Rationale and Objectives
To investigate for differences in metabolic concentrations and ratios between patients with systemic lupus erythematosus (SLE) without (group SLE) and those with neurological symptoms (group NPSLE) compared to a healthy control (group HC) in three normal-appearing brain regions: the frontal white matter, right insula (RI), and occipital gray matter and whether changes in any of the metabolites or metabolic ratios are correlated to disease activity and other clinical parameters.
Materials and Methods
Twenty patients with SLE (18 women and 2 men, age range 23.4–64.6 years, mean age 43.9 years), 23 NPSLE patients (23 women, age range 23.7–69.8 years, mean age 42.4 years), and 21 HC (19 women and 2 men, age range 21.0–65.7 years, mean age 43.4 years) were included. All subjects had conventional brain magnetic resonance imaging and 1 H single-voxel spectroscopy, clinical assessment, and laboratory testing.
Results
NPSLE patients had significantly reduced N -acetylaspartate (NAA)/creatine compared to HC ( P = .02) and SLE patients ( P = .01) in the RI. Lower glutamine/creatine levels were also detected in RI in both patient groups and in frontal white matter in NPSLE patients compared to HC ( P = .01, P = .02). NAA/Cr ratio in the RI was significantly negatively correlated with the Systemic Lupus Erythematosus Disease Activity Index ( r = −0.41; P = .008), and patients with active SLE symptoms also had a trend toward lower NAA/creatine ratios (1.02 vs 1.12; P = .07).
Conclusions
The present data support previous findings of abnormal metabolic changes in normal-appearing regions in the brain of both SLE and NPSLE patients and raise the possibility that especially NAA, glutamine, and glutamate may be additional biomarkers for cerebral disease activity in SLE patients as these early metabolic changes occur in the brain of SLE patients before neurologic and imaging manifestations become apparent.
Systemic lupus erythematosus (SLE) is a chronic inflammatory, immune-mediated disease that affects 0.1% of the general population. Neuropsychiatric SLE (NPSLE) is a severe and life-threatening condition, reported to occur in 25% to 70% of patients with SLE and associated with increased morbidity and mortality . Clinically, NPSLE can present with acute symptoms such as stroke, seizures, or movement disorders, which are usually diagnosed promptly and reliably. However, many individuals with SLE develop a variety of other symptoms, including headaches, psychosis, cognitive dysfunction, depression, or other less specific symptoms, and the diagnosis and attribution to NPSLE are much less certain. The wide variation in NSPLE incidence emphasizes the need for better diagnostic tests. Clinical manifestations of NPSLE include headaches, stroke, myelopathy, seizures, psychosis, confusional states, and cognitive impairment but also peripheral manifestations such as cranial neuropathies and inflammatory demyelinating polyradiculoneuropathies. Patients with concomitant antiphospholipid antibodies are at additional risk for neuropsychiatric events. Lupus patients are also at increased risk for a wide range of central nervous system (CNS) events related to immunosuppressive therapy, including infection and drug toxicity.
Magnetic resonance imaging (MRI) is frequently used to diagnose or exclude main brain alterations and has become part of the routine clinical workup of such alterations . Abnormal conventional MRI findings are common in both SLE and NPSLE patients and range from nonspecific small punctate focal lesions in white matter (WM) (present in the majority of NPSLE patients but not specific) to more severe findings such as cortical atrophy, ventricular dilation, cerebral edema, cerebral infarctions, and intracranial hemorrhage . These findings are attributed to different mechanisms, including thrombosis, vasculopathy, and antibody-mediated neuronal injury .
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Materials and methods
Participants
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Conventional MRI and Proton MRS
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Clinical Outcomes
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MR Image Evaluation
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Statistical Evaluation
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Results
Clinical Manifestations, Disease Severity, and Serological Data
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Table 1
Demographic and Disease Severity of the Study Subjects
HC (n = 21) SLE (n = 20) NPSLE (n = 23)P Value Age 21–66 23–65 23–70 .9 43.9 43.9 42.4 Female (n) 19 (90.5%) 18 (90%) 23 (100%) .3 Age at disease onset (yr) N/A 18–56 13–65 .8 33.4 ± 10.9 32.7 ± 13.5 Disease duration (yr) N/A 3–19 2–25 1.0 9.4 ± 5.2 10.5 ± 6.8 SLEDAI N/A 0–8 1–25 <.001 2.1 ± 2.5 11.3 ± 6.2 SLICC N/A 0–3 0–4 >.2 0.53 ± 1.01 0.95 ± 1.12 Mini-Mental State Examination score 32–33 31–33 31–32 >.2
HC, healthy controls; SLE, systemic lupus erythematosus; NPSLE, neuropsychiatric systemic lupus erythematosus; SLEDAI, Systemic Lupus Erythematosus Disease Activity Index; SLICC, Systemic Lupus Erythematosus International Collaborating Clinics; N/A, not applicable.
Values are range and mean ± SD unless otherwise noted.
Table 2
Laboratory Results and Antibody Data for Study Subjects
HC (n = 21) SLE (n = 20) NPSLE (n = 23)P Value Hemoglobin 11.6–15.5 10.9–15.8 9.5–14.7 1.162 ∗ 13.51/1.066 13.44/1.084 12.92/1.522 WBC 3.9–8.4 2.6–9.2 2.9–17.3 1.868 ∗ 5.9/1.272 5.847/1.99 7.25/3.64 Platelet count 214–365 152–405 176–683 .598 ∗ 268.6/46.54 265.74/56.58 289.9/110.58 Creatinine 0.6–1.2 0.6–1.50 0.5–1.0 1.961 ∗ 0.778/0.157 0.823/0.206 0.755/0.147 Double-stranded DNA N/A 0–28 0–126 .069 9.535/10.22 26.44/35.95 C3 N/A 85–145 65–189 .375 114.94/18.22 122.43/30.15 C4 N/A 7–40 11–39 .880 23.53/8.156 23.95/8.513 ESR N/A 4–27 2–43 .546 14.65/7.566 17.056/14.53 CRP N/A 0–1 0–3.3 .161 0.212/0.237 1.021/2.317 β2G-1 IgG N/A 0–25 0–110 .399 2.267/6.703 7.8/24.34 β2G-l IgM N/A 0–9 0–230 .312 0.867/2.475 14.55/51.404 β2G-l IgA N/A 0–9 0–18 .043 1.0/2.7 4.05/5.094 CAL IgG N/A 0–32 0–40 .438 2.412/7.722 5.1/12.19 CAL IgM N/A 0–13 0–36 .491 1.06/3.172 2.5/7.997 LAC 0–1 0–1 0–1 .078 All negative 4 of 20 positive 1 of 20 positive .239
HC, healthy controls; SLE, systemic lupus erythematosus; NPSLE, neuropsychiatric systemic lupus erythematosus; β2-GPI, β2-glycoprotein I; C3, C3 complement; C4, C4 complement; aCL, anticardiolipin antibody; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; LAC, lupus anticoagulant (binominal); WBC, white blood cell count; N/A, not applicable; IgG GPL, IgG phospholipid unit; IgM MPL, IgM phospholipid unit.
Values are range and mean ± SD unless otherwise noted.
The serological data are presented for the 20 patients NPSLE in whom data was available.
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Conventional MRI
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MRS
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Metabolic Ratios
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Table 3
The Different Metabolic Ratios in the Three Evaluated Brain Regions Among the Three Groups
Metabolite HC SLE NPSLE_F_ Value_P_ Value Mean SD Mean SD Mean SD Right insula NAA/Cr 1.1241 0.07755 1.1342 0.15597 1.0250 0.15572 4.20 .02 Glu/Cr 1.0838 0.28334 1.0577 0.21900 1.0009 0.18186 0.73 .49 Gln/Cr 0.6029 0.3699 0.3823 0.12546 0.4023 0.11629 4.21 .02 Glx/Cr 1.5355 0.6542 1.3609 0.32481 1.3672 0.24571 1.00 .37 Cho/Cr 0.2282 0.0723 0.2517 0.04114 0.2336 0.04234 1.02 .37 Myoinositol/Cr 0.5090 0.1874 0.5837 0.16625 0.5236 0.14535 1.09 .34 Frontal white matter NAA/Cr 1.3331 0.12839 1.1948 0.35731 1.2287 0.11899 2.19 .12 glu/Cr 1.0936 0.33804 1.0558 0.21130 0.9220 0.15644 2.68 .08 gln/Cr 0.6384 0.41502 0.4193 0.31141 0.3628 0.15552 3.24 .05 Glx/Cr 1.5770 0.68329 1.2759 0.73870 1.2056 0.23912 2.38 .10 Cho/Cr 0.3089 0.08411 0.2509 0.10511 0.3098 0.05755 2.84 .07 Myoinositol/Cr 0.7939 0.70784 0.6657 0.17832 0.6413 0.12802 0.73 .49 Occipital gray matter NAA/Cr 1.4329 0.10830 1.4286 0.16598 1.3086 0.31613 2.12 .13 Glu/Cr 0.9116 0.09624 0.9381 0.15049 0.8737 0.22014 0.76 .47 Gln/Cr 0.2554 0.12949 0.2723 0.08932 0.2922 0.15251 0.23 .79 Glx/Cr 1.1283 0.16053 1.1507 0.22297 1.1102 0.32390 0.13 .88 Cho/Cr 0.1720 0.02321 0.1993 0.09818 0.1720 0.02737 1.36 .26 Myoinositol/Cr 0.5772 0.08476 0.6547 0.14335 0.5840 0.09660 2.95 .06
NAA, N -acetylaspartate; Cho, choline; Cr, creatine; Glu, glutamate; Gln, glutamine; Glx, combined Glu and Gln; HC, healthy controls; SLE, systemic lupus erythematosus; NPSLE, neuropsychiatric systemic lupus erytematosus.
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Metabolic Concentrations
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Metabolite Ratios and SLEDAI
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Longitudinal Follow-up of Metabolic Ratios
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Table 4
Longitudinal Follow-up of the Different Metabolic Ratios in the Insula in the NPSLE Patients
Metabolite Baseline 3 Months 6 Months_F_ Value_P_ Value Mean SD Mean SD Mean SD Insula NAA/Cr 1.03071 0.173151 1.09793 0.117026 1.16893 0.159068 4.52 .035 Glu/Cr 0.99243 0.169869 1.06321 0.160445 1.07129 0.198004 1.55 .25 Gln/Cr 0.39169 0.113944 0.39282 0.082682 0.44621 0.288669 0.38 .69 Glx/Cr 1.36129 0.185026 1.41314 0.209649 1.51743 0.427220 0.77 .48 Cho/Cr 0.23843 0.047144 0.26179 0.031737 0.2559 0.04290 1.25 .32 Myoinositol/Cr 0.51264 0.161923 0.57471 0.101972 0.5911 0.14314 1.29 .31
NAA, N -acetylaspartate; Cho, choline; Cr, creatine; Glu, glutamate; Gln, glutamine; Glx, combined Glu and Gln; NPSLE, neuropsychiatric systemic lupus erytematosus.
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Discussion
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Conclusions
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