and meta-analysisAuthors:Stewart J. Wiseman1, Mark E. Bastin1, Iona F. Hamilton1, David Hunt1, Stuart J. Ritchie2,3, E. Nicole Amft4, Susan Thomson5, Jill F.F. Belch5, Stuart H. Ralston6, Joanna M. Wardlaw1. Affiliation:1 Centre for Clinical Brain Sciences, University of Edinburgh, UK2 Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, UK3 Department of Psychology, University of Edinburgh, UK4 Department of Rheumatology, Western General Hospital, Edinburgh, UK5 Division of Cardiovascular and Diabetes Medicine, University of Dundee, UK6 Centre for Genomic and Experimental Medicine, University of Edinburgh, UKCorrespondence:Joanna Wardlaw, CCBS, Chancellor’s Building, Royal Infirmary of Edinburgh, 49 Little France Crescent, Edinburgh, EH16 4SB. E-mail: Joanna.Wardlaw@ed.ac.uk; Tel: 0131 242 6200; Fax: 0131 242 6210.Running head: Fatigue and cognition in SLEKeywords: autoimmune diseases, cytokines, inflammation, Systemic Lupus ErythematosusAbstractObjective:To investigate fatigue and cognitive impairments in systemic lupus erythematous (SLE) in relation to diffuse white matter microstructural brain damage.Methods: Diffusion tensor MRI, used to generate biomarkers of brain white matter microstructural integrity, was obtained in patients with SLE and age-matched controls. Fatigue and cognitive function were assessed and related to SLE activity, clinical data and plasma biomarkers of inflammation and endothelial dysfunction.Results:Fifty-one patients with SLE (mean age 48.8 ± 14.3 years) were included. Mean diffusivity (MD) was significantly higher in all white matter fibre tracts in SLE patients versus age-matched healthy controls (p<0.0001). Fatigue in SLE was higher than a normal reference range (p<0.0001) and associated with lower MD (? = –0.61, p=0.02), depression (? = 0.17, p=0.001), anxiety (? = 0.13, p=0.006) and higher body mass index (? = 0.10, p=0.004) in adjusted analyses. Poorer cognitive function was associated with longer SLE disease duration (p=0.003) and higher MD (p=0.03) and, in adjusted analysis, higher levels of IL-6 (? = –0.15, p=0.02) but not with MD. Meta-analysis (10 studies, n=261, including the present study) confirmed that patients with SLE have higher MD than controls.Conclusion:Patients with SLE have more microstructural brain white matter damage for age than the general population, but this does not explain increased fatigue or lower cognition in SLE. The association between raised IL-6 and worse current cognitive function in SLE should be explored in larger datasets.INTRODUCTIONSystemic lupus erythematosus (SLE) is a chronic autoimmune disease. It is associated with increased risk of strokeADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1136/rmdopen-2015-000168", "ISSN" : "2056-5933", "author" : [ { "dropping-particle" : "", "family" : "Holmqvist", "given" : "Marie", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Simard", "given" : "Julia F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Asplund", "given" : "Kjell", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "V", "family" : "Arkema", "given" : "Elizabeth", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "RMD Open", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2015" ] ] }, "note" : "GOOD, SYS REV", "page" : "e000168", "title" : "Stroke in systemic lupus erythematosus: a meta-analysis of population-based cohort studies", "type" : "article-journal", "volume" : "1" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1161/STROKEAHA.115.012052", "author" : [ { "dropping-particle" : "", "family" : "Wiseman", "given" : "Stewart J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ralston", "given" : "Stuart H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wardlaw", "given" : "Joanna M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Stroke", "id" : "ITEM-2", "issued" : { "date-parts" : [ [ "2016" ] ] }, "page" : "1-9", "title" : "Cerebrovascular disease in rheumatic diseases: A systematic review and meta-analysis", "type" : "article-journal", "volume" : "47" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "^1,2", "plainTextFormattedCitation" : "1,2", "previouslyFormattedCitation" : "^1,2" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }1,2 and cognitive decline has been reported.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Carlomagno", "given" : "S.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "MigliaresiS.", "given" : "", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ambrosone", "given" : "L.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sannino", "given" : "M.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sanges", "given" : "G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lorio", "given" : "G.", "non-dropping-particle" : "Di", "parse-names" : false, "suffix" : "" } ], "container-title" : "J Neurol", "id" : "ITEM-1", "issue" : "4", "issued" : { "date-parts" : [ [ "2000" ] ] }, "page" : "273-9", "title" : "Cognitive impairment in systemic lupus erythematosus: a follow-up study", "type" : "article-journal", "volume" : "247" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "³", "plainTextFormattedCitation" : "3", "previouslyFormattedCitation" : "³" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }3 Fatigue is a commonADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "abstract" : "Musculoskeletal conditions (MSC) are among the most frequent in adults in France, with over 20% of the population experiencing bone, joint, and muscle disorders. MSC are an increasing health concern in France, growing in importance on the public health agenda. Some of the present governmental plans are connected with MSC (Pain, the Disabled, Nutrition, Geriatrics). An overview of the present situation in France is provided, regarding the burden, the present situation, and steps forward. Scientific societies and patient groups are actively involved in campaigning in several fields; 2 examples are described: osteoporosis and rheumatoid arthritis and spondyloarthropathies. The Bone and Joint Decade initiative, officially endorsed by the French Government on June 20, 2000, provides the opportunity to develop more coordinated actions through the national network and international partnership as well (including the European League Against Rheumatism) to finally improve the health-related quality of life for people with MSC.", "author" : [ { "dropping-particle" : "", "family" : "Hewlett", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Nicklin", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Treharne", "given" : "G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The Journal Of Rheumatology Supplement", "id" : "ITEM-1", "issue" : "Series 6", "issued" : { "date-parts" : [ [ "2003" ] ] }, "page" : "42-44", "title" : "Fatigue in musculoskeletal conditions", "type" : "article-journal", "volume" : "67" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "⁴", "plainTextFormattedCitation" : "4", "previouslyFormattedCitation" : "⁴" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }4 but unexplained feature of SLE which increases distress and lost work days and has been associated with increased burden of brain white matter hyperintensities (WMH),ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1136/jnnp.2007.120626", "ISSN" : "1468-330X", "PMID" : "17872980", "abstract" : "BACKGROUND: Fatigue is a disabling phenomenon in many patients who have systemic lupus erythematosus (SLE). The pathophysiological processes are unknown, and no known biological disease factors influence the phenomenon. Because depressive mood is consistently associated with fatigue, and drug treatment for SLE does not ameliorate fatigue, a psychological explanation could be an alternative. In search of a somatic basis for fatigue, we looked for alternative markers of biologic activity associated with fatigue. Cerebral white matter hyperintensities (WMHs) represent biochemical changes of brain tissue and are frequently encountered in patients with SLE, and are associated with cognitive impairment in patients with multiple sclerosis. Presence of such an association between fatigue and WMHs in SLE would favour a biological axis to fatigue.\n\nMETHODS: A cross-sectional, case-control study with 62 unselected patients with SLE and 62 age- and gender-matched healthy subjects. Fatigue was evaluated using the Fatigue Severity Scale (FSS) and a fatigue visual analogue scale (VAS). WMHs were rated using Scheltens' method.\n\nRESULTS: Greater fatigue and more WMHs appeared in patients with SLE versus healthy subjects. In the full group of patients (n = 62), fatigue VAS was associated with total WMH score (p = 0.009). In subgroup analysis of patients without clinical depression (n = 40), the association with total WMH remained (p = 0.035), whereas this was not the case in the depressed group (n = 18) (p = 0.211).\n\nCONCLUSION: Increased cerebral WMH load is associated with increased fatigue, indicating a biological origin for some portion of fatigue in patients with SLE.", "author" : [ { "dropping-particle" : "", "family" : "Harboe", "given" : "E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Greve", "given" : "O J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Beyer", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "G\u00f8ransson", "given" : "L G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tjensvoll", "given" : "a B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Maroni", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Omdal", "given" : "R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of neurology, neurosurgery, and psychiatry", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "2008", "2" ] ] }, "page" : "199-201", "title" : "Fatigue is associated with cerebral white matter hyperintensities in patients with systemic lupus erythematosus.", "type" : "article-journal", "volume" : "79" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "⁵", "plainTextFormattedCitation" : "5", "previouslyFormattedCitation" : "⁵" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }5 suggestive of cerebral small vessel disease (SVD).ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/S1474-4422(13)70060-7", "ISSN" : "1474-4465", "PMID" : "23602162", "abstract" : "The term cerebral small vessel disease (SVD) describes a range of neuroimaging, pathological, and associated clinical features. Clinical features range from none, to discrete focal neurological symptoms (eg, stroke), to insidious global neurological dysfunction and dementia. The burden on public health is substantial. The pathogenesis of SVD is largely unknown. Although the pathological processes leading to the arteriolar disease are associated with vascular risk factors and are believed to result from an intrinsic cerebral arteriolar occlusive disease, little is known about how these processes result in brain disease, how SVD lesions contribute to neurological or cognitive symptoms, and the association with risk factors. Pathology often shows end-stage disease, which makes identification of the earliest stages difficult. Neuroimaging provides considerable insights; although the small vessels are not easily seen themselves, the effects of their malfunction on the brain can be tracked with detailed brain imaging. We discuss potential mechanisms, detectable with neuroimaging, that might better fit the available evidence and provide testable hypotheses for future study.", "author" : [ { "dropping-particle" : "", "family" : "Wardlaw", "given" : "Joanna M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Smith", "given" : "Colin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dichgans", "given" : "Martin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Lancet neurology", "id" : "ITEM-1", "issue" : "5", "issued" : { "date-parts" : [ [ "2013", "5" ] ] }, "page" : "483-97", "publisher" : "Elsevier Ltd", "title" : "Mechanisms of sporadic cerebral small vessel disease: insights from neuroimaging.", "type" : "article-journal", "volume" : "12" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "⁶", "plainTextFormattedCitation" : "6", "previouslyFormattedCitation" : "⁶" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }6Diffusion tensor MRI (DT-MRI) can map the brain’s white matter tracts (bundles of individual white matter fibres) and provide biomarkers for microstructural integrity. Water molecules preferentially diffuse along the principal fibre direction in healthy white matter, while loss of structural integrity, which has a deleterious effect on brain function, increases free water movement. The magnitude and directionality of water molecule diffusion can be quantified within segmented tracts using mean diffusivity (MD) and fractional anisotropy (FA),ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/mp.2012.66", "ISSN" : "1476-5578", "PMID" : "22614288", "abstract" : "General intelligence is a robust predictor of important life outcomes, including educational and occupational attainment, successfully managing everyday life situations, good health and longevity. Some neuronal correlates of intelligence have been discovered, mainly indicating that larger cortices in widespread parieto-frontal brain networks and efficient neuronal information processing support higher intelligence. However, there is a lack of established associations between general intelligence and any basic structural brain parameters that have a clear functional meaning. Here, we provide evidence that lower brain-wide white matter tract integrity exerts a substantial negative effect on general intelligence through reduced information-processing speed. Structural brain magnetic resonance imaging scans were acquired from 420 older adults in their early 70s. Using quantitative tractography, we measured fractional anisotropy and two white matter integrity biomarkers that are novel to the study of intelligence: longitudinal relaxation time (T1) and magnetisation transfer ratio. Substantial correlations among 12 major white matter tracts studied allowed the extraction of three general factors of biomarker-specific brain-wide white matter tract integrity. Each was independently associated with general intelligence, together explaining 10% of the variance, and their effect was completely mediated by information-processing speed. Unlike most previously established neurostructural correlates of intelligence, these findings suggest a functionally plausible model of intelligence, where structurally intact axonal fibres across the brain provide the neuroanatomical infrastructure for fast information processing within widespread brain networks, supporting general intelligence.", "author" : [ { "dropping-particle" : "", "family" : "Penke", "given" : "L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Maniega", "given" : "S Mu\u00f1oz", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bastin", "given" : "M E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Vald\u00e9s Hern\u00e1ndez", "given" : "M C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Murray", "given" : "C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Royle", "given" : "N a", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Starr", "given" : "J M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wardlaw", "given" : "J M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Deary", "given" : "I J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Molecular psychiatry", "id" : "ITEM-1", "issue" : "10", "issued" : { "date-parts" : [ [ "2012", "10" ] ] }, "page" : "1026-30", "title" : "Brain white matter tract integrity as a neural foundation for general intelligence.", "type" : "article-journal", "volume" : "17" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "⁷", "plainTextFormattedCitation" : "7", "previouslyFormattedCitation" : "⁷" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }7 with low MD and high FA indicating structurally intact white matter.Nine small (average n=24 patients) studiesADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Zimny", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Szewczyk", "given" : "P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bladowska", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gruszka", "given" : "E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Lupus", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2014" ] ] }, "page" : "10-19", "title" : "In vivo evaluation of brain damage in the course of systemic lupus erythematosus using magnetic resonance spectroscopy , perfusion-weighted and diffusion-tensor imaging", "type" : "article-journal", "volume" : "23" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1016/j.nicl.2014.07.001", "ISSN" : "2213-1582", "PMID" : "25161895", "abstract" : "PURPOSE: Systemic lupus erythematosus (SLE) is an autoimmune connective tissue disease that can affect the central nervous system. Neuropsychiatric symptoms are found in 25-70% of patients. Using diffusion tensor imaging (DTI) various studies have reported changes in white matter integrity in SLE patients with neuropsychiatric symptoms (NPSLE patients). The purpose of this study was to investigate, if regional changes in white matter integrity can also be detected in SLE patients without neuropsychiatric symptoms (non-NPSLE patients).\n\nMETHODS: Applying DTI and tract based spatial statistics (TBSS) we investigated 19 NPSLE patients, 19 non-NPSLE and 18 healthy controls. Groups were matched for age and sex. Image pre-processing was performed using FSL, following the TBSS pipeline (eddy current correction, estimation of fractional anisotropy (FA), normalization, skeletonization of the group mean FA image). A general linear model with threshold-free cluster enhancement was used to assess significant differences between the three groups.\n\nRESULTS: Statistical analyses revealed several regions of decreased prefrontal white matter integrity (decreased FA) in both groups of SLE patients. The changes found in the non-NPSLE patients (as compared to healthy controls) overlapped with those in the NPSLE patients, but were not as pronounced.\n\nCONCLUSIONS: Our data suggest that changes in regional white matter integrity, in terms of a decrease in FA, are present not only in NPSLE patients, but also in non-NPSLE patients, though to a lesser degree. We also demonstrate that the way statistical maps are corrected for multiple comparisons has a profound influence on whether alterations in white matter integrity in non-NPSLE patients are deemed significant.", "author" : [ { "dropping-particle" : "", "family" : "Schmidt-Wilcke", "given" : "Tobias", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cagnoli", "given" : "Patricia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wang", "given" : "Page", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schultz", "given" : "Thomas", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lotz", "given" : "Anne", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mccune", "given" : "William J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sundgren", "given" : "Pia C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "NeuroImage. Clinical", "id" : "ITEM-2", "issued" : { "date-parts" : [ [ "2014", "1" ] ] }, "page" : "291-7", "publisher" : "Elsevier B.V.", "title" : "Diminished white matter integrity in patients with systemic lupus erythematosus.", "type" : "article-journal", "volume" : "5" }, "uris" : [ "" ] }, { "id" : "ITEM-3", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Zivadinov", "given" : "R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Shucard", "given" : "J L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hussein", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Durfee", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cox", "given" : "J L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bergsland", "given" : "N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dwyer", "given" : "M G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Benedict", "given" : "R H B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "id" : "ITEM-3", "issue" : "2013", "issued" : { "date-parts" : [ [ "2015" ] ] }, "page" : "675-683", "title" : "Multimodal imaging in systemic lupus erythematosus patients with diffuse neuropsychiatric involvement", "type" : "article-journal" }, "uris" : [ "" ] }, { "id" : "ITEM-4", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Jung", "given" : "Rex E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Caprihan", "given" : "Arvind", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chavez", "given" : "Robert S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Flores", "given" : "Ranee A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sharrar", "given" : "Janeen", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Qualls", "given" : "Clifford R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sibbitt", "given" : "Wilmer", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Roldan", "given" : "Carlos A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "BMC neurology", "id" : "ITEM-4", "issue" : "65", "issued" : { "date-parts" : [ [ "2010" ] ] }, "title" : "Diffusion tensor imaging in neuropsychiatric systemic lupus erythematosus", "type" : "article-journal", "volume" : "10" }, "uris" : [ "" ] }, { "id" : "ITEM-5", "itemData" : { "DOI" : "10.1002/art.27717", "ISSN" : "1529-0131", "PMID" : "20722009", "abstract" : "OBJECTIVE: The aim of this study was to determine whether there are differences in white matter integrity between systemic lupus erythematosus (SLE) patients and healthy controls, as determined using tract-based spatial statistics (TBSS) analysis of diffusion tensor imaging data.\n\nMETHODS: Twelve patients with SLE (mean age 42 years [range 15-61 years]) diagnosed according to the American College of Rheumatology 1982 revised criteria for SLE and 28 healthy controls (mean age 46 years [range 21-61 years]) were included in the study. Magnetic resonance imaging was performed on a 3.0T scanner. Fractional anisotropy (FA) maps were calculated for each patient. TBSS analysis was used to compare the FA maps. The TBSS technique projects the FA data into a common space through the use of an initial approximate nonlinear registration, followed by projection onto an alignment-invariant tract representation (mean FA skeleton). The cluster results were corrected for multiple comparisons across space, and a threshold of significance of 0.05 was used.\n\nRESULTS: The white matter of tracts in the inferior fronto-occipital fasciculus, the fasciculus uncinatus, as well as the fornix, the posterior limb of the internal capsule (corticospinal tract), and the anterior limb of the internal capsule (anterior thalamic radiation) of patients with SLE showed reduced integrity as compared with normal subjects.\n\nCONCLUSION: In this preliminary study, the integrity of white matter tracts in areas around limbic structures and in the internal capsule was found to be reduced. Larger studies could improve our understanding of the pathologic mechanisms behind the reduced white matter tract integrity in SLE.", "author" : [ { "dropping-particle" : "", "family" : "Emmer", "given" : "Bart J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Veer", "given" : "Ilya M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Steup-Beekman", "given" : "Gerda M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Huizinga", "given" : "Tom W J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Grond", "given" : "Jeroen", "non-dropping-particle" : "van der", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Buchem", "given" : "Mark a", "non-dropping-particle" : "van", "parse-names" : false, "suffix" : "" } ], "container-title" : "Arthritis and rheumatism", "id" : "ITEM-5", "issue" : "12", "issued" : { "date-parts" : [ [ "2010", "12" ] ] }, "page" : "3716-21", "title" : "Tract-based spatial statistics on diffusion tensor imaging in systemic lupus erythematosus reveals localized involvement of white matter tracts.", "type" : "article-journal", "volume" : "62" }, "uris" : [ "" ] }, { "id" : "ITEM-6", "itemData" : { "DOI" : "10.1002/jmri.21036", "ISSN" : "1053-1807", "PMID" : "17729344", "abstract" : "PURPOSE: To investigate the source of significant difference in apparent diffusion coefficient (ADC) between patients with acute symptoms of neuropsychiatric (NP) systematic lupus erythematosus (SLE) (NPSLE) and normal controls.\n\nMATERIALS AND METHODS: Diffusion-weighted echo-planar imaging was performed on 1.5-T scanners in 17 female and four male NPSLE patients with acute neurological symptoms (23-76 years, mean = 42.7 years), and in 21 aged-matched healthy controls (16 female, five male, 26-63 years, mean = 41.1 years). ADC histograms were calculated for whole brain, gray matter tissue, and white matter tissue.\n\nRESULTS: Of the 17 NPSLE patients, 13 (72%) had abnormal findings on MR imaging. The NPSLE patients had a mean ADC value of (1105.1 +/- 23.6) x 10(-6) mm(2)/second and the control had a mean ADC value of (1012.5 +/- 9.4) x 10(-6) mm(2)/second (P < or = 0.0012). Significant differences were also found in white matter (P < or = 0.0020) and gray matter (P < or = 0.0022).\n\nCONCLUSION: ADC histogram analysis demonstrated increased general diffusivity in the brain in NPSLE patients with acute symptoms compared with healthy normal controls. This finding suggests that in the brain parenchyma of NPSLE patients a loss of tissue integrity occurs facilitating motility of free-water protons.", "author" : [ { "dropping-particle" : "", "family" : "Welsh", "given" : "Robert C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rahbar", "given" : "Habib", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Foerster", "given" : "Bradley", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Thurnher", "given" : "Majda", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sundgren", "given" : "Pia C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of magnetic resonance imaging : JMRI", "id" : "ITEM-6", "issue" : "3", "issued" : { "date-parts" : [ [ "2007", "9" ] ] }, "page" : "541-51", "title" : "Brain diffusivity in patients with neuropsychiatric systemic lupus erythematosus with new acute neurological symptoms.", "type" : "article-journal", "volume" : "26" }, "uris" : [ "" ] }, { "id" : "ITEM-7", "itemData" : { "DOI" : "10.1080/02841850601105825", "ISSN" : "0284-1851", "PMID" : "17354144", "abstract" : "PURPOSE: To investigate whether apparent diffusion coefficient (ADC), fractional anisotropy (FA), and eigenvalues in neuropsychiatric systemic lupus erythematosus (NPSLE) patients differ from those of healthy controls.\n\nMATERIAL AND METHODS: Eight NPSLE patients (aged 23-55 years, mean 42.9 years) and 20 healthy age-matched controls (aged 22-59 years, mean 44.4 years) underwent conventional brain magnetic resonance (MR) and diffusion tensor imaging (DTI). The ADC, FA, principal eigenvalue (lambda parallel), and the corresponding average perpendicular eigenvalue (lambda perpendicular) (=(lambda2+lambda3)/2) were measured in selected regions of normal appearing gray and white matter brain parenchyma. For statistical evaluation of differences between the two groups, a Student's t-test was used. The P value for statistical significance was set to P=0.0025 after Bonferroni correction for multiple measurements.\n\nRESULTS: Significantly increased ADC values were demonstrated in normal-appearing areas in the insular cortex (P<0.001), thalamus (P<0.001), and the parietal and frontal white matter (P<0.001 and P<0.001, respectively) in NPSLE patients. Significantly decreased FA values were demonstrated in normal-appearing thalamus (P<0.001), corpus callosum (P=0.002), and in the parietal and frontal white matter (P<0.001 and P<0.001, respectively) in NPSLE patients compared to healthy controls. The lambda perpendicular was significantly higher in several of these regions in NPSLE patients compared to healthy controls.\n\nCONCLUSION: Our study demonstrates alterations in normal-appearing gray and white matter brain parenchyma of patients with NPSLE by means of abnormal ADC, FA, and eigenvalues. These alterations may be based on loss of tissue integrity in part due to demyelination. It is possible that DTI in the future could assist in the diagnosis of NPSLE and possibly help to further elucidate the pathogenesis of NPSLE.", "author" : [ { "dropping-particle" : "", "family" : "Hughes", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sundgren", "given" : "P C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fan", "given" : "X", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Foerster", "given" : "B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Nan", "given" : "B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Welsh", "given" : "R C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Williamson", "given" : "J a", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Attwood", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "V", "family" : "Maly", "given" : "P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chenevert", "given" : "T L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McCune", "given" : "W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gebarski", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Acta radiologica (Stockholm, Sweden : 1987)", "id" : "ITEM-7", "issue" : "2", "issued" : { "date-parts" : [ [ "2007", "3" ] ] }, "page" : "213-22", "title" : "Diffusion tensor imaging in patients with acute onset of neuropsychiatric systemic lupus erythematosus: a prospective study of apparent diffusion coefficient, fractional anisotropy values, and eigenvalues in different regions of the brain.", "type" : "article-journal", "volume" : "48" }, "uris" : [ "" ] }, { "id" : "ITEM-8", "itemData" : { "DOI" : "10.1016/j.mri.2006.09.037", "ISSN" : "0730-725X", "PMID" : "17371731", "abstract" : "BACKGROUND AND PURPOSE: Systemic lupus erythematosus (SLE) is an autoimmune disease in which almost all the organs are involved. Neuropsychiatric SLE is of one of the major concerns in the clinical evaluation of this disease. Routine magnetic resonance imaging (MRI) findings are often nonspecific or negative. In this study, we explored the use of diffusion tensor imaging in assisting with the diagnosis of SLE.\n\nMETHODS: Data from 34 SLE patients (age range, 18-73 years) and 29 age-matched volunteers (age range, 29-64 years) were analyzed. MRI was performed on a 1.5-T clinical MR scanner with a quadrature head coil. The average diffusion constant (D(av)) and diffusion anisotropy maps [fractional anisotropy (FA)] were determined on a pixel-by-pixel basis. Regional diffusion measurements were made by region of interest in the genu and splenium of the corpus callosum (CC), anterior and posterior limb of the internal capsule (IC) and frontal lobe and thalamus. The diffusion distribution was fitted to a triple-Gaussian model. The mean of the brain tissue distribution was determined as a mean diffusion constant for the whole brain (BD(av)). Student's t test was used to determine the diffusion difference between SLE patients and control subjects. The SLE patients were separated into two groups according to their MRI results. A P value lower than .05 was considered to be statistically significant.\n\nRESULTS: Twenty of the 34 SLE patients with abnormal MRI results showed findings dominated by nonspecific white matter disease. The BD(av) and D(av) values of the frontal lobe, splenium CC and anterior IC were significantly higher in all SLE patients as compared with the control subjects. The SLE patients with normal MRI results also showed higher BD(av) and D(av) values in the frontal lobe, splenium and anterior and posterior limbs of the IC as compared with the control subjects. There was no significant difference in the D(av) values of the thalamus between the SLE patients and the control subjects. The BD(av) value in the SLE patient group was robustly correlated with the D(av) values of the frontal lobe, splenium and thalamus. These correlations were found to be similarly significant for the SLE patients with normal MRI findings. The diffusion anisotropy measurements showed that splenium CC had the highest FA value in both the control subjects and SLE patients. Overall, SLE patients had lower FA values in the genu and splenium CC as compared with the control subje\u2026", "author" : [ { "dropping-particle" : "", "family" : "Zhang", "given" : "Lijuan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Harrison", "given" : "Melanie", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Heier", "given" : "Linda a", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zimmerman", "given" : "Robert D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ravdin", "given" : "Lisa", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lockshin", "given" : "Michael", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ulu\u011f", "given" : "Aziz M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Magnetic resonance imaging", "id" : "ITEM-8", "issue" : "3", "issued" : { "date-parts" : [ [ "2007", "5" ] ] }, "page" : "399-405", "title" : "Diffusion changes in patients with systemic lupus erythematosus.", "type" : "article-journal", "volume" : "25" }, "uris" : [ "" ] }, { "id" : "ITEM-9", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Bosma", "given" : "Gerlof P Th", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Huizinga", "given" : "Tom W J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mooijaart", "given" : "Simon P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "Van", "family" : "Buchem", "given" : "Mark A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "id" : "ITEM-9", "issue" : "May", "issued" : { "date-parts" : [ [ "2003" ] ] }, "page" : "850-854", "title" : "Abnormal Brain Diffusivity in Patients with Neuropsychiatric Systemic Lupus Erythematosus", "type" : "article-journal" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "^8\u201316", "plainTextFormattedCitation" : "8\u201316", "previouslyFormattedCitation" : "^8\u201316" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }8–16 show microstructural tract damage in SLE and neuropsychiatric SLE (NPSLE) versus healthy controls. However, none of these studies has investigated whether sub-visible DT-MRI-detected brain damage associates with fatigue or cognitive function.Our aims were: (1) compare water diffusion values in major white matter tracts in SLE patients with age-matched healthy controls, (2) identify if fatigue or cognitive function in SLE were related to DT-MRI parameters, SLE disease activity or plasma biomarkers of inflammation and endothelial dysfunction and (3) to consider the totality of the data on DTI-MRI in SLE by meta-analysing the current and all prior studies.METHODSSubjectsFrom April to December 2014, patients with SLE were prospectively recruited into a neuroimaging study and underwent DT-MRI to quantify white matter tract integrity. We invited patients consecutively as they attended clinic, of whom 31/51 (60.7%) were already members of the prospective Scottish Lupus Exchange registry project (). All patients were seen by a consultant rheumatologist. SLE was diagnosed according to updated American College of Rheumatology 1997 criteriaADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1002/1529-0131(200103)44:3<735::AID-ANR125>3.0.CO;2-F", "ISBN" : "0004-3591 (Print) 0004-3591 (Linking)", "ISSN" : "1529-0131", "PMID" : "9324032", "abstract" : "1997 update of 1982 American College of Rheumatology Revised Criteria for classification of SLE", "author" : [ { "dropping-particle" : "", "family" : "Hochberg", "given" : "Mc C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Arthritis & Rheumatism", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "1997" ] ] }, "page" : "1725", "title" : "Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus", "type" : "article-journal", "volume" : "40" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹⁷", "plainTextFormattedCitation" : "17", "previouslyFormattedCitation" : "¹⁷" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }17. We excluded patients with concurrent infection. The project received research ethics committee approval (South East Scotland REC 01, 14/SS/0003) and all participants gave written informed consent. We compared DT-MRI biomarkers in the SLE group with control data obtained from a group of consenting healthy volunteers scanned on the same scanner with the same sequences under a study approved by the Lothian Research Ethics Committees (REC 05/S1104/45). FatigueWe assessed fatigue using the Fatigue Severity Scale (FSS)ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0003-9942", "PMID" : "2803071", "abstract" : "Fatigue is a prominent disabling symptom in a variety of medical and neurologic disorders. To facilitate research in this area, we developed a fatigue severity scale, subjected it to tests of internal consistency and validity, and used it to compare fatigue in two chronic conditions: systemic lupus erythematosus and multiple sclerosis. Administration of the fatigue severity scale to 25 patients with multiple sclerosis, 29 patients with systemic lupus erythematosus, and 20 healthy adults revealed that the fatigue severity scale was internally consistent, correlated well with visual analogue measures, clearly differentiated controls from patients, and could detect clinically predicted changes in fatigue over time. Fatigue had a greater deleterious impact on daily living in patients with multiple sclerosis and systemic lupus erythematosus compared with controls. The results further showed that fatigue was largely independent of self-reported depressive symptoms and that several characteristics could differentiate fatigue that accompanies multiple sclerosis from fatigue that accompanies systemic lupus erythematosus. This study demonstrates (1) the clinical and research applications of a scale that measures fatigue severity and (2) helps to identify features that distinguish fatigue between two chronic medical disorders.", "author" : [ { "dropping-particle" : "", "family" : "Krupp", "given" : "L B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "LaRocca", "given" : "N G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Muir-Nash", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Steinberg", "given" : "a D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Archives of neurology", "id" : "ITEM-1", "issue" : "10", "issued" : { "date-parts" : [ [ "1989", "10" ] ] }, "page" : "1121-3", "title" : "The fatigue severity scale. Application to patients with multiple sclerosis and systemic lupus erythematosus.", "type" : "article-journal", "volume" : "46" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹⁸", "plainTextFormattedCitation" : "18", "previouslyFormattedCitation" : "¹⁸" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }18 with higher scores indicating more severe fatigue. The mean (± SD) from normal healthy adults in the standardisation sample was 2.3 (± 0.7).ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0003-9942", "PMID" : "2803071", "abstract" : "Fatigue is a prominent disabling symptom in a variety of medical and neurologic disorders. To facilitate research in this area, we developed a fatigue severity scale, subjected it to tests of internal consistency and validity, and used it to compare fatigue in two chronic conditions: systemic lupus erythematosus and multiple sclerosis. Administration of the fatigue severity scale to 25 patients with multiple sclerosis, 29 patients with systemic lupus erythematosus, and 20 healthy adults revealed that the fatigue severity scale was internally consistent, correlated well with visual analogue measures, clearly differentiated controls from patients, and could detect clinically predicted changes in fatigue over time. Fatigue had a greater deleterious impact on daily living in patients with multiple sclerosis and systemic lupus erythematosus compared with controls. The results further showed that fatigue was largely independent of self-reported depressive symptoms and that several characteristics could differentiate fatigue that accompanies multiple sclerosis from fatigue that accompanies systemic lupus erythematosus. This study demonstrates (1) the clinical and research applications of a scale that measures fatigue severity and (2) helps to identify features that distinguish fatigue between two chronic medical disorders.", "author" : [ { "dropping-particle" : "", "family" : "Krupp", "given" : "L B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "LaRocca", "given" : "N G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Muir-Nash", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Steinberg", "given" : "a D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Archives of neurology", "id" : "ITEM-1", "issue" : "10", "issued" : { "date-parts" : [ [ "1989", "10" ] ] }, "page" : "1121-3", "title" : "The fatigue severity scale. Application to patients with multiple sclerosis and systemic lupus erythematosus.", "type" : "article-journal", "volume" : "46" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹⁸", "plainTextFormattedCitation" : "18", "previouslyFormattedCitation" : "¹⁸" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }18Cognitive assessmentsWe used Hospital Anxiety and Depression Scale (HADS),ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Zigmond", "given" : "AS", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Snaith", "given" : "RP", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Acta Psychiatr Scand", "id" : "ITEM-1", "issue" : "6", "issued" : { "date-parts" : [ [ "1983" ] ] }, "page" : "361-70", "title" : "The hospital anxiety and depression scale", "type" : "article-journal", "volume" : "67" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹⁹", "plainTextFormattedCitation" : "19", "previouslyFormattedCitation" : "¹⁹" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }19 Montreal Cognitive Assessment (MoCA),ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Narseddine", "given" : "ZS", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Phillips", "given" : "NA", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bedirian", "given" : "V", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Charbonneau", "given" : "Simon", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Whitehead", "given" : "Victor", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Collin", "given" : "Isabelle", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cummings", "given" : "JL", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chertkow", "given" : "H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of the American Geriatrics Society", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2005" ] ] }, "page" : "695-9", "title" : "The Montreal Cognitive Assessment , MoCA : A Brief Screening Tool for Mild Cognitive Impairment", "type" : "article-journal", "volume" : "53" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "²⁰", "plainTextFormattedCitation" : "20", "previouslyFormattedCitation" : "²⁰" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }20 Addenbrooke’s Cognitive Examination – Revised (ACER)ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1159/000351671", "ISSN" : "1421-9824", "PMID" : "23949210", "abstract" : "BACKGROUND/AIMS: The aims of this study were to validate the newly developed version of the Addenbrooke's Cognitive Examination (ACE-III) against standardised neuropsychological tests and its predecessor (ACE-R) in early dementia.\n\nMETHODS: A total of 61 patients with dementia (frontotemporal dementia, FTD, n = 33, and Alzheimer's disease, AD, n = 28) and 25 controls were included in the study.\n\nRESULTS: ACE-III cognitive domains correlated significantly with standardised neuropsychological tests used in the assessment of attention, language, verbal memory and visuospatial function. The ACE-III also compared very favourably with its predecessor, the ACE-R, with similar levels of sensitivity and specificity.\n\nCONCLUSION: The results of this study provide objective validation of the ACE-III as a screening tool for cognitive deficits in FTD and AD.", "author" : [ { "dropping-particle" : "", "family" : "Hsieh", "given" : "Sharpley", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schubert", "given" : "Samantha", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hoon", "given" : "Christopher", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mioshi", "given" : "Eneida", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hodges", "given" : "John R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Dementia and geriatric cognitive disorders", "id" : "ITEM-1", "issue" : "3-4", "issued" : { "date-parts" : [ [ "2013", "1" ] ] }, "page" : "242-50", "title" : "Validation of the Addenbrooke's Cognitive Examination III in frontotemporal dementia and Alzheimer's disease.", "type" : "article-journal", "volume" : "36" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "²¹", "plainTextFormattedCitation" : "21", "previouslyFormattedCitation" : "²¹" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }21 and Mini Mental State Examination (MMSE)ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Folstein", "given" : "MF", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Folstein", "given" : "SE", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McHugh", "given" : "PR", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "J. Psychiat. Res.", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "1975" ] ] }, "page" : "189-98", "title" : "Mini-mental state. A practical method for grading the cognitive state of patients for the clinician.", "type" : "article-journal", "volume" : "12" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "²²", "plainTextFormattedCitation" : "22", "previouslyFormattedCitation" : "²²" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }22 to assess anxiety, depression and cognitive function, while the National Adult Reading Test (NART)ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Nelson", "given" : "HR", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Willison", "given" : "JR", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "NFER_Nelson Publishing", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "1982" ] ] }, "title" : "National Adult Reading Test (NART):Test Manual.", "type" : "article-journal" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "²³", "plainTextFormattedCitation" : "23", "previouslyFormattedCitation" : "²³" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }23 was used to adjust for premorbid intelligence. The NART is a validatedADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "McGurn", "given" : "B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Starr", "given" : "J M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Topfer", "given" : "J A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pattie", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Whiteman", "given" : "M C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lemmon", "given" : "H A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Whalley", "given" : "L J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Deary", "given" : "I J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Neurology", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2004" ] ] }, "page" : "1184-87", "title" : "Pronunciation of irregular words is preserved in dementia , validating premorbid IQ estimation", "type" : "article-journal", "volume" : "62" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "²⁴", "plainTextFormattedCitation" : "24", "previouslyFormattedCitation" : "²⁴" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }24 estimate of childhood peak premorbid intelligence as it appears broadly resilient to age-related cognitive decline. Clinical dataMedical history including cardiovascular risk factors such as smoking status, prior cerebrovascular events, hypertension and diabetes were recorded together with height, weight and body mass index (BMI).Disease activityCurrent SLE disease activity was assessed using the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K)ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Gladman", "given" : "DD", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ibanez", "given" : "D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Urowitz", "given" : "MB", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "J Rheumatol", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2002" ] ] }, "page" : "288-91", "title" : "Systemic lupus erythematosus disease activity index 2000.", "type" : "article-journal", "volume" : "29" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "²⁵", "plainTextFormattedCitation" : "25", "previouslyFormattedCitation" : "²⁵" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }25 and British Isles Lupus Assessment Group 2004 (BILAG)ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1093/rheumatology/keh624", "ISSN" : "1462-0324", "PMID" : "15814577", "abstract" : "OBJECTIVE: To devise a more discriminating version of the British Isles Lupus Assessment Group (BILAG) disease activity index and to show that it is reliable.\n\nMETHODS: A nominal consensus approach was undertaken by members of BILAG to update and improve the BILAG lupus disease activity index. The index has been revised following intense consultations over a 1-yr period. It has been assessed in two real-patient exercises. These involved patients with diverse clinical features of SLE, including gastrointestinal, hepatic and ophthalmic problems, which the earlier versions of the index did not fully take into account. Reliability in terms of the ability to differentiate patients was assessed by calculating intraclass correlation coefficients. The level of agreement between physicians was determined by calculating the ratio of estimates of the standard error (SE) attributable to the physicians to the SE attributable to the patients.\n\nRESULTS: Good reliability and high levels of physician agreement were observed in one or both exercises in the constitutional, mucocutaneous, neurological, cardiorespiratory, renal, ophthalmic and haematological systems. In contrast, the musculoskeletal system did not score as well, although providing more clear-cut glossary definitions should greatly improve the situation.\n\nCONCLUSIONS: Some significant changes in the BILAG disease activity index to assess patients with SLE are proposed. The process of demonstrating validity and reliability has started with these two exercises assessing real patients. Further validation studies are under way. BILAG 2004 is likely to be valuable in clinical trials assessing new therapies for the treatment of SLE, as it provides a more comprehensive system-based disease activity measure than has been available previously.", "author" : [ { "dropping-particle" : "", "family" : "Isenberg", "given" : "D a", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rahman", "given" : "a", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Allen", "given" : "E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Farewell", "given" : "V", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Akil", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bruce", "given" : "I N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "D'Cruz", "given" : "D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Griffiths", "given" : "B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Khamashta", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Maddison", "given" : "P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McHugh", "given" : "N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Snaith", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Teh", "given" : "L S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Yee", "given" : "C S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zoma", "given" : "a", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gordon", "given" : "C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Rheumatology (Oxford, England)", "id" : "ITEM-1", "issue" : "7", "issued" : { "date-parts" : [ [ "2005", "7" ] ] }, "page" : "902-6", "title" : "BILAG 2004. Development and initial validation of an updated version of the British Isles Lupus Assessment Group's disease activity index for patients with systemic lupus erythematosus.", "type" : "article-journal", "volume" : "44" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "²⁶", "plainTextFormattedCitation" : "26", "previouslyFormattedCitation" : "²⁶" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }26 tools. Accumulated permanent damage was assessed with the Systemic Lupus International Collaborating Clinics (SLICC)ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Gladman", "given" : "Dafna", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ginzler", "given" : "Ellen", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Goldsmith", "given" : "Charles", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fortin", "given" : "Paul", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Liang", "given" : "Matthew", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Urowitz", "given" : "Murray", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bacon", "given" : "Paul", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bombardieri", "given" : "Stefan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hanly", "given" : "John", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hay", "given" : "Elaine", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Isenberg", "given" : "David", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jones", "given" : "John", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kalunian", "given" : "Kenneth", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Maddison", "given" : "Peter", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Nived", "given" : "O L A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Petri", "given" : "Michelle", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Richter", "given" : "Martin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sanchez-guerrero", "given" : "Jorge", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Snaith", "given" : "Michael", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sturfelt", "given" : "Gunnar", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Symmons", "given" : "Deborah", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zoma", "given" : "Asad", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Arthritis & Rheumatism", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "1996" ] ] }, "page" : "363-369", "title" : "The development and initial validation of the systemic lupus international collaborating clinics / America College of Rheumatology Damage Index for systemic lupus erythematosus", "type" : "article-journal", "volume" : "39" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Gladman", "given" : "DD", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Goldsmith", "given" : "CH", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Urowitz", "given" : "MB", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bacon", "given" : "P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fortin", "given" : "P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ginzler", "given" : "E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gordon", "given" : "C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hanly", "given" : "JG", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Isenberg", "given" : "DA", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Petri", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Nived", "given" : "O", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Snaith", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sturfelt", "given" : "G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "J Rheumatol", "id" : "ITEM-2", "issue" : "2", "issued" : { "date-parts" : [ [ "2000" ] ] }, "page" : "373-6", "title" : "The Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) Damage Index for Systemic Lupus Erythematosus International Comparison", "type" : "article-journal", "volume" : "27" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "^27,28", "plainTextFormattedCitation" : "27,28", "previouslyFormattedCitation" : "^27,28" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }27,28 tool. MRIAll subjects were scanned at 1.5T with an 8-channel phased-array head coil (GE, Milwaukee, WI). The scan protocol included axial T2, gradient-recalled echo, fluid-attenuated inversion recovery, sagittal T2, high-resolution coronal 3D T1 volume, and whole brain DT-MRI sequences. The DT-MRI sequence consisted of thee T2-weighted and 32 diffusion-weighted (b=1000 s mm-2) axial single-shot spin-echo echo-planar imaging volumes (field of view 240240 mm, matrix 128128, TR 13.75s, TE 78.4ms). Each volume comprised 56 contiguous 2.5 mm thick axial slices with 1.875 mm in-plane resolution. Detailed scanning parameters are shown in Supplementary Table 1.TractographyTractography analysis was performed blind to all other data. Major white matter tracts were identified using probabilistic neighbourhood tractography (PNT), an automatic tract segmentation method based on modelling tract topology, as implemented in the TractoR package for fibre tracking analysis (). Further details are provided in Supplementary Material.Plasma markersAll participants had blood drawn on the day of MRI scanning. We measured the pro-inflammatory cytokine interleukin-6 (IL-6), endothelial dysfunction (von Willebrand Factor antigen (vWF Ag) and two measures of vWF activity: factor VIIIc (fVIIIc) and ristocetin cofactor (RCOF)), endothelial toxicity (homocysteine), cholesterol (total, high- (HDL) and low-density (LDL) lipoprotein) and anti-phospholipid antibodies (anti-cardiolipin Immunoglobulin G (IgG) and M (IgM)). We also had access to blood data from recent clinic visits (most within one month; all within six months) including SLE disease activity (C3, C4 and anti-double stranded DNA) and routine inflammatory markers (C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR)). Additionally, interferon beta (IFN) signatures were measured by analysis of messenger ribonucleic acid in a subset of 25 (49%) patients. Statistical analysisData distributions were checked graphically for normality and presented as means (± SD) or medians (Q1–Q3) as appropriate. Principal components analysis (PCA) was used to create a ‘general factor’ of MD and FA representing all tracts (‘tract-averaged’) from the individual tracts. PCA is a data reduction technique that extracts a latent variable calculated from several measured variables. Tract-averaged MD and FA were compared between SLE patients and healthy controls using Student’s t test. Mean fatigue in patients was compared with a normal reference rangeADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0003-9942", "PMID" : "2803071", "abstract" : "Fatigue is a prominent disabling symptom in a variety of medical and neurologic disorders. To facilitate research in this area, we developed a fatigue severity scale, subjected it to tests of internal consistency and validity, and used it to compare fatigue in two chronic conditions: systemic lupus erythematosus and multiple sclerosis. Administration of the fatigue severity scale to 25 patients with multiple sclerosis, 29 patients with systemic lupus erythematosus, and 20 healthy adults revealed that the fatigue severity scale was internally consistent, correlated well with visual analogue measures, clearly differentiated controls from patients, and could detect clinically predicted changes in fatigue over time. Fatigue had a greater deleterious impact on daily living in patients with multiple sclerosis and systemic lupus erythematosus compared with controls. The results further showed that fatigue was largely independent of self-reported depressive symptoms and that several characteristics could differentiate fatigue that accompanies multiple sclerosis from fatigue that accompanies systemic lupus erythematosus. This study demonstrates (1) the clinical and research applications of a scale that measures fatigue severity and (2) helps to identify features that distinguish fatigue between two chronic medical disorders.", "author" : [ { "dropping-particle" : "", "family" : "Krupp", "given" : "L B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "LaRocca", "given" : "N G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Muir-Nash", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Steinberg", "given" : "a D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Archives of neurology", "id" : "ITEM-1", "issue" : "10", "issued" : { "date-parts" : [ [ "1989", "10" ] ] }, "page" : "1121-3", "title" : "The fatigue severity scale. Application to patients with multiple sclerosis and systemic lupus erythematosus.", "type" : "article-journal", "volume" : "46" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹⁸", "plainTextFormattedCitation" : "18", "previouslyFormattedCitation" : "¹⁸" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }18 using the Welch two-sample t test. Linear regression was used to examine the association between fatigue and other variables by univariate analyses. Multiple linear regression was used to adjust for age alone, then age + disease duration + steroids. PCA was used to create a general factor of cognitive function (g)ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Jensen", "given" : "AR", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "1998" ] ] }, "publisher" : "Praeger", "publisher-place" : "London", "title" : "The g Factor:The science of mental ability.", "type" : "book" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "²⁹", "plainTextFormattedCitation" : "29", "previouslyFormattedCitation" : "²⁹" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }29 from the three cognitive tools (MoCA, ACER, MMSE). Linear regression was used to examine the association between g and other variables, and included use of NART to adjust for a person’s prior (peak) cognitive function before the deleterious effect of age and SLE disease duration, if any, and any impact from current steroid use. For all regression models, we checked multicollinearity, independence, constancy of variance and normality in the residuals. A p value of <0.05 was considered significant. In the interests of transparency, we report results from all analyses regardless of the p value as this aids interpretation of the entire study and we did not adjust the p values for multiple comparisonsADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "v", "family" : "Perneger", "given" : "Thomas", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "BMJ", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "1998" ] ] }, "page" : "1236", "title" : "What's wrong with Bonferroni adjustments", "type" : "article-journal", "volume" : "316" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "³⁰", "plainTextFormattedCitation" : "30", "previouslyFormattedCitation" : "³⁰" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }30. All analyses were performed with the statistical programming language R version 3.0.1 ().ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "R Core Team", "given" : "", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2013" ] ] }, "page" : "R Foundation for Statistical Computing, Vienna, Au", "title" : "R: A language and environment for statistical computing.", "type" : "article-journal" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "³¹", "plainTextFormattedCitation" : "31", "previouslyFormattedCitation" : "³¹" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }31Literature review and meta-analysisWe searched MEDLINE and EMBASE (from 1990) on 15th January 2015 using the terms “diffusion-tensor imaging” and “diffusion-weighted imaging” in conjunction with the terms “lupus”, “systemic lupus erythematosus” and “neuropsychiatric systemic lupus erythematosus”. Acronyms and different combinations of the main search terms were also used. We checked reference lists of relevant papers for additional studies. We extracted data on study population (demographics, sample size, disease duration), imaging parameters, part of the brain measured (whole brain, specific tracts) and the reported diffusion measures. Standardised mean differences were calculated using the Cochrane Collaboration’s Review Manager 5 software and used to compare DT-MRI findings in the meta-analysis. RESULTSSubjectsFifty-one patients with SLE were recruited with mean age 48.8±14.3 years (range 20 to 76 years), including 47 women (92%) which is consistent with community prevalence. Clinical, fatigue and cognitive data are given in Table 1. MD, FA and NART scores were available for 51 age- and sex-matched healthy controls of mean age 44.9±11.1 years, including 39 women (76%). A third of patients (18/51 (35%)) were currently prescribed corticosteroids. General factors for MD and FADT-MRI failed in four patients so the following analyses are based on 47 patients. In SLE, the general factors MD and FA accounted for 40% and 27% of the variance among tracts, respectively. A similar level of variance was explained in the control group. Factor loadings of each tract are given in Supplementary Table 2. An image illustrating whole brain white matter tractography from a representative patient along with a group map illustrating two tracts (the genu and splenium of corpus callosum) is shown in Figure paring MD and FA to healthy controlsMD was significantly higher in all tracts (p<0.0001 for all tracts) in SLE patients versus controls (Table 2). FA was significantly higher in SLE patients than controls in the genu (p<0.0001) and left corticospinal tract (p<0.0001), and significantly lower in the splenium (p=0.008), and left (p=0.04) and right (p=0.01) cingulum bundles (Table 2). The expected increase in MD and decrease in FA with age appeared accelerated in SLE patients versus controls (Figure 2). However, the patients’ and controls’ regression slopes (for both MD and FA) did not differ when tested via an interaction term in a linear regression model.FatigueFatigue in SLE was significantly higher than the expected normal rangeADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0003-9942", "PMID" : "2803071", "abstract" : "Fatigue is a prominent disabling symptom in a variety of medical and neurologic disorders. To facilitate research in this area, we developed a fatigue severity scale, subjected it to tests of internal consistency and validity, and used it to compare fatigue in two chronic conditions: systemic lupus erythematosus and multiple sclerosis. Administration of the fatigue severity scale to 25 patients with multiple sclerosis, 29 patients with systemic lupus erythematosus, and 20 healthy adults revealed that the fatigue severity scale was internally consistent, correlated well with visual analogue measures, clearly differentiated controls from patients, and could detect clinically predicted changes in fatigue over time. Fatigue had a greater deleterious impact on daily living in patients with multiple sclerosis and systemic lupus erythematosus compared with controls. The results further showed that fatigue was largely independent of self-reported depressive symptoms and that several characteristics could differentiate fatigue that accompanies multiple sclerosis from fatigue that accompanies systemic lupus erythematosus. This study demonstrates (1) the clinical and research applications of a scale that measures fatigue severity and (2) helps to identify features that distinguish fatigue between two chronic medical disorders.", "author" : [ { "dropping-particle" : "", "family" : "Krupp", "given" : "L B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "LaRocca", "given" : "N G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Muir-Nash", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Steinberg", "given" : "a D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Archives of neurology", "id" : "ITEM-1", "issue" : "10", "issued" : { "date-parts" : [ [ "1989", "10" ] ] }, "page" : "1121-3", "title" : "The fatigue severity scale. Application to patients with multiple sclerosis and systemic lupus erythematosus.", "type" : "article-journal", "volume" : "46" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹⁸", "plainTextFormattedCitation" : "18", "previouslyFormattedCitation" : "¹⁸" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }18 (5.0±1.7 v 2.3±0.7, p<0.0001). Fatigue was non-significantly negatively correlated with age (r = –0.24, p=0.09) (Supplementary Table 3; Supplementary Figure 5, panel (A)). In the univariate analysis, higher fatigue was associated with higher depression (? = 0.17, r = 0.47, p=0.0004), higher anxiety (? = 0.13, r = 0.41, p=0.002), higher BMI (? = 0.09, r = 0.36, p=0.01), lower MD (? = –0.58, r = –0.35, p=0.01), lower IFN (? = –0.09, r = –0.54, p=0.006) and lower vWF (RCOF (? = –1.43, r = –0.34, p=0.02) and fVIIIc (? = –1.17, r = –0.30, p=0.04)) (Supplementary Tables 3 and 4). Except vWF (RCOF), all associations remained after adjusting for age only. Except vWF (RCOF) and IFN all associations remained after adjusting for age, disease duration and steroids (Table 3).Cognitive functionOne patient was excluded from the analysis of cognitive results as English was not his first language. On average, patients met the minimum levels required for normal cognition by the three individual tests (Table 1). However, 19/50 (38%) (MoCA), 13/50 (26%) (ACER) and 5/50 (10%) (MMSE) patients scored below the tests’ commonly-used cut-offs indicating clinical levels of cognitive impairment. The mean NART score in SLE was significantly lower than age-matched healthy controls (34 v 40, p=0.0008). In the univariate analysis, poorer cognitive function (g) was associated with longer SLE disease duration (? = –0.003, r = –0.41, p=0.003), higher MD (? = –0.27, r = –0.31, p=0.03), higher vWF (Ag (? = –0.80, r = –0.51, p=0.0003) and RCOF (? = –0.89, r = –0.35, p=0.02)) and higher IL-6 (? = –0.23, r = –0.43, p=0.006) (Supplementary Tables 3 and 4). Except MD, all associations remained after adjusting for age (Table 3). After adjusting for age, disease duration, steroids and NART, only higher IL-6 (? = –0.15, p=0.02) remained independently and significantly associated with poorer cognitive function (Table 3). Literature review and meta-analysisThe search uncovered 19 papers of which 10 were excluded as not relevant (no measure of MD or FA in SLE or NPSLE). We meta-analysed results in 3 groups: (1) SLE versus healthy controls, (2) NPSLE versus healthy controls and (3) SLE versus NPSLE.NineADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Zimny", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Szewczyk", "given" : "P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bladowska", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gruszka", "given" : "E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Lupus", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2014" ] ] }, "page" : "10-19", "title" : "In vivo evaluation of brain damage in the course of systemic lupus erythematosus using magnetic resonance spectroscopy , perfusion-weighted and diffusion-tensor imaging", "type" : "article-journal", "volume" : "23" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1016/j.nicl.2014.07.001", "ISSN" : "2213-1582", "PMID" : "25161895", "abstract" : "PURPOSE: Systemic lupus erythematosus (SLE) is an autoimmune connective tissue disease that can affect the central nervous system. Neuropsychiatric symptoms are found in 25-70% of patients. Using diffusion tensor imaging (DTI) various studies have reported changes in white matter integrity in SLE patients with neuropsychiatric symptoms (NPSLE patients). The purpose of this study was to investigate, if regional changes in white matter integrity can also be detected in SLE patients without neuropsychiatric symptoms (non-NPSLE patients).\n\nMETHODS: Applying DTI and tract based spatial statistics (TBSS) we investigated 19 NPSLE patients, 19 non-NPSLE and 18 healthy controls. Groups were matched for age and sex. Image pre-processing was performed using FSL, following the TBSS pipeline (eddy current correction, estimation of fractional anisotropy (FA), normalization, skeletonization of the group mean FA image). A general linear model with threshold-free cluster enhancement was used to assess significant differences between the three groups.\n\nRESULTS: Statistical analyses revealed several regions of decreased prefrontal white matter integrity (decreased FA) in both groups of SLE patients. The changes found in the non-NPSLE patients (as compared to healthy controls) overlapped with those in the NPSLE patients, but were not as pronounced.\n\nCONCLUSIONS: Our data suggest that changes in regional white matter integrity, in terms of a decrease in FA, are present not only in NPSLE patients, but also in non-NPSLE patients, though to a lesser degree. We also demonstrate that the way statistical maps are corrected for multiple comparisons has a profound influence on whether alterations in white matter integrity in non-NPSLE patients are deemed significant.", "author" : [ { "dropping-particle" : "", "family" : "Schmidt-Wilcke", "given" : "Tobias", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cagnoli", "given" : "Patricia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wang", "given" : "Page", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schultz", "given" : "Thomas", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lotz", "given" : "Anne", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mccune", "given" : "William J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sundgren", "given" : "Pia C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "NeuroImage. Clinical", "id" : "ITEM-2", "issued" : { "date-parts" : [ [ "2014", "1" ] ] }, "page" : "291-7", "publisher" : "Elsevier B.V.", "title" : "Diminished white matter integrity in patients with systemic lupus erythematosus.", "type" : "article-journal", "volume" : "5" }, "uris" : [ "" ] }, { "id" : "ITEM-3", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Zivadinov", "given" : "R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Shucard", "given" : "J L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hussein", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Durfee", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cox", "given" : "J L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bergsland", "given" : "N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dwyer", "given" : "M G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Benedict", "given" : "R H B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "id" : "ITEM-3", "issue" : "2013", "issued" : { "date-parts" : [ [ "2015" ] ] }, "page" : "675-683", "title" : "Multimodal imaging in systemic lupus erythematosus patients with diffuse neuropsychiatric involvement", "type" : "article-journal" }, "uris" : [ "" ] }, { "id" : "ITEM-4", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Jung", "given" : "Rex E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Caprihan", "given" : "Arvind", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chavez", "given" : "Robert S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Flores", "given" : "Ranee A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sharrar", "given" : "Janeen", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Qualls", "given" : "Clifford R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sibbitt", "given" : "Wilmer", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Roldan", "given" : "Carlos A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "BMC neurology", "id" : "ITEM-4", "issue" : "65", "issued" : { "date-parts" : [ [ "2010" ] ] }, "title" : "Diffusion tensor imaging in neuropsychiatric systemic lupus erythematosus", "type" : "article-journal", "volume" : "10" }, "uris" : [ "" ] }, { "id" : "ITEM-5", "itemData" : { "DOI" : "10.1002/art.27717", "ISSN" : "1529-0131", "PMID" : "20722009", "abstract" : "OBJECTIVE: The aim of this study was to determine whether there are differences in white matter integrity between systemic lupus erythematosus (SLE) patients and healthy controls, as determined using tract-based spatial statistics (TBSS) analysis of diffusion tensor imaging data.\n\nMETHODS: Twelve patients with SLE (mean age 42 years [range 15-61 years]) diagnosed according to the American College of Rheumatology 1982 revised criteria for SLE and 28 healthy controls (mean age 46 years [range 21-61 years]) were included in the study. Magnetic resonance imaging was performed on a 3.0T scanner. Fractional anisotropy (FA) maps were calculated for each patient. TBSS analysis was used to compare the FA maps. The TBSS technique projects the FA data into a common space through the use of an initial approximate nonlinear registration, followed by projection onto an alignment-invariant tract representation (mean FA skeleton). The cluster results were corrected for multiple comparisons across space, and a threshold of significance of 0.05 was used.\n\nRESULTS: The white matter of tracts in the inferior fronto-occipital fasciculus, the fasciculus uncinatus, as well as the fornix, the posterior limb of the internal capsule (corticospinal tract), and the anterior limb of the internal capsule (anterior thalamic radiation) of patients with SLE showed reduced integrity as compared with normal subjects.\n\nCONCLUSION: In this preliminary study, the integrity of white matter tracts in areas around limbic structures and in the internal capsule was found to be reduced. Larger studies could improve our understanding of the pathologic mechanisms behind the reduced white matter tract integrity in SLE.", "author" : [ { "dropping-particle" : "", "family" : "Emmer", "given" : "Bart J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Veer", "given" : "Ilya M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Steup-Beekman", "given" : "Gerda M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Huizinga", "given" : "Tom W J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Grond", "given" : "Jeroen", "non-dropping-particle" : "van der", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Buchem", "given" : "Mark a", "non-dropping-particle" : "van", "parse-names" : false, "suffix" : "" } ], "container-title" : "Arthritis and rheumatism", "id" : "ITEM-5", "issue" : "12", "issued" : { "date-parts" : [ [ "2010", "12" ] ] }, "page" : "3716-21", "title" : "Tract-based spatial statistics on diffusion tensor imaging in systemic lupus erythematosus reveals localized involvement of white matter tracts.", "type" : "article-journal", "volume" : "62" }, "uris" : [ "" ] }, { "id" : "ITEM-6", "itemData" : { "DOI" : "10.1002/jmri.21036", "ISSN" : "1053-1807", "PMID" : "17729344", "abstract" : "PURPOSE: To investigate the source of significant difference in apparent diffusion coefficient (ADC) between patients with acute symptoms of neuropsychiatric (NP) systematic lupus erythematosus (SLE) (NPSLE) and normal controls.\n\nMATERIALS AND METHODS: Diffusion-weighted echo-planar imaging was performed on 1.5-T scanners in 17 female and four male NPSLE patients with acute neurological symptoms (23-76 years, mean = 42.7 years), and in 21 aged-matched healthy controls (16 female, five male, 26-63 years, mean = 41.1 years). ADC histograms were calculated for whole brain, gray matter tissue, and white matter tissue.\n\nRESULTS: Of the 17 NPSLE patients, 13 (72%) had abnormal findings on MR imaging. The NPSLE patients had a mean ADC value of (1105.1 +/- 23.6) x 10(-6) mm(2)/second and the control had a mean ADC value of (1012.5 +/- 9.4) x 10(-6) mm(2)/second (P < or = 0.0012). Significant differences were also found in white matter (P < or = 0.0020) and gray matter (P < or = 0.0022).\n\nCONCLUSION: ADC histogram analysis demonstrated increased general diffusivity in the brain in NPSLE patients with acute symptoms compared with healthy normal controls. This finding suggests that in the brain parenchyma of NPSLE patients a loss of tissue integrity occurs facilitating motility of free-water protons.", "author" : [ { "dropping-particle" : "", "family" : "Welsh", "given" : "Robert C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rahbar", "given" : "Habib", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Foerster", "given" : "Bradley", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Thurnher", "given" : "Majda", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sundgren", "given" : "Pia C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of magnetic resonance imaging : JMRI", "id" : "ITEM-6", "issue" : "3", "issued" : { "date-parts" : [ [ "2007", "9" ] ] }, "page" : "541-51", "title" : "Brain diffusivity in patients with neuropsychiatric systemic lupus erythematosus with new acute neurological symptoms.", "type" : "article-journal", "volume" : "26" }, "uris" : [ "" ] }, { "id" : "ITEM-7", "itemData" : { "DOI" : "10.1080/02841850601105825", "ISSN" : "0284-1851", "PMID" : "17354144", "abstract" : "PURPOSE: To investigate whether apparent diffusion coefficient (ADC), fractional anisotropy (FA), and eigenvalues in neuropsychiatric systemic lupus erythematosus (NPSLE) patients differ from those of healthy controls.\n\nMATERIAL AND METHODS: Eight NPSLE patients (aged 23-55 years, mean 42.9 years) and 20 healthy age-matched controls (aged 22-59 years, mean 44.4 years) underwent conventional brain magnetic resonance (MR) and diffusion tensor imaging (DTI). The ADC, FA, principal eigenvalue (lambda parallel), and the corresponding average perpendicular eigenvalue (lambda perpendicular) (=(lambda2+lambda3)/2) were measured in selected regions of normal appearing gray and white matter brain parenchyma. For statistical evaluation of differences between the two groups, a Student's t-test was used. The P value for statistical significance was set to P=0.0025 after Bonferroni correction for multiple measurements.\n\nRESULTS: Significantly increased ADC values were demonstrated in normal-appearing areas in the insular cortex (P<0.001), thalamus (P<0.001), and the parietal and frontal white matter (P<0.001 and P<0.001, respectively) in NPSLE patients. Significantly decreased FA values were demonstrated in normal-appearing thalamus (P<0.001), corpus callosum (P=0.002), and in the parietal and frontal white matter (P<0.001 and P<0.001, respectively) in NPSLE patients compared to healthy controls. The lambda perpendicular was significantly higher in several of these regions in NPSLE patients compared to healthy controls.\n\nCONCLUSION: Our study demonstrates alterations in normal-appearing gray and white matter brain parenchyma of patients with NPSLE by means of abnormal ADC, FA, and eigenvalues. These alterations may be based on loss of tissue integrity in part due to demyelination. It is possible that DTI in the future could assist in the diagnosis of NPSLE and possibly help to further elucidate the pathogenesis of NPSLE.", "author" : [ { "dropping-particle" : "", "family" : "Hughes", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sundgren", "given" : "P C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fan", "given" : "X", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Foerster", "given" : "B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Nan", "given" : "B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Welsh", "given" : "R C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Williamson", "given" : "J a", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Attwood", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "V", "family" : "Maly", "given" : "P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chenevert", "given" : "T L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "McCune", "given" : "W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gebarski", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Acta radiologica (Stockholm, Sweden : 1987)", "id" : "ITEM-7", "issue" : "2", "issued" : { "date-parts" : [ [ "2007", "3" ] ] }, "page" : "213-22", "title" : "Diffusion tensor imaging in patients with acute onset of neuropsychiatric systemic lupus erythematosus: a prospective study of apparent diffusion coefficient, fractional anisotropy values, and eigenvalues in different regions of the brain.", "type" : "article-journal", "volume" : "48" }, "uris" : [ "" ] }, { "id" : "ITEM-8", "itemData" : { "DOI" : "10.1016/j.mri.2006.09.037", "ISSN" : "0730-725X", "PMID" : "17371731", "abstract" : "BACKGROUND AND PURPOSE: Systemic lupus erythematosus (SLE) is an autoimmune disease in which almost all the organs are involved. Neuropsychiatric SLE is of one of the major concerns in the clinical evaluation of this disease. Routine magnetic resonance imaging (MRI) findings are often nonspecific or negative. In this study, we explored the use of diffusion tensor imaging in assisting with the diagnosis of SLE.\n\nMETHODS: Data from 34 SLE patients (age range, 18-73 years) and 29 age-matched volunteers (age range, 29-64 years) were analyzed. MRI was performed on a 1.5-T clinical MR scanner with a quadrature head coil. The average diffusion constant (D(av)) and diffusion anisotropy maps [fractional anisotropy (FA)] were determined on a pixel-by-pixel basis. Regional diffusion measurements were made by region of interest in the genu and splenium of the corpus callosum (CC), anterior and posterior limb of the internal capsule (IC) and frontal lobe and thalamus. The diffusion distribution was fitted to a triple-Gaussian model. The mean of the brain tissue distribution was determined as a mean diffusion constant for the whole brain (BD(av)). Student's t test was used to determine the diffusion difference between SLE patients and control subjects. The SLE patients were separated into two groups according to their MRI results. A P value lower than .05 was considered to be statistically significant.\n\nRESULTS: Twenty of the 34 SLE patients with abnormal MRI results showed findings dominated by nonspecific white matter disease. The BD(av) and D(av) values of the frontal lobe, splenium CC and anterior IC were significantly higher in all SLE patients as compared with the control subjects. The SLE patients with normal MRI results also showed higher BD(av) and D(av) values in the frontal lobe, splenium and anterior and posterior limbs of the IC as compared with the control subjects. There was no significant difference in the D(av) values of the thalamus between the SLE patients and the control subjects. The BD(av) value in the SLE patient group was robustly correlated with the D(av) values of the frontal lobe, splenium and thalamus. These correlations were found to be similarly significant for the SLE patients with normal MRI findings. The diffusion anisotropy measurements showed that splenium CC had the highest FA value in both the control subjects and SLE patients. Overall, SLE patients had lower FA values in the genu and splenium CC as compared with the control subje\u2026", "author" : [ { "dropping-particle" : "", "family" : "Zhang", "given" : "Lijuan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Harrison", "given" : "Melanie", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Heier", "given" : "Linda a", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zimmerman", "given" : "Robert D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ravdin", "given" : "Lisa", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lockshin", "given" : "Michael", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ulu\u011f", "given" : "Aziz M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Magnetic resonance imaging", "id" : "ITEM-8", "issue" : "3", "issued" : { "date-parts" : [ [ "2007", "5" ] ] }, "page" : "399-405", "title" : "Diffusion changes in patients with systemic lupus erythematosus.", "type" : "article-journal", "volume" : "25" }, "uris" : [ "" ] }, { "id" : "ITEM-9", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Bosma", "given" : "Gerlof P Th", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Huizinga", "given" : "Tom W J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mooijaart", "given" : "Simon P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "Van", "family" : "Buchem", "given" : "Mark A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "id" : "ITEM-9", "issue" : "May", "issued" : { "date-parts" : [ [ "2003" ] ] }, "page" : "850-854", "title" : "Abnormal Brain Diffusivity in Patients with Neuropsychiatric Systemic Lupus Erythematosus", "type" : "article-journal" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "^8\u201316", "plainTextFormattedCitation" : "8\u201316", "previouslyFormattedCitation" : "^8\u201316" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }8–16 prior studies were reviewed (n=214 patients; n=24 average per study) and added to the current study for meta-analysis (Table 4 and Supplementary Figures 1–4). Four studiesADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.nicl.2014.07.001", "ISSN" : "2213-1582", "PMID" : "25161895", "abstract" : "PURPOSE: Systemic lupus erythematosus (SLE) is an autoimmune connective tissue disease that can affect the central nervous system. Neuropsychiatric symptoms are found in 25-70% of patients. Using diffusion tensor imaging (DTI) various studies have reported changes in white matter integrity in SLE patients with neuropsychiatric symptoms (NPSLE patients). The purpose of this study was to investigate, if regional changes in white matter integrity can also be detected in SLE patients without neuropsychiatric symptoms (non-NPSLE patients).\n\nMETHODS: Applying DTI and tract based spatial statistics (TBSS) we investigated 19 NPSLE patients, 19 non-NPSLE and 18 healthy controls. Groups were matched for age and sex. Image pre-processing was performed using FSL, following the TBSS pipeline (eddy current correction, estimation of fractional anisotropy (FA), normalization, skeletonization of the group mean FA image). A general linear model with threshold-free cluster enhancement was used to assess significant differences between the three groups.\n\nRESULTS: Statistical analyses revealed several regions of decreased prefrontal white matter integrity (decreased FA) in both groups of SLE patients. The changes found in the non-NPSLE patients (as compared to healthy controls) overlapped with those in the NPSLE patients, but were not as pronounced.\n\nCONCLUSIONS: Our data suggest that changes in regional white matter integrity, in terms of a decrease in FA, are present not only in NPSLE patients, but also in non-NPSLE patients, though to a lesser degree. We also demonstrate that the way statistical maps are corrected for multiple comparisons has a profound influence on whether alterations in white matter integrity in non-NPSLE patients are deemed significant.", "author" : [ { "dropping-particle" : "", "family" : "Schmidt-Wilcke", "given" : "Tobias", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cagnoli", "given" : "Patricia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wang", "given" : "Page", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schultz", "given" : "Thomas", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lotz", "given" : "Anne", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mccune", "given" : "William J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sundgren", "given" : "Pia C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "NeuroImage. Clinical", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2014", "1" ] ] }, "page" : "291-7", "publisher" : "Elsevier B.V.", "title" : "Diminished white matter integrity in patients with systemic lupus erythematosus.", "type" : "article-journal", "volume" : "5" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Zivadinov", "given" : "R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Shucard", "given" : "J L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hussein", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Durfee", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cox", "given" : "J L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bergsland", "given" : "N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dwyer", "given" : "M G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Benedict", "given" : "R H B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "id" : "ITEM-2", "issue" : "2013", "issued" : { "date-parts" : [ [ "2015" ] ] }, "page" : "675-683", "title" : "Multimodal imaging in systemic lupus erythematosus patients with diffuse neuropsychiatric involvement", "type" : "article-journal" }, "uris" : [ "" ] }, { "id" : "ITEM-3", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Jung", "given" : "Rex E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Caprihan", "given" : "Arvind", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chavez", "given" : "Robert S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Flores", "given" : "Ranee A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sharrar", "given" : "Janeen", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Qualls", "given" : "Clifford R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sibbitt", "given" : "Wilmer", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Roldan", "given" : "Carlos A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "BMC neurology", "id" : "ITEM-3", "issue" : "65", "issued" : { "date-parts" : [ [ "2010" ] ] }, "title" : "Diffusion tensor imaging in neuropsychiatric systemic lupus erythematosus", "type" : "article-journal", "volume" : "10" }, "uris" : [ "" ] }, { "id" : "ITEM-4", "itemData" : { "DOI" : "10.1002/art.27717", "ISSN" : "1529-0131", "PMID" : "20722009", "abstract" : "OBJECTIVE: The aim of this study was to determine whether there are differences in white matter integrity between systemic lupus erythematosus (SLE) patients and healthy controls, as determined using tract-based spatial statistics (TBSS) analysis of diffusion tensor imaging data.\n\nMETHODS: Twelve patients with SLE (mean age 42 years [range 15-61 years]) diagnosed according to the American College of Rheumatology 1982 revised criteria for SLE and 28 healthy controls (mean age 46 years [range 21-61 years]) were included in the study. Magnetic resonance imaging was performed on a 3.0T scanner. Fractional anisotropy (FA) maps were calculated for each patient. TBSS analysis was used to compare the FA maps. The TBSS technique projects the FA data into a common space through the use of an initial approximate nonlinear registration, followed by projection onto an alignment-invariant tract representation (mean FA skeleton). The cluster results were corrected for multiple comparisons across space, and a threshold of significance of 0.05 was used.\n\nRESULTS: The white matter of tracts in the inferior fronto-occipital fasciculus, the fasciculus uncinatus, as well as the fornix, the posterior limb of the internal capsule (corticospinal tract), and the anterior limb of the internal capsule (anterior thalamic radiation) of patients with SLE showed reduced integrity as compared with normal subjects.\n\nCONCLUSION: In this preliminary study, the integrity of white matter tracts in areas around limbic structures and in the internal capsule was found to be reduced. Larger studies could improve our understanding of the pathologic mechanisms behind the reduced white matter tract integrity in SLE.", "author" : [ { "dropping-particle" : "", "family" : "Emmer", "given" : "Bart J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Veer", "given" : "Ilya M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Steup-Beekman", "given" : "Gerda M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Huizinga", "given" : "Tom W J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Grond", "given" : "Jeroen", "non-dropping-particle" : "van der", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Buchem", "given" : "Mark a", "non-dropping-particle" : "van", "parse-names" : false, "suffix" : "" } ], "container-title" : "Arthritis and rheumatism", "id" : "ITEM-4", "issue" : "12", "issued" : { "date-parts" : [ [ "2010", "12" ] ] }, "page" : "3716-21", "title" : "Tract-based spatial statistics on diffusion tensor imaging in systemic lupus erythematosus reveals localized involvement of white matter tracts.", "type" : "article-journal", "volume" : "62" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "^9\u201312", "plainTextFormattedCitation" : "9\u201312", "previouslyFormattedCitation" : "^9\u201312" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }9–12 did not provide data to permit inclusion in the forest plots and are summarised with the other studies in Table 4 only.In general, among most tracts, MD was significantly increased (standardised mean difference (SMD) 1.07 (95% CI, 0.62 to 1.52)) and FA non-significantly reduced (SMD –0.16 (–0.48 to 0.17)) in SLE patients versus healthy controls (Supplementary Figures 1 and 2). A similar pattern was seen in NPSLE versus healthy controls. Data comparing SLE to NPSLE were limited: only one studyADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Jung", "given" : "Rex E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Caprihan", "given" : "Arvind", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chavez", "given" : "Robert S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Flores", "given" : "Ranee A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sharrar", "given" : "Janeen", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Qualls", "given" : "Clifford R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sibbitt", "given" : "Wilmer", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Roldan", "given" : "Carlos A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "BMC neurology", "id" : "ITEM-1", "issue" : "65", "issued" : { "date-parts" : [ [ "2010" ] ] }, "title" : "Diffusion tensor imaging in neuropsychiatric systemic lupus erythematosus", "type" : "article-journal", "volume" : "10" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "¹¹", "plainTextFormattedCitation" : "11", "previouslyFormattedCitation" : "¹¹" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }11 provided data on MD, and whereas three studiesADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Jung", "given" : "Rex E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Caprihan", "given" : "Arvind", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chavez", "given" : "Robert S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Flores", "given" : "Ranee A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sharrar", "given" : "Janeen", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Qualls", "given" : "Clifford R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sibbitt", "given" : "Wilmer", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Roldan", "given" : "Carlos A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "BMC neurology", "id" : "ITEM-1", "issue" : "65", "issued" : { "date-parts" : [ [ "2010" ] ] }, "title" : "Diffusion tensor imaging in neuropsychiatric systemic lupus erythematosus", "type" : "article-journal", "volume" : "10" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Zimny", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Szewczyk", "given" : "P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bladowska", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gruszka", "given" : "E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Lupus", "id" : "ITEM-2", "issued" : { "date-parts" : [ [ "2014" ] ] }, "page" : "10-19", "title" : "In vivo evaluation of brain damage in the course of systemic lupus erythematosus using magnetic resonance spectroscopy , perfusion-weighted and diffusion-tensor imaging", "type" : "article-journal", "volume" : "23" }, "uris" : [ "" ] }, { "id" : "ITEM-3", "itemData" : { "DOI" : "10.1016/j.nicl.2014.07.001", "ISSN" : "2213-1582", "PMID" : "25161895", "abstract" : "PURPOSE: Systemic lupus erythematosus (SLE) is an autoimmune connective tissue disease that can affect the central nervous system. Neuropsychiatric symptoms are found in 25-70% of patients. Using diffusion tensor imaging (DTI) various studies have reported changes in white matter integrity in SLE patients with neuropsychiatric symptoms (NPSLE patients). The purpose of this study was to investigate, if regional changes in white matter integrity can also be detected in SLE patients without neuropsychiatric symptoms (non-NPSLE patients).\n\nMETHODS: Applying DTI and tract based spatial statistics (TBSS) we investigated 19 NPSLE patients, 19 non-NPSLE and 18 healthy controls. Groups were matched for age and sex. Image pre-processing was performed using FSL, following the TBSS pipeline (eddy current correction, estimation of fractional anisotropy (FA), normalization, skeletonization of the group mean FA image). A general linear model with threshold-free cluster enhancement was used to assess significant differences between the three groups.\n\nRESULTS: Statistical analyses revealed several regions of decreased prefrontal white matter integrity (decreased FA) in both groups of SLE patients. The changes found in the non-NPSLE patients (as compared to healthy controls) overlapped with those in the NPSLE patients, but were not as pronounced.\n\nCONCLUSIONS: Our data suggest that changes in regional white matter integrity, in terms of a decrease in FA, are present not only in NPSLE patients, but also in non-NPSLE patients, though to a lesser degree. We also demonstrate that the way statistical maps are corrected for multiple comparisons has a profound influence on whether alterations in white matter integrity in non-NPSLE patients are deemed significant.", "author" : [ { "dropping-particle" : "", "family" : "Schmidt-Wilcke", "given" : "Tobias", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cagnoli", "given" : "Patricia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wang", "given" : "Page", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schultz", "given" : "Thomas", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lotz", "given" : "Anne", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mccune", "given" : "William J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sundgren", "given" : "Pia C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "NeuroImage. Clinical", "id" : "ITEM-3", "issued" : { "date-parts" : [ [ "2014", "1" ] ] }, "page" : "291-7", "publisher" : "Elsevier B.V.", "title" : "Diminished white matter integrity in patients with systemic lupus erythematosus.", "type" : "article-journal", "volume" : "5" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "^8,9,11", "plainTextFormattedCitation" : "8,9,11", "previouslyFormattedCitation" : "^8,9,11" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }8,9,11 reported on FA, there were no data suitable for pooling although the general observation was little difference in water diffusion measures between SLE and NPSLE (Table 4). DISCUSSIONThe main findings in the present study, the largest to date on DT-MRI in SLE adding ~25% more to the total available data and the only one to use quantitative tractography, were that: (i) MD was higher in eight major white matter tracts in SLE versus healthy controls but the MD levels did not account for either fatigue or cognitive function in adjusted analyses; (ii) fatigue in patients was higher than a normal reference range and (iii) patients with SLE had poorer current cognitive function which was independently associated with higher levels of the pro-inflammatory biomarker IL-6.The direction of the regression slopes relating MD (rising) and FA (declining) with age were as expected but steeper in SLE patients versus controls, indicating accelerated decline in white matter microstructure with age. However, when we tested the slopes using an interaction term in a linear regression model there was no significant difference between patients and controls and a larger sample will be needed to confirm a modest difference in accelerated ageing. Nonetheless, significantly higher MD levels were found in all white matter tracts in patients versus controls which is in accordance with prior literature. This indicates a diffuse increase in brain water mobility in SLE, possibly indicating a subtle decline in white matter microstructural integrity. We recently demonstrated increased stroke risk in SLE versus the general population with greatest risk in those <50 yearsADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1161/STROKEAHA.115.012052", "author" : [ { "dropping-particle" : "", "family" : "Wiseman", "given" : "Stewart J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ralston", "given" : "Stuart H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wardlaw", "given" : "Joanna M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Stroke", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2016" ] ] }, "page" : "1-9", "title" : "Cerebrovascular disease in rheumatic diseases: A systematic review and meta-analysis", "type" : "article-journal", "volume" : "47" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "²", "plainTextFormattedCitation" : "2", "previouslyFormattedCitation" : "²" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }2; again possibly indicative of accelerated ageing.In SLE, higher fatigue was associated with lower MD, although this likely reflects higher fatigue scores being more common in younger participants. A much larger study will be required to determine if fatigue in SLE is associated with reduced MD levels for a given age. Higher fatigue was also associated with lower IFN, lower vWF (fVIIIc and RCOF) and approached significance with higher CRP. Higher levels of fatigue were associated with higher BMI in the current study, and has been established previously.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1097/RHU.0b013e3180645865", "ISBN" : "1076-1608", "ISSN" : "1076-1608", "abstract" : "Objective: The aim of this study was to examine the impact of an increased body mass index (BMI) on disease activity, damage accrual, fatigue, self-reported health-related quality of life (HRQOL), and fibromyalgia in patients with lupus using longitudinal data from LUMINA, a large multiethnic cohort., Methods: SLE patients (>=4 ACR revised criteria), <=5 years disease duration at entry into the cohort (T0), of Hispanic (from Texas or from the Island of Puerto Rico), African American, or white ethnicity were included. BMI was ascertained at T0 or first recorded. The average scores from all visits for disease activity (SLAM-R), self-reported HRQOL (physical and mental component summary measures of the SF-36) and fatigue (Fatigue Severity Scale), the score at last visit for damage accrual (SLICC Damage Index), and fibromyalgia (ACR criteria), if present at any visit, were examined for their association with an increased BMI by univariable and multivariable analyses., Results: Three-hundred sixty-four patients were included; 28% were obese (BMI >=30 kg/m2). An increased BMI was associated with older age, less social support, higher degree of helplessness, depression, more abnormal illness-related behaviors, poorer self-reported HRQOL, fatigue, and fibromyalgia, but not with disease activity or damage accrual by univariable analyses. In multivariable analyses, BMI was independently associated with fibromyalgia but not with disease activity, fatigue, or self-reported HRQOL., Conclusions: An increased BMI is independently associated with presence of fibromyalgia but not with disease activity, damage accrual, fatigue or self-reported quality of life in patients with SLE. Optimizing weight merits investigation to see if it can significantly impact this pervasive SLE-associated manifestation., (C) 2007 Lippincott Williams & Wilkins, Inc.", "author" : [ { "dropping-particle" : "", "family" : "Chaiamnuay", "given" : "Sumapa", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bertoli", "given" : "Ana", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Fernandez", "given" : "Monica", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Apte", "given" : "Mandar", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Vila", "given" : "Luis", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Reveille", "given" : "John", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Alarcon", "given" : "Graciela", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "MD", "given" : "M P H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "J. clin. rheumatol.", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2007" ] ] }, "page" : "128-133", "title" : "The impact of increased Body Mass Index on Systemic Lupus Erythematosus: Data from LUMINA, a multiethnic cohort.", "type" : "article-journal", "volume" : "13" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "³²", "plainTextFormattedCitation" : "32", "previouslyFormattedCitation" : "³²" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }32 Higher levels of fatigue were also associated with lower levels of endothelial dysfunction (vWF). The plasma marker that had the highest association with fatigue was IFN, independent of age, although the direction was unexpected. Fatigue is a common side effect of IFN therapy; meanwhile, prior studies of endogenous IFN in SLE did not show associations with fatigue.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.jneuroim.2010.03.018", "ISBN" : "0165-5728", "ISSN" : "01655728", "PMID" : "20416954", "abstract" : "Patients with systemic lupus erythematosus (SLE) often suffer from depression and fatigue in addition to the physical manifestations of the autoimmune disease. Elevated production of type-I interferons (IFN-I) has been found in lupus patients and IFN-I can precipitate a variety of neuropsychiatric side effects. This study was conducted to evaluate the relationship between dysregulated IFN-I production and the presence of depression or fatigue in lupus patients. Through cross-sectional and longitudinal analysis we found no significant correlation between abnormal IFN-I levels (as measured by peripheral blood expression of IFN-I-stimulated genes) and neuropsychiatric manifestations. Elevation of endogenous serum IFN-I levels is unlikely to account for the depression and fatigue associated with SLE. ?? 2010.", "author" : [ { "dropping-particle" : "", "family" : "Kellner", "given" : "Erinn S.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lee", "given" : "Pui Y.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Li", "given" : "Yi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Switanek", "given" : "Juliana", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zhuang", "given" : "Haoyang", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Segal", "given" : "Mark S.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sobel", "given" : "Eric S.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Satoh", "given" : "Minoru", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Reeves", "given" : "Westley H.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of Neuroimmunology", "id" : "ITEM-1", "issue" : "1-2", "issued" : { "date-parts" : [ [ "2010" ] ] }, "page" : "13-19", "publisher" : "Elsevier B.V.", "title" : "Endogenous type-I interferon activity is not associated with depression or fatigue in systemic lupus erythematosus", "type" : "article-journal", "volume" : "223" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Omdal", "given" : "R.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mellgren", "given" : "SI.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Koldingsness", "given" : "W.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jacobsen", "given" : "EA.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Husby", "given" : "G.", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "J Rheumatol", "id" : "ITEM-2", "issue" : "3", "issued" : { "date-parts" : [ [ "202" ] ] }, "page" : "482-6", "title" : "Fatigue in patients with systemic lupus erythematosus: lack of associations to serum cytokines, antiphospholipid antibodies, or other disease characteristics.", "type" : "article-journal", "volume" : "29" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "^33,34", "plainTextFormattedCitation" : "33,34", "previouslyFormattedCitation" : "^33,34" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }33,34Lower levels of current cognitive function were associated with longer SLE disease duration and higher MD and between 10% and 38% of patients had cognitive test scores indicating clinical levels of cognitive impairment. Our finding that lower levels of cognitive function were associated with higher MD is in agreement with Bosma et al. ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1002/art.10574", "ISSN" : "0004-3591", "PMID" : "12384925", "abstract" : "OBJECTIVE: To investigate the relationship between quantitative estimates of global brain damage based on magnetization transfer imaging (MTI) and cerebral functioning, as measured by neurologic, psychiatric, and cognitive assessments, as well as disease duration in patients with a history of neuropsychiatric systemic lupus erythematosus (NPSLE).\n\nMETHODS: In a clinically heterogeneous group of 24 female patients (age range 19-65 years, mean age 35 years) with a history of NPSLE, the correlation values of several volumetric MTI measures and an estimate of cerebral atrophy, neurologic functioning (Kurtzke's Expanded Disability Status Scale [EDSS]), psychiatric functioning (the Hospital Anxiety and Depression Scale [HADS]), and cognitive functioning (cognitive impairment score [CIS] derived from the revised Wechsler Adult Intelligence Scale), as well as several measures of disease duration were assessed using Pearson's correlation coefficient.\n\nRESULTS: Quantitative volumetric estimates of global brain damage based on MTI and a measure of global brain atrophy correlated significantly with the EDSS, HADS, and CIS scores. No significant correlation was found between the quantitative estimates of global brain damage and the measures of disease duration.\n\nCONCLUSION: The results of this study demonstrate that volumetric MTI parameters and cerebral atrophy reflect functionally relevant brain damage in patients with NPSLE. Furthermore, the absence of a linear relationship between disease duration and results of volumetric MTI measures and atrophy suggests a complicated pattern of accumulating brain damage in patients with NPSLE.", "author" : [ { "dropping-particle" : "", "family" : "Bosma", "given" : "G P Th", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Middelkoop", "given" : "H a M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rood", "given" : "M J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bollen", "given" : "E L E M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Huizinga", "given" : "T W J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Buchem", "given" : "M a", "non-dropping-particle" : "van", "parse-names" : false, "suffix" : "" } ], "container-title" : "Arthritis and rheumatism", "id" : "ITEM-1", "issue" : "10", "issued" : { "date-parts" : [ [ "2002", "10" ] ] }, "page" : "2665-72", "title" : "Association of global brain damage and clinical functioning in neuropsychiatric systemic lupus erythematosus.", "type" : "article-journal", "volume" : "46" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "³⁵", "plainTextFormattedCitation" : "35", "previouslyFormattedCitation" : "³⁵" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }35 who examined 24 patients diagnosed with NPSLE. Bosma and colleagues also correlated lower levels of neurological functioning (essentially motor skills) with higher levels of magnetization transfer MRI parameters.Poorer current cognitive function was also associated with higher levels of the pro-inflammatory cytokine IL-6, independent of age and prior cognitive abilities. The PROSPERADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1111/joim.12052", "ISSN" : "1365-2796", "PMID" : "23414490", "abstract" : "BACKGROUND: Inflammation is involved in the pathogenesis of cardiovascular disease and cognitive decline. Interleukin-6 (IL-6) has a role in cardiovascular disease, but the association of IL-6 concentration and the functional IL-6 -174 polymorphism with cognitive decline has not been demonstrated unequivocally. The objective of this study was to investigate the associations between both high concentration of IL-6 and the -174 promoter polymorphism, and increased cognitive decline in old age.\n\nMETHODS: Over 5000 participants of the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) with a mean age of 75 years and a history of cardiovascular disease or its risk factors were included in this study. We determined baseline concentrations of IL-6 and genotype of the IL-6 -174 polymorphism, of which the C allele was previously shown to be associated with higher circulating concentrations of IL-6. A cognitive test battery was administered at baseline and repeatedly during follow-up (mean 39 months).\n\nRESULTS: In the cross-sectional analysis of 5653 participants, higher IL-6 concentration was associated with worse executive cognitive function (P < 0.001), independent of cardiovascular disease status and risk factors. No association was found between IL-6 concentration and memory function (P > 0.14). In the prospective analysis, higher IL-6 concentration was associated with an increased rate of cognitive decline in both executive function (P = 0.002) and memory function (P = 0.002), again independent of cardiovascular disease status and risk factors. Although not associated with IL-6 concentrations, the IL-6 -174 CC genotype was associated with worse performance on the Stroop test (P = 0.045).\n\nCONCLUSIONS: Higher circulating levels of IL-6 were associated with worse cognitive function and steeper cognitive decline and provide preliminary genetic evidence for a potential causal association. The findings support the importance of the need for further investigation of the IL-6 pathway in cognitive decline.", "author" : [ { "dropping-particle" : "", "family" : "Mooijaart", "given" : "S P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sattar", "given" : "N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Trompet", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lucke", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Stott", "given" : "D J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ford", "given" : "I", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jukema", "given" : "J W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Westendorp", "given" : "R G J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Craen", "given" : "a J M", "non-dropping-particle" : "de", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of internal medicine", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2013", "7" ] ] }, "page" : "77-85", "title" : "Circulating interleukin-6 concentration and cognitive decline in old age: the PROSPER study.", "type" : "article-journal", "volume" : "274" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "³⁶", "plainTextFormattedCitation" : "36", "previouslyFormattedCitation" : "³⁶" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }36 study (randomised controlled trial; n=5,653) associated higher IL-6 with worse executive function (p<0.001), independent of age. At follow-up (mean 39 months), higher IL-6 was independently associated with an increased rate of cognitive decline in both executive function (p=0.002) and memory (p=0.002).ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1111/joim.12052", "ISSN" : "1365-2796", "PMID" : "23414490", "abstract" : "BACKGROUND: Inflammation is involved in the pathogenesis of cardiovascular disease and cognitive decline. Interleukin-6 (IL-6) has a role in cardiovascular disease, but the association of IL-6 concentration and the functional IL-6 -174 polymorphism with cognitive decline has not been demonstrated unequivocally. The objective of this study was to investigate the associations between both high concentration of IL-6 and the -174 promoter polymorphism, and increased cognitive decline in old age.\n\nMETHODS: Over 5000 participants of the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) with a mean age of 75 years and a history of cardiovascular disease or its risk factors were included in this study. We determined baseline concentrations of IL-6 and genotype of the IL-6 -174 polymorphism, of which the C allele was previously shown to be associated with higher circulating concentrations of IL-6. A cognitive test battery was administered at baseline and repeatedly during follow-up (mean 39 months).\n\nRESULTS: In the cross-sectional analysis of 5653 participants, higher IL-6 concentration was associated with worse executive cognitive function (P < 0.001), independent of cardiovascular disease status and risk factors. No association was found between IL-6 concentration and memory function (P > 0.14). In the prospective analysis, higher IL-6 concentration was associated with an increased rate of cognitive decline in both executive function (P = 0.002) and memory function (P = 0.002), again independent of cardiovascular disease status and risk factors. Although not associated with IL-6 concentrations, the IL-6 -174 CC genotype was associated with worse performance on the Stroop test (P = 0.045).\n\nCONCLUSIONS: Higher circulating levels of IL-6 were associated with worse cognitive function and steeper cognitive decline and provide preliminary genetic evidence for a potential causal association. The findings support the importance of the need for further investigation of the IL-6 pathway in cognitive decline.", "author" : [ { "dropping-particle" : "", "family" : "Mooijaart", "given" : "S P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sattar", "given" : "N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Trompet", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lucke", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Stott", "given" : "D J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ford", "given" : "I", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jukema", "given" : "J W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Westendorp", "given" : "R G J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Craen", "given" : "a J M", "non-dropping-particle" : "de", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of internal medicine", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2013", "7" ] ] }, "page" : "77-85", "title" : "Circulating interleukin-6 concentration and cognitive decline in old age: the PROSPER study.", "type" : "article-journal", "volume" : "274" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "³⁶", "plainTextFormattedCitation" : "36", "previouslyFormattedCitation" : "³⁶" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }36 The mean age of participants in the PROSPER study was 75 years, considerably older than the mean age of participants in the current study, yet the similarity in findings could indicate that SLE patients are experiencing aged-related effects on the brain at younger ages. The PROSPER study corrected for educational level but not premorbid intelligence using NART.In contrast to the findings of Nishimura et al. (n=43 steroid-na?ve SLE patients)ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "K", "given" : "Nishimura", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "M", "given" : "Omori", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Y", "given" : "Katsumata", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "E", "given" : "Sato", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "T", "given" : "Gono", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Y", "given" : "Kawaguchi", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "M", "given" : "Harigai", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "M", "given" : "Mimura", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "H", "given" : "Yamanaka", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "J", "given" : "Ishigooka", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "J Rheumatol", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2015" ] ] }, "page" : "441-448", "title" : "Neurocognitive impairment in corticosteroid-naive patients with active systemic lupus erythematosus: a prospective study.", "type" : "article-journal", "volume" : "42" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "³⁷", "plainTextFormattedCitation" : "37", "previouslyFormattedCitation" : "³⁷" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }37 we did not find an association between current cognitive impairment and SLE activity (in univariate analysis or after correcting for steroid use), possibly due to different measures of psychological assessment used between studies. Other variables associated with cognitive function on univariate analysis became nonsignificant when NART was added to the regression models. Current cognitive impairment is thus mostly explained by premorbid IQ, although inflammation also plays a role. Strengths of the present study include use of a continuum of fatigue and cognitive scores rather than dichotomised data, the 32 diffusion-encoding gradient directions in the DT-MRI exam which increases the precision of the imaging data, a large sample size relative to existing DT-MRI studies (although we note our sample is still small, limiting study power) in SLE and use of quantitative tractography rather than ‘region of interest’ or ‘voxel-based’ methods. PNT has the advantage that it segments tracts automatically in native space, avoiding brain distortion by use of registration to standard space and thereby providing objective measures of tract microstructure that can be correlated with phenotypic data. Additionally, our study did not solely focus on patients that were neurologically symptomatic or diagnosed with NPSLE but instead included a range of SLE patients making our findings relevant to the wider SLE patient population. In the multiple linear regression models we corrected for age, disease duration, and where current cognitive function was the outcome, NART, to adjust for an inferred prior (peak) IQ, but had limited power to adjust for other variables.The study also had weaknesses. Although being larger than all prior studies and adding 25% more data to the available literature, the sample size limited statistical testing and, although we report all results for transparency, we urge caution in the interpretation and confirmation in larger studies. We did not assess reaction times, information processing speeds or motor skills and so are unable to comment on these aspects of neurological function. Although subjects were asked to consider their fatigue over the prior week, they were seen at different times of the day and this could have impacted the self-reported fatigue scores via diurnal variation. The main observation from the literature review and meta-analysis (increased MD and decreased FA in SLE versus controls) was in agreement with findings in this study. Studies of other inflammatory autoimmune diseases show a similar pattern of findings, for example, in Sj?gren Syndrome (n=19; method = TBSS) there was increased MD and decreased FA in several tracts compared to controls.ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Tzarouchi", "given" : "L C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Zikou", "given" : "A K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tsifetaki", "given" : "N", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Astrakas", "given" : "L G", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Konitsiotis", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Voulgari", "given" : "P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Drosos", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Argyropoulou", "given" : "M I", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "AJNR Am J Neuroradiol", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2014" ] ] }, "page" : "680-5", "title" : "White matter water diffusion changes in Primary Sjogren Syndrome", "type" : "article-journal", "volume" : "35" }, "uris" : [ "" ] } ], "mendeley" : { "formattedCitation" : "³⁸", "plainTextFormattedCitation" : "38", "previouslyFormattedCitation" : "³⁸" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }38ConclusionPatients with SLE have more microstructural brain white matter damage for age than the general population, but this does not explain increased fatigue or lower cognition in SLE. Worse current cognitive function in SLE is related to lower prior cognitive ability although inflammation also plays a detrimental role and the association with raised IL-6 should be explored in larger datasets.Acknowledgements:We acknowledge support from the Scottish Lupus Exchange registry. We thank Dr Francesca Chappell for expert statistical advice, Gayle Barclay for helping to develop the scan protocol and Gayle Barclay, Charlotte Jardine, Iona Hamilton and Elaine Sandeman (all Brain Research Imaging Centre, University of Edinburgh, UK) for administering some of the cognitive tests. We acknowledge Gillian Rice (University of Manchester) and Yanick Crow (Institut Imagine, Paris, France) for the interferon analysis.Conflicts of Interest / Disclosures:NoneFunding:This study was funded by Lupus UK. Stewart Wiseman is supported by a Principal’s Career Development PhD Scholarship from the University of Edinburgh. References1Holmqvist M, Simard JF, Asplund K, Arkema EV. Stroke in systemic lupus erythematosus: a meta-analysis of population-based cohort studies. RMD Open 2015; 1: e000168.2.Wiseman SJ, Ralston SH, Wardlaw JM. Cerebrovascular disease in rheumatic diseases: A systematic review and meta-analysis. Stroke 2016; 47: 0–0.3.Carlomagno S, Migliaresi S., Ambrosone L, Sannino M, Sanges G, Di Lorio G. Cognitive impairment in systemic lupus erythematosus: a follow-up study. J Neurol 2000; 247: 273-279.4.Hewlett S, Nicklin J, Treharne G. Fatigue in musculoskeletal conditions. J Rheumatol Suppl. 2003; 67(Series 6): 42-44. 5. Harboe E, Greve OJ, Beyer M, et al. Fatigue is associated with cerebral white matter hyperintensities in patients with systemic lupus erythematosus. J Neurol Neurosurg Psychiatry 2008; 79: 199-201.6. Wardlaw JM, Smith C, Dichgans M. Mechanisms of sporadic cerebral small vessel disease: insights from neuroimaging. Lancet Neurol 2013; 12: 483-497. 7. Penke L, Maniega SM, Bastin ME, et al. Brain white matter tract integrity as a neural foundation for general intelligence. Mol Psychiatry 2012; 17: 1026-1030.8. Zimny A, Szewczyk P, Bladowska J, et al. In vivo evaluation of brain damage in the course of systemic lupus erythematosus using magnetic resonance spectroscopy, perfusion-weighted and diffusion-tensor imaging. Lupus 2014; 23: 10-19.9. Schmidt-Wilcke T, Cagnoli P, Wang P, et al. Diminished white matter integrity in patients with systemic lupus erythematosus. NeuroImage Clin 2014; 5: 291-297.10. Zivadinov R, Shucard JL, Hussein S, et al. Multimodal imaging in systemic lupus erythematosus patients with diffuse neuropsychiatric involvement. Lupus 2013; 22: 675-683.11. Jung RE, Caprihan A, Chavez RS, et al. Diffusion tensor imaging in neuropsychiatric systemic lupus erythematosus. BMC Neurol 2010; 10: 65.12. Emmer BJ, Veer IM, Steup-Beekman GM, Huizinga TWJ, van der Grond J, van Buchem MA. Tract-based spatial statistics on diffusion tensor imaging in systemic lupus erythematosus reveals localized involvement of white matter tracts. Arthritis Rheum 2010; 62: 3716-3721.13. Welsh RC, Rahbar H, Foerster B, Thurnher M, Sundgren PC. Brain diffusivity in patients with neuropsychiatric systemic lupus erythematosus with new acute neurological symptoms. J Magn Reson Imaging 2007; 26: 541-551. 14. Hughes M, Sundgren PC, Fan X, et al. Diffusion tensor imaging in patients with acute onset of neuropsychiatric systemic lupus erythematosus: a prospective study of apparent diffusion coefficient, fractional anisotropy values, and eigenvalues in different regions of the brain. Acta Radiol 2007; 48: 213-222.15. Zhang L, Harrison M, Heier LA, et al. Diffusion changes in patients with systemic lupus erythematosus. Magn Reson Imaging 2007; 25: 399-405.16. Bosma GPT, Huizinga TWJ, Mooijaart SP, van Buchem MA. Abnormal brain diffusivity in patients with neuropsychiatric systemic lupus erythematosus. AJNR Am J Neuroradiol 2003; 24: 850-854.17. Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1997; 40: 1725.18. Krupp LB, LaRocca NG, Muir-Nash J, Steinberg AD. The fatigue severity scale. Application to patients with multiple sclerosis and systemic lupus erythematosus. Arch Neurol 1989; 46: 1121-1123. 19. Zigmond A, Snaith R. The hospital anxiety and depression scale. Acta Psychiatr Scand 1983; 67: 361-370.20. Narseddine Z, Phillips N, Bedirian V, et al. The Montreal Cognitive Assessment, MoCA?: A brief screening tool for mild cognitive impairment. J Am Geriatr Soc 2005; 53: 695-699.21. Hsieh S, Schubert S, Hoon C, Mioshi E, Hodges JR. Validation of the Addenbrooke’s Cognitive Examination III in frontotemporal dementia and Alzheimer's disease. Dement Geriatr Cogn Disord 2013; 36: 242-250. 22. Folstein M, Folstein S, McHugh P. Mini-mental state. A practical method for grading the cognitive state of patients for the clinician. J Psychiat Res 1975; 12: 189-198.23. Nelson H, Willison J. National Adult Reading Test (NART):Test Manual. NFER_Nelson Publ. 1982.24. McGurn B, Starr JM, Topfer JA, et al. Pronunciation of irregular words is preserved in dementia, validating premorbid IQ estimation. Neurology 2004; 62: 1184-1187.25. Gladman D, Ibanez D, Urowitz M. Systemc lupus erythematosus disease activity index 2000. J Rheumatol 2002; 29: 288–291.26. Isenberg DA, Rahman A, Allen E, et al. BILAG 2004. Development and initial validation of an updated version of the British Isles Lupus Assessment Group’s disease activity index for patients with systemic lupus erythematosus. Rheumatology 2005; 44: 902-906. 27. Gladman D, Ginzler E, Goldsmith C, et al. The development and initial validation of the systemic lupus international collaborating clinics / America College of Rheumatology Damage Index for systemic lupus erythematosus. Arthritis Rheum 1996; 39: 363-369.28. Gladman D, Goldsmith C, Urowitz M, et al. The Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) Damage Index for Systemic Lupus Erythematosus International Comparison. J Rheumatol 2000; 27: 373-376.29.Jensen A. The g Factor: The science of mental ability. London: Praeger; 1998.30. Perneger TV. What’s wrong with Bonferroni adjustments. BMJ 1998; 316: 1236.31. R Core Team. R: A language and environment for statistical computing. 2013:R Foundation for Statistical Computing, Vienna, Au.32. Chaiamnuay S, Bertoli A, Fernandez M, et al. The impact of increased body mass index on systemic lupus erythematosus: Data from LUMINA, a multiethnic cohort. J Clin Rheumatol 2007; 13: 128-133. 33. Kellner ES, Lee PY, Li Y, et al. Endogenous type-I interferon activity is not associated with depression or fatigue in systemic lupus erythematosus. J Neuroimmunol 2010; 223: 13-19.34. Omdal R, Mellgren S, Koldingsness W, Jacobsen EA, Husby G. Fatigue in patients with systemic lupus erythematosus: lack of associations to serum cytokines, antiphospholipid antibodies, or other disease characteristics. J Rheumatol 2002; 29: 482-486.35. Bosma GPT, Middelkoop HAM, Rood MJ, Bollen ELEM, Huizinga TWJ, van Buchem MA. Association of global brain damage and clinical functioning in neuropsychiatric systemic lupus erythematosus. Arthritis Rheum 2002; 46: 2665-2672. 36. Mooijaart SP, Sattar N, Trompet S, et al. Circulating interleukin-6 concentration and cognitive decline in old age: the PROSPER study. J Intern Med 2013; 274: 77-85.37. Nishimura K, Omori M, Katsumata Y, et al. Neurocognitive impairment in corticosteroid-naive patients with active systemic lupus erythematosus: a prospective study. J Rhematol 2015; 42: 441-448.38. Tzarouchi LC, Zikou AK, Tsifetaki N, et al. White matter water diffusion changes in Primary Sjogren Syndrome. AJNR Am J Neuroradiol 2014; 35: 680-685.Table 1 Subject charactersiticsN (%) or mean ± SD or median (Q1–Q3)Reference data from controls or standard rangesSLE patients, n = 51Female47 (92%)39 (76%); p=0.06Age (years)48.8 ± 14.344.9 ± 11.1; p=0.12Disease duration (months)50 (24.5–148)Members of SLEx registry31 (61%)NPSLE4 (8%)BMI (kg / m2)29 (6.5)20-25 normal, 25-30 overweight, 30-35 obese, 35+ clinically obeseCurrent smoker6 (12%)Hypertension9 (18%)≥140/90 mm HgFatigue (score)5.0 ± 1.72.3 ± 0.7; p<0.0001Anxiety (score)6 (3–12 )0-7 non-case, 8-10 borderline, 11+ caseDepression (score)8 (6–12)As anxietyCurrent steroids18 (35%)MoCA (score) (n=50)26 (24–28) 0–30. Normal ≥26 ACER (score) (n=50)91 (87–94)0–100. Normal ≥88MMSE (score) (n=50)28 (27–30)0–30. Normal ≥27NART (score) (n=50)34 (27–39)40 (34–42); p=0.0008ACER = Addenbrooke’s Cognitive Examination – Revised, BMI = body mass index, MoCA = Montreal Cognitive Assessment, MMSE = Mini Mental State Examination, NART = National Adult Reading TestTable 2 Comparison of MD and FA values for white matter tracts between SLE patients and healthy controlsSLE (n=47)Controls (n=47)p valueCohen’s dFemale n (%)43 (91.5%)41 (87.2%)p=0.74 NAAge (years)48.5 ± 13.744.6 ± 11.5p=0.14 NAMD (10-6 mm2 /s)Genu833.18 ± 68.13751.29 ± 57.36p<0.0001 1.33Splenium1072.33 ± 162.98761.49 ± 129.37p<0.0001 2.19Left cingulum740.69 ± 44.08624.21 ± 35.41p<0.0001 3.01Right cingulum721.06 ± 43.33619.70 ± 35.74p<0.0001 2.62Left CST729.25 ± 30.76667.24 ± 39.4p<0.0001 1.82Right CST740.96 ± 30.18683.32 ± 35.31p<0.0001 1.79Left ILF781.68 ± 49.53728.42 ± 66.48p<0.0001 0.96Right ILF818.16 ± 136.72703.82 ± 63.03p<0.0001 1.29Average804.6 ± 39.8692.4 ± 32.2p<0.0001 3.20FA (unitless, values lie in the range 0 to 1)Genu0.49 ± 0.060.42 ± 0.04p<0.0001 1.42Splenium0.52 ± 0.070.55 ± 0.06p=0.008-0.57Left cingulum0.44 ± 0.050.46 ± 0.04p=0.04-0.45Right cingulum0.42 ± 0.040.44 ± 0.03p=0.01-0.57Left CST0.49 ± 0.040.44 ± 0.04p<0.0001 1.26Right CST0.47 ± 0.040.48 ± 0.04p=0.24-0.25Left ILF0.45 ± 0.050.43 ± 0.04p=0.08 0.36Right ILF0.42 ± 0.050.43 ± 0.04p=0.59-0.11Average0.46 ± 0.020.46 ± 0.02p=0.250.24CST = corticospinal tract, FA = fractional anisotropy, ILF = inferior longitudinal fasciculus, MD = mean diffusivity. Table 3 Multiple linear regression models of fatigue and cognitive function in SLE patientsUnadjustedAge adjustedFully adjustedaBSE Bp valueBSE Bp valueBSE Bp valueFatigueBMI (kg / m2)0.0930.0340.010.1060.0330.0030.1020.0330.004Anxiety0.1320.0410.0030.1190.0440.010.1270.0440.006Depression0.1750.0460.00040.1620.0480.0010.1700.0470.001MD (10-6 mm2 /s)-0.5800.2340.02-0.5560.2490.03-0.6100.2530.02IFN (RQ value)-0.0900.0300.006-0.0910.0290.005-0.0800.0400.06vWF (fVIIIc) (IU / mL)-1.1680.5500.04-1.1210.5390.04-1.1110.5330.04vWF (RCOF) (IU / mL)-1.4260.5990.02-1.2120.6230.06-1.1540.6160.07Cognitive functionDisease duration (months)-0.0030.0010.003-0.0030.0010.005-0.0010.0000.07MD (10-6 mm2 /s)-0.2710.1260.04-0.2640.1350.06-0.0120.1080.91vWF (Ag) (IU / mL)-0.8000.2040.0003-0.7940.2150.0006-0.2860.2080.18vWF (RCOF) (IU / mL)-0.8890.3580.02-0.8480.3800.03-0.2960.3170.36IL-6 (pg / mL)-0.2340.0800.006-0.2410.0800.005-0.1510.0630.02a Fatigue adjusted for age, disease duration and seroids; Cognitive function adusted for age, disease duration, steroids and NART. B = beta coefficient, IL-6 = interleukin-6, MD = mean difussivity, NART = national adult reading test, SE B = standard error for beta coefficient, vWF Ag = von Willebrand Factor antigen, vWF fVIIIc = von Willebrand Factor VIII, vWF RCOF = von Willebrand Factor ristocen co-factorTable 4 Diffusion imaging studies in SLE and NPSLEStudySequence, gradient directionsFieldTechniquen (mean age in years)ComparisonMeasurementRegionFindingsSLE versus healthy controlsZhang, 2007DTI, 261.5TMTR and ADC histogram, and ROI34 (47)SLE v HCFA and MDWhole brain andVarious regions MD in brain in SLE FA in SLE in most regions MD in SLE in most regionsEmmer, 2010DTI, 63TTBSS12 (42)SLE v HCFAVarious tracts FA in SLE in most tractsJung, 2010DTI, 121.5TTBSS16 (37)SLE v HCFA and MDVarious tractsNo difference in FANo difference in MDSchmidt-Wilcke, 2014DTI, 153TTBSS & TFCE19 (38)SLE v HCFAVoxels and clusters across WM FA in SLE in prefrontal WM Zimny, 2014DTI, 251.5TROI13 (34)SLE v HCFA14 WM tracts FA in SLE in most tracts (see FP)Wiseman, 2015DTI, 321.5TQuantitative tractography47 (48)SLE v HCFA and MD8 WM tracts FA in SLE in most tracts (see FP) MD in SLE in all tracts (see FP)NPSLE versus healthy controlsBosma, 2003DWI, 31.5TADC histogram11 (35)NPSLE v HCmean ADCWhole brain mean ADC in brain in NPSLEWelsh, 2007DWI, 31.5TADC histogram17 (43)NPSLE v HCmean ADCWhole brain and segmented tissues mean ADC in brain in NPSLE mean ADC in GM & WM in NPSLEHughes, 2007DTI, 91.5TROI8 (43)NPSLE v HCFA and MDVarious regions FA in NPSLE in various regions MD in NPSLE in various regionsJung, 2010DTI, 121.5TTBSS17 (39)NPSLE v HCFA and MDVarious tracts FA in NPSLE in some tracts MD in NPSLE in most tractsZivadinov, 2013DTI, 393TVoxel based with tissue segmentation26 (48)NPSLE v HCMDNAWM MD in NAWM in NPSLESchmidt-Wilcke, 2014DTI, 153TTBSS19 (39)NPSLE v HCFAVoxels and clusters across WM FA in SLE in prefrontal WMZimny, 2014DTI, 251.5TROI in WM tracts22 (35)NPSLE v HCFA14 WM tracts FA in NPSLE in most tracts (see FP)SLE versus NPSLEJung, 2010DTI, 121.5TTBSS16 (37)SLE v NPSLEFA and MDVarious tracts FA in SLE in 2 tracts MD in SLE in 3 tractsSchmidt-Wilcke, 2014DTI, 153TTBSS19 (38)SLE v NPSLEFAVoxels and clusters across WMNo difference in FA between SLE and NPSLEZimny, 2014DTI, 251.5TROI13 (34)SLE v NPSLEFA14 WM tractsGenerally no difference in FA between SLE and NPSLE (see FP)ADC = average diffusion coefficient, FA = fractional anisotropy, FP = forest plot (see Supplementary Material), GM = grey matter, MD = mean diffusivity, MTR = mean transit ratio, NPSLE = neuropsychiatric SLE, NAT = normal appearing tissue, NAWM = normal appearing white matter, ROI = region of interest, SLE = systemic lupus erythematosus, TBSS = tract based spatial statistics, WM = white matterFigure 1 Whole brain white matter tractography and group maps. The first row shows maps of whole brain white matter structure from a representative patient. White matter tracts running predominantly anterior/posterior are coloured green, superior/inferior blue and right/left red. The second row shows group maps (all patients superimposed on each other) of two major tracts, the genu and splenium of corpus callosum for all 47 patients. Note the close correspondence of these tracts, indicated by the lighter red/yellow colours, which allows the integrity of the same structure to be measured across the cohort.Figure 2 General factors for (A) mean diffusivity and (B) fractional anisotropy in relation to age among SLE patients and healthy controls. ................
................

In order to avoid copyright disputes, this page is only a partial summary.

Google Online Preview   Download