Neuroimaging of translocator protein in patients with systemic lupus erythematosus: a pilot study using [ 11 C]DPA-713 positron emission tomography

Abstract

Objective

Inflammation secondary to autoantibody-mediated effects occurring in multiple organs is a hallmark of systemic lupus erythematosus (SLE). The inflammatory response to SLE-mediated damage in brain parenchyma has been postulated in both normal and cognitively impaired individuals. Our goal is to use molecular imaging to investigate the distribution within the brain of the mitochondrial translocator protein (TSPO) that is upregulated during glial cell activation, and is considered as a marker of brain injury and repair.

Methods

We sought to characterize TSPO distribution in the brain of SLE patients using positron emission tomography (PET) and [¹¹C]DPA-713 (DPA), a radiopharmaceutical that targets TSPO. We imaged 11 healthy controls and 10 patients with SLE (years of diagnosis: 13.0 ± 7.7), all between the ages of 22 and 52. Results: Among the nine brain regions studied, no statistically significant increases in DPA binding were observed in SLE. Instead, there was a significant decrease in TSPO distribution in the cerebellum and hippocampus of SLE patients, as compared to healthy controls. Such decreases were most significant in cognitively normal SLE subjects, but showed pseudo-normalization in those with cognitive impairment, due to higher cerebellar and hippocampal DPA binding in the cognitively impaired (versus normal) SLE brain.

Conclusions

Results from this pilot study suggest a link between diminished regional TSPO expression in the brain of patients with SLE, as well as possible glial cell activation within the cerebellum and hippocampus of cognitively impaired individuals with SLE. Further studies are needed to elucidate how mitochondrial dysfunction and glial cell activation may act together in SLE and SLE-mediated neurocognitive deficits.

Keywords

Brain cerebellum cognitive impairment glial cell activation hippocampus lupus mitochondria mitochondrial translocator protein molecular imaging neurocognitive deficits positron emission tomography systemic lupus erythematosus translocator protein

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References

Ramage

Fox

Brey

. Neuroimaging evidence of white matter inflammation in newly diagnosed systemic lupus erythematosus. Arthritis Rheum 2011; 63: 3048–3057. .

Santer

Yoshio

Minota

Moller

Elkon

. Potent induction of IFN-alpha and chemokines by autoantibodies in the cerebrospinal fluid of patients with neuropsychiatric lupus. J Immunol 2009; 182: 1192–1201.

Brooks

Sibbitt

Kornfeld

. The histopathologic associates of neurometabolite abnormalities in fatal neuropsychiatric systemic lupus erythematosus. Arthritis Rheum 2010; 62: 2055–2063.

Curiel

Akin

Beaulieu

DePalma

Hashefi

. PET/CT imaging in systemic lupus erythematosus. Ann NY Acad Sci 2011; 1228: 71–80.

Jamar

Buscombe

Chiti

. EANM/SNMMI guideline for 18F-FDG use in inflammation and infection. J Nucl Med 2013; 54: 647–658.

Chauveau

Boutin

Van Camp

Dolle

Tavitian

. Nuclear imaging of neuroinflammation: A comprehensive review of [11C]PK11195 challengers. Eur J Nucl Med Mol Imag 2008; 35: 2304–2319.

Banati

Middleton

Chan

. Positron emission tomography and functional characterization of a complete PBR/TSPO knockout. Nat Commun 2014; 5: 5452, .

Fan

Campioli

Midzak

Culty

Papadopoulos

. Conditional steroidogenic cell-targeted deletion of TSPO unveils a crucial role in viability and hormone-dependent steroid formation. Proc Natl Acad Sci USA 2015; 112: 7261–7266.

Selvaraj

Stocco

. The changing landscape in translocator protein (TSPO) function. Trends Endocrinol Metab 2015; 7: 341–348. .

10.

Chen

Guilarte

. Translocator protein 18 kDa (TSPO): Molecular sensor of brain injury and repair. Pharmacol Ther 2008; 118: 1–17.

11.

Perl

. Oxidative stress in the pathology and treatment of systemic lupus erythematosus. Nat Rev Rheumatol 2013; 9: 674–686.

12.

Perl

Gergely

Jr Banki

. Mitochondrial dysfunction in T cells of patients with systemic lupus erythematosus. Int Rev Immunol 2004; 23: 293–313.

13.

Aguzzi

Barres

Bennett

. Microglia: Scapegoat, saboteur, or something else? Science 2013; 339: 156–161.

14.

Manji

Kato

Di Prospero

. Impaired mitochondrial function in psychiatric disorders. Nat Rev Neurosci 2012; 13: 293–307.

15.

Stephan

Hunter

Harris

. The neuropathological profile of mild cognitive impairment (MCI): A systematic review. Mol Psychiatry 2012; 17: 1056–1076.

16.

Doorduin

de Vries

Willemsen

. Neuroinflammation in schizophrenia-related psychosis: A PET study. J Nucl Med 2009; 50: 1801–1807.

17.

Venneti

Lopresti

Wiley

. The peripheral benzodiazepine receptor (translocator protein 18 kDa) in microglia: From pathology to imaging. Prog Neurobiol 2006; 80: 308–322.

18.

Kreisl

Lyoo

McGwier

. In vivo radioligand binding to translocator protein correlates with severity of Alzheimer's disease. Brain 2013; 136: 2228–2238.

19.

Endres

Pomper

James

. Initial evaluation of 11C-DPA-713, a novel TSPO PET ligand, in humans. J Nucl Med 2009; 50: 1276–1282.

20.

Brown

Fujita

Fujimura

. Radiation dosimetry and biodistribution in monkey and man of 11C-PBR28: A PET radioligand to image inflammation. J Nucl Med 2007; 48: 2072–2079. .

21.

Rusjan

Wilson

Bloomfield

. Quantitation of translocator protein binding in human brain with the novel radioligand [18F]-FEPPA and positron emission tomography. J Cereb Blood Flow Metab 2011; 31: 180716.

22.

Coughlin

Wang

. Regional brain distribution of translocator protein using [11C]DPA-713 PET in individuals infected with HIV. J Neurovirol 2014; 3: 219–232.

23.

Owen

Yeo

Gunn

. An 18-kDa translocator protein (TSPO) polymorphism explains differences in binding affinity of the PET radioligand PBR28. J Cereb Blood Flow Metab 2012; 32: 1–5.

24.

Bribes

Galiegue

Bourrie

Casellas

. Involvement of the peripheral benzodiazepine receptor in the development of cutaneous pathology in Mrl/Lpr mice. Immunol Lett 2003; 85: 13–18.

25.

Reeves D. Automated neuropsychological assessment metrics (ANAM V3.11a/96). User's manual: Clinical and neurotoxicology subset. Report, National Cognitive Foundation. Report No. NCRF-SR-96-01, 1996. San Diego: National Cognitive Foundation.

26.

Petri

Naqibuddin

Carson

. Depression and cognitive impairment in newly diagnosed systemic lupus erythematosus. J Rheumatol 2010; 37: 2032–2038.

27.

Fangtham

Petri

. 2013 Update: Hopkins Lupus Cohort. Curr Rheumatol Rep 2013; 15: 360.

28.

Thominiaux

Dollé

James

. Improved synthesis of the peripheral benzodiazepine receptor ligand [11C]DPA-713 using [11C]methyl triflate. Appl Radiat Isot 2006; 64: 570–3. .

29.

Wienhard

Schmand

Casey

. The ECAT HRRT: Performance and first clinical application of the new high resolution research tomograph. IEEE Trans Nucl Sci 2002; 49: 104–110. .

30.

Rahmim

Lenox

Reader

. Statistical list-mode image reconstruction for the high resolution research tomograph. Phys Med Biol 2004; 49: 4239–4258.

31.

Fischl

Salat

Busa

. Whole brain segmentation: Automated labeling of neuroanatomical structures in the human brain. Neuron 2002; 33: 341–355.

32.

Zardi

Taccone

Marigliano

Margiotta

Afeltra

. Neuropsychiatric systemic lupus erythematosus: Tools for the diagnosis. Autoimmun Rev 2014; 8: 831–839. .

33.

Watson

Storbeck

Mattis

Mackay

. Cognitive and emotional abnormalities in systemic lupus erythematosus: Evidence for amygdala dysfunction. Neuropsychol Rev 2012; 22: 252–270.

34.

Lee

Park

Lee

Park

. The efficacy of brain (18)F-fluorodeoxyglucose positron emission tomography in neuropsychiatric lupus patients with normal brain magnetic resonance imaging findings. Lupus 2012; 21: 1531–1537. .

35.

Lin

Zou

Wang

. Localization of cerebral functional deficits in patients with non-neuropsychiatric systemic lupus erythematosus. Hum Brain Mapp 2011; 32: 1847–1855.

36.

Muscal

Brey

. Neurologic manifestations of systemic lupus erythematosus in children and adults. Neurol Clin 2010; 28: 61–73.

37.

Innis

Cunningham

Delforge

. Consensus nomenclature for in vivo imaging of reversibly binding radioligands. J Cereb Blood Flow Metab 2007; 27: 1533–1539.

38.

Gulyas

Vas

Tóth

. Age and disease-related changes in the translocator protein (TSPO) system in the human brain: Positron emission tomography measurements with [11C]vinpocetine. Neuroimage 2011; 56: 1111–1121.

39.

Kumar

Muzik

Shandal

. Evaluation of age-related changes in translocator protein (TSPO) in human brain using (11)C-[R]-PK11195 PET. J Neuroinflammation 2012; 9: 232.

40.

Suridjan

Rusjan

Voineskos

. Neuroinflammation in healthy aging: A PET study using a novel translocator protein 18kDa (TSPO) radioligand, [(18)F]-FEPPA. Neuroimage 2014; 84: 868–875.

41.

Zavala

Veber

Descamps-Latscha

. Altered expression of neutrophil peripheral benzodiazepine receptor in X-linked chronic granulomatous disease. Blood 1990; 76: 184–188.

42.

Hammoud

Endres

Hammond

. Imaging serotonergic transmission with [11C]DASB-PET in depressed and non-depressed patients infected with HIV. Neuroimage 2010; 49: 2588–2595.