Evaluating the Clinical Utility of TSPO-PET in MS and the Influence of Methodological Heterogeneity

Abstract

Background and Objectives PET imaging targeting the 18-kDa translocator protein (TSPO) is a widely used method to detect neuroinflammation in vivo and shows promise for detecting innate inflammatory activity in multiple sclerosis (MS). However, TSPO-PET findings in MS vary substantially across studies. We performed a systematic review and meta-analysis to quantify TSPO-PET signal differences between people with MS (PwMS) and healthy controls (HCs) and to evaluate the impact of methodological factors on study outcomes. Methods A systematic search of Scopus, MEDLINE, Web of Science, and Embase databases was conducted through September 10, 2025. Original TSPO-PET studies in PwMS were included. Standardized mean differences (SMDs) in TSPO-PET signal between PwMS and HC were pooled using random-effects models with cluster robust variances. Heterogeneity was assessed using I2 statistics. Meta-regression and subgroup analyses investigated methodological sources of heterogeneity. Patient-level data were analyzed for associations with clinical and demographic variables. Risk of bias and certainty of evidence were assessed using quality assessment of diagnostic accuracy studies 2 tool and GRADE framework, respectively. Results Forty-nine studies met inclusion criteria. Overall meta-analysis revealed significantly increased TSPO-PET signal in PwMS vs HC (SMD = 0.44, 95% CI: 0.27–0.61, p = 0.0002, I2: 97.00%). TSPO-PET signal was also significantly higher in progressive MS than in relapsing-remitting MS, indicating discrimination across MS clinical subtypes. Meta-regression attributed study heterogeneity to tracer (11.47%), PET quantification method (15.37%), and region of interest (19.71%) differences. Significant PwMS vs HC differences were most consistently observed with select tracers ([11C]PBR28, [18F]DPA-714, [11C]ER176, and [11C]PK11195) and with distribution volume ratio (DVR), nondisplaceable binding potential (BPND), and standardized uptake value ratio metrics. Significant effects were found in perilesional, thalamic, cortical, hippocampal, normal-appearing white matter, and T2-weighted white matter lesion regions. Patient-level analyses, while limited in power, showed significant associations between TSPO-PET signal (DVR) and disability measures (expanded disability status scale). Discussion TSPO-PET effectively distinguishes PwMS from HC and differentiates MS subtypes. However, radiotracer, quantification method, image analysis method, reference tissue, and region of interest significantly impact TSPO-PET outcomes and must be considered when designing and interpreting studies. Methodological standardization and improved reporting will be essential to enhance cross-study comparability and clinical interpretability.