N-Acetylaspertate (NAA) as a biomarker for disease in neuropsychiatric lupus

(NPSLE) patients

A MR spectroscopy study

P. Wang, R. Harris, P. Cagnoli, D. Frechtling, D. Bekris, S. Gebarski, J. McCune, and P. Sundgren

no disclosures

University of Michigan (US) & Lund University (Sweden)

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introduction

SLE is an autoimmune disorderneuropsychiatric systemic lupus

erythematosus or NPSLE30-40% of lupus patients

at the time of diagnosis or 2 years thereafter

worse prognosis increased morbidity and mortality

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NPSLE presents clinically with:headachestroke or stroke like symptomspsychosisseizurescognitive dysfunction

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NPSLE presents anatomically with:

white matter changes

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NPSLE presents anatomically with:

Copied with permission from Appenzeller et al. Arthritis Rheum. 2005 Sep 52 (9):2783-9.

cerebral and corpus callosum atrophy

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NPSLE histopathologic features gross and microinfarctscortical atrophyhemorrhagedemyelination

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NPSLE diagnosis

confirm diagnosis of lupuscareful history and physical exam targeted workup for symptoms

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NPSLE treatment

largely uncontrolled trials and anecdotal experiences

immunosuppressive txanticoagulation/antiplatelet tx

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who cares?

some patients have no serologic or systemic signs

detect early metabolic changes help narrow the differential diagnosismonitor therapy run outcome trials to validate

treatment

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aim

use MR spectroscopy to investigate whether differences in metabolic ratios exist between patients with: NPSLE SLE healthy controls

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methods

20 SLE patients with no neurological sx 18 F: 2 M (ages 21.0-61.0; mean 40.7)

20 SLE patients with neurological sx 20 F (ages 25.2-67.3; mean 41.5)

20 healthy controls 17 F: 3M (ages 18.8-61.0; mean 40.7)

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methods

clinical workup including: laboratory testingSLE Disease Activity Index score

(SLEDAI)mini-mental status examination fatigue, depression, and pain

questionnaire

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methods

3T MRI of the brain, which was evaluated for: signal abnormalities hemorrhage ischemic events focal lesions atrophy

frontal white matter

right insula

occipital gray matter

SVS (single-voxel spectroscopy) MR

PRESSTR 2000 msTE 30 ms2x2x2 cm voxel size

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LC model

Cho

Cr

NAA

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Healthy Controls

SLE

NPSLE

NAACho Cr

Cho

Cho

Cho

Cr

Cr

Cr

NAA

NAA

NAA results

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results – frontal white matterfrontal white matter Cho/Cr ratio:

SLE: 0.22 mean [0.13 SD]NPSLE: 0.30 mean [0.09 SD]HC: 0.31 mean [0.09 SD]

p = 0.04 (NPSLE) and 0.02 (HC)

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results – right insula

right insular NAA/Cr ratio:

SLE: 1.12 mean [0.17 SD]NPSLE: 0.98 mean [0.12 SD]HC: 1.12 mean [0.078 SD]

p = 0.002 (SLE & HC)

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results – SLEDAI scores

high neurobiologic involvement NAA/Cr ratios = 0.98 mean [0.04 SD]

no neurobiologic involvement NAA/Cr ratios = 1.10 mean [0.17 SD]

NAA/Cr was significantly negatively correlated with the SLEDAI score (r= -0.45; p = 0.005)

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conclusion

NPSLE patients have decreased NAA/Cr in the insular region indicating: neuronal injury/loss and demyelination

Therefore, NAA may be an helpful biomarker for the diagnosis of NPSLE.

Thank you

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disease in systemic lupus erythematosus. Lupus 2006;15:835-9. Harel L, Snadborg C, Lee T, von Scheven E. Neuropsychiatric manifestiation in

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Hanley JG, Urowitz MB, Sanchez-Guerrero J. et al. Neuropsychiatric evens at the time of diagnosis of systemic lupus ertheymatosus: An international inception cohort study. Arthritis and Rheumatism 2007;56:265-73.

Hanly JG. Neuropsychiatric lupus. Curr Rheumatol Rep. 2001; 3:205-212. Hanly JG. Walsh NM, Sangalang V. Brain pathology in systemic lupus erythematosus.

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erythematosis. Clin Rev Allergy Immunology 2003; 25:3-12 Kovacs J, Urowitz M, Gladman D. Dilemmas in neuropsychiatric lupus. Rheum Dis Clin

North Am 1993; 19:795-819 Rivest C, Lew RA, Welsing PM et al. Association between clinical factors,

socioeconomic status, and organ damage in recent onset systemic lupus erythematosus. J Rheumatol. 2000; 27:680-4

Shimojima Y, Matsuda M, GonoT et al relationship between clinical factors and neuropsychiatric manifestations in sytemic lupus erythematosus. Clin Rheumatol. 2005; 24:469-75.

Sibbitt WL Jr, Sibbitt RR, Brooks WM. Neuroimaging in neuropsychiatric systemic lupus erythematosus. Arthritis Rheum 1999; 42:2026-38

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why do pts develop NPSLE?We do not know… theories include:damage from anti-phospholipid

antibodymicroangiopathyatherosclerosis intrathecal production of

proinflammatory cytokines

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results – active SLE symptomsActive SLE sx

NAA/Cr ratio = 0.99 mean [0.15 SD]No SLE sx

NAA/Cr ratio = 1.12 mean [0.15 SD]p = 0.01