Early prognosticators of later TSPO-PET-measurable microglial activation in multiple sclerosis.

BACKGROUND: Factors driving increased innate immune cell activation in multiple sclerosis (MS) brain are not well understood. As higher prevalence of microglial/macrophage activation in association with chronic lesions and diffusely in the normal appearing white matter predict more rapid accumulation of clinical disability, it is of high importance to understand processes behind this. Objective of the study was to explore demographic, clinical and paraclinical variables associating with later positron emission tomography (PET)-measurable innate immune cell activation. METHODS: PET-imaging using a TSPO-binding [11C]PK11195 was performed to evaluate microglial activation in patients with relapsing-remitting MS aged 40-55 years with a minimum disease duration of five years (n = 37). Medical records and diagnostic MR images were reviewed for relevant early MS disease-related clinical and paraclinical parameters. RESULTS: More prominent microglial activation was associated with higher number of T2 lesions in the diagnostic MRI, a higher immunoglobulin G (IgG) index in the diagnostic CSF and Expanded Disability Status Scale (EDSS) ≥ 2.0 five years after diagnosis. CONCLUSION: The number of T2 lesions in MRI, and CSF immunoglobulin content measured by IgG index at the time of MS diagnosis associated with later TSPO-PET-measurable innate immune cell activation. This suggests that both focal and diffuse early inflammatory phenomena impact the development of later progression-related pathology.

Dimethyl fumarate decreases short-term but not long-term inflammation in a focal EAE model of neuroinflammation.

BACKGROUND: Dimethyl fumarate (DMF) is an oral immunomodulatory drug used in the treatment of autoimmune diseases. Here, we sought to study whether the effect of DMF can be detected using positron emission tomography (PET) targeting the 18-kDa translocator protein (TSPO) in the focal delayed-type hypersensitivity rat model of multiple sclerosis (fDTH-EAE). The rats were treated orally twice daily from lesion activation (day 0) with either vehicle (tap water with 0.08% Methocel, 200 µL; control group n = 4 (3 after week four)) or 15 mg/kg DMF (n = 4) in 0.08% aqueous Methocel (200 µL) for 8 weeks. The animals were imaged by PET using the TSPO tracer [18F]GE-180 in weeks 0, 1, 2, 4, 8, and 18 following lesion activation, and the non-displaceable binding potential (BPND) was calculated. Immunohistochemical staining for Iba1, CD4, and CD8 was performed in week 18, and in separate cohorts of animals, following 2 or 4 weeks of treatment. RESULTS: Using the fDTH-EAE model, DMF reduced the [18F]GE-180 BPND in the DMF-treated animals compared to control animals after 1 week of treatment (two-tailed unpaired t test, p = 0.031), but not in weeks 2, 4, 8, or 18 when imaged in vivo by PET. Immunostaining for Iba1 showed that DMF had no effect on the perilesional volume or the core lesion volume after 2 or 4 weeks of treatment, or at 18 weeks. However, the optical density (OD) measurements of CD4+ staining showed reduced OD in the lesions of the treated rats. CONCLUSIONS: DMF reduced the microglial activation in the fDTH-EAE model after 1 week of treatment, as detected by PET imaging of the TSPO ligand [18F]GE-180. However, over an extended time course, reduced microglial activation was not observed using [18F]GE-180 or by immunohistochemistry for Iba1+ microglia/macrophages. Additionally, DMF did affect the infiltration of CD4+ and CD8+ T-lymphocytes at the fDTH-EAE lesion.

Hip resurfacing arthroplasty versus large-diameter head metal-on-metal total hip arthroplasty: comparison of three designs from the Finnish Arthroplasty Register.

BACKGROUND AND AIMS: Large headed metal-on-metal total hip arthroplasty may produce more metal ions than hip resurfacing arthroplasty. Increased metal-ion levels may be associated with higher revision rates due to adverse reaction to metal debris. The purpose of our study was to compare the survivorship of three hip resurfacing arthroplasty designs with their analogous cementless large-diameter head metal-on-metal total hip arthroplasties. MATERIAL AND METHODS: Based on data obtained from the Finnish Arthroplasty Register, the revision risks of three metal-on-metal hip resurfacing arthroplasty/total hip arthroplasty design couples performed during 2001-2011 were analyzed using the Cox regression model. RESULTS: In the Cox regression analysis for compared design pairs adjusted for age, gender, operated side, head size, diagnosis, and implant, there was no statistically significant difference in revision risk between ReCap hip resurfacing arthroplasty and Bimetric/ReCap total hip arthroplasty (risk ratio = 1.43, confidence interval = 0.95-2.14, p = 0.09) or between Birmingham hip resurfacing arthroplasty and Synergy/Birmingham hip resurfacing total hip arthroplasty (risk ratio = 1.35, confidence interval = 0.75-2.43, p = 0.31). However, the revision risk of Corail and Summit/articular surface replacement total hip arthroplasty (ASR HRA) was significantly increased compared to ASR HRA. (risk ratio = 0.73, confidence interval = 0.54-0.98, p = 0.04). CONCLUSION: We conclude that the short-term revision risk of large headed metal-on-metal total hip arthroplasties was not increased compared to analogous hip resurfacing arthroplasties in two out of three devices studied at a nationwide level. There may be implant-related factors having an effect on the success of single manufacturer devices. However, more information on the incidence of adverse soft-tissue reactions in these patient cohorts is needed.