Imaging disease activity of rheumatoid arthritis by macrophage targeting using second generation translocator protein positron emission tomography tracers.

BACKGROUND: Positron emission tomography (PET) imaging of macrophages using the translocator protein (TSPO) tracer (R)-[11C]PK11195 has shown the promise to image rheumatoid arthritis (RA). To further improve TSPO PET for RA imaging, second generation TSPO tracers [11C]DPA-713 and [18F]DPA-714 have recently been evaluated pre-clinically showing better imaging characteristics. OBJECTIVE: A clinical proof of concept study to evaluate [11C]DPA-713 and [18F]DPA-714 to visualize arthritis in RA patients. METHODS: RA patients (n = 13) with at least two active hand joints were included. PET/CT scans of the hands were obtained after injection of [18F]DPA-714, [11C]DPA-713 and/or (R)-[11C]PK11195 (max. 2 tracers pp). Standardized uptake values (SUVs) and target-to-background (T/B) ratios were determined. Imaging data of the 3 different tracers were compared by pooled post-hoc testing, and by a head to head comparison. RESULTS: Clinically active arthritis was present in 110 hand joints (2-17 pp). Arthritic joints were visualized with both [11C]DPA-713 and [18F]DPA-714. Visual tracer uptake corresponded with clinical signs of arthritis in 80% of the joints. Mean absolute uptake in PET-positive joints was significantly higher for [11C]DPA-713 than for [18F]DPA-714, the latter being not significantly different from (R)-[11C]PK11195 uptake. Background uptake was lower for both DPA tracers compared with that of (R)-[11C]PK11195. Higher absolute uptake and lower background resulted in two-fold higher T/B ratios for [11C]DPA-713. CONCLUSIONS: [11C]DPA-713 and [18F]DPA-714 visualize arthritic joints in active RA patients and most optimal arthritis imaging results were obtained for [11C]DPA-713. Second generation TSPO macrophage PET provides new opportunities for both early diagnosis and therapy monitoring of RA.

Present role of positron emission tomography in the diagnosis and monitoring of peripheral inflammatory arthritis: a systematic review.

OBJECTIVE: To determine the current status of positron emission tomography (PET) as a tool for diagnosis and monitoring of peripheral inflammatory arthritis (IA). METHODS: For conducting this systematic review, the PubMed (Medline), Embase, and Cochrane Library databases were searched until December 31, 2012. Studies of PET for diagnosis and/or therapy monitoring of peripheral IA were included. Data were summarized qualitatively using best evidence synthesis. RESULTS: Eighteen articles met our inclusion criteria. The majority of studies were feasibility studies with varying methods applied. All studies demonstrated that PET visualized IA with high sensitivity, corresponding to clinical assessments. PET outcome of clinically active IA also matched that of ultrasound and magnetic resonance imaging. PET differentiates from other modalities by (quantitative) imaging of molecular sites in the synovium. The first studies reporting on the potential clinical applications of PET to image subclinical synovitis in preclinical RA and during therapy have been published. The results are promising, but the number and study populations of these studies are still limited. CONCLUSION: Thus far, a limited number of PET studies addressing IA imaging have been published. The PET modality seems to offer highly sensitive and potentially specific imaging of IA at the (quantitative) molecular level. Clinical application studies for early diagnostics and therapy monitoring are arising, but these topics should be further explored in future studies with larger cohorts. For integration in clinical practice, aspects such as radiation burden and cost-effectiveness should also be taken into account.

Amyloid-beta-stimulated plasminogen activation by tissue-type plasminogen activator results in processing of neuroendocrine factors.

Alzheimer's disease brain is characterized by the abundant presence of amyloid deposits. Accumulation of the major constituent of these deposits, amyloid-beta (Abeta), has been associated with decreased neurotransmission, increased neuronal cell death, and with cognitive decline. The mechanisms underlying these phenomena have not yet been fully elucidated. We have previously shown that amyloid peptides like Abeta bind tissue-type plasminogen activator (tPA) and cause enhanced plasmin production. Here we describe the identification of five major neuronal cell-produced Abeta-associated proteins and how Abeta-stimulated plasmin formation affects their processing. These five proteins are all neuroendocrine factors (NEFs): chromogranins A, B and C; truncated chromogranin B; and VGF. Plasminogen caused processing of Abeta-bound (but not soluble) tPA, chromogranin B and VGF and the degradation products were released from Abeta. Processing of the neuroendocrine factors was dependent on tPA as it was largely abrogated in tPA-/- cells or in the presence of a specific tPA-inhibitor. If plasmin indeed produces NEF-derived peptides in vivo, some of these peptides may have biological activity, for instance in regulating neurotransmitter release that may affect the pathology of Alzheimer's disease.