HAI Book 2025 - Flipbook - Page 366
Pascual, Belen
81
TSPO-PET before and after low-dose interleukin-2 in patients with
mild to moderate Alzheimer's disease
Belen Pascual1, Alireza Faridar1, Quentin Finn1, Nazaret Gamez1, Stanley Appel1, Joseph
Masdeu1
1
Houston Methodist Stanley H. Appel Department of Neurology, Houston Methodist Research Institute, Weill Cornell
Medicine, Houston, TX, US
Background: Brain inflammation can be assessed using translocator protein (TSPO) PET. TSPO is highly
expressed by microglia, peripherally-derived macrophages, and astrocytes. However, TSPO PET does not
distinguish between M1 (neurotoxic) and M2 (neuroprotective) microglial phenotypes. Since the applicability of
TSPO PET to study the evolution of brain inflammation in AD clinical trials targeting inflammation has not been
studied, we performed TSPO-PET in a clinical trial using 11C-ER176, which has high specific binding, a favorable
metabolite profile, and is increased in brain areas with high tau levels.
Methods: Thirty-eight AD patients (ages 50-86, MMSE scores 12-26) participated in a phase 2a, randomized,
double-blind, placebo-controlled trial evaluating two dosing frequencies of Interleukin-2 (IL-2). Over a 21-week
period, 9 participants received IL-2 every 4 weeks (IL-2 q4wks), 10 received IL-2 every 2 weeks (IL-2 q2wks), and
19 received placebo. 11C-ER176 PET (using standard methods and an arterial-input function), blood/CSF
biomarkers, and clinical scores were obtained before and after treatment.
Results: Group analyses did not show TSPO-PET binding differences before and after the different IL-2 dosing
regimens or placebo. At the individual level, TSPO-PET binding was reduced in the hippocampus after treatment
in most participants on IL-2 but not in those on placebo. Both IL-2 dosing regimens increased Treg numbers and
function, but IL-2 q4wks was superior in enhancing Treg counts and Foxp3 mean fluorescent intensity. In the IL-2
q4wks group, CSF A´42 levels improved significantly (p=0.045), with a promising trend toward stabilized CSF-NfL
levels (p=0.061) and slowed cognitive decline compared to placebo.
Conclusions: While IL-2 immunotherapy every 4 weeks enhanced Treg populations, showing promising trends in
AD biomarkers and clinical scales, TSPO-PET was largely unchanged over the 21 weeks of the trial. A longer followup, a larger sample or, more likely, PET tracers specific for M1 and M2 are needed for clinical trials.
Keywords: TSPO, 11C-ER176 PET, Inflammation, IL-2 immunotherapy, Alzheimer’s disease
HAI2025 - 366
