Objective: To assess in vivo in Huntington’s disease (HD) changes in microglia activation state, due to treatment with laquinimod, as reflected by changes in ¹¹C-PBR28 cerebral binding.

Background: Activated microglia is believed to contribute to HD pathology. Laquinimod has shown in vitro and in vivo potential to downregulate microglia activation. The state of microglia activation can be assessed in vivo using PET imaging, by targeting the translocator protein (TSPO) which is highly expressed in microglia. ¹¹C-PBR28 is a TSPO-specific PET radioligand, with favourable kinetics and improved signal-to-noise ratio.

Method: Laquinimod was assessed versus placebo in a double-blinded, phase 2, clinical trial for one year (LEGATO-HD, NCT02215616). 15 HD patients of the UK cohort (9M:6F; age: 45.16±7.38 years; disease duration from onset: 5.60±2.96 years) were treated with laquinimod (0.5mg, N=4; 1.0mg, N=6) or placebo (N=5). All subjects had ¹¹C-PBR28 PET and MRI at baseline and at the end of treatment. Data were analysed to calculate regional distribution volume ratios (DVRs) for the caudate and the putamen employing reference Logan kinetic modelling and the corpus callosum as the reference region. Partial volume effect correction was performed using the Müller-Gartner algorithm to account for the HD-related striatal atrophy. Over time differences in clinical scores [Unified HD Rating Scale (UHDRS-TMS, UHDRS-TFC)] and striatal DVR values were calculated for each individual. Comparisons of baseline and follow-up ¹¹C-PBR28 DVR values and clinical scores between the two treatment groups were performed with appropriate parametric and non-parametric tests.

Results: At the end of the one-year treatment, the 10 HD patients who had laquinimod did not show a change in their regional ¹¹C-PBR28 DVR values for both caudate (p=0.70) and putamen (p=0.88). In the placebo group, the mean ¹¹C-PBR28 DVR did not change significantly in both caudate (p= 0.44) and putamen (p=0.46). The HD patients treated with laquinimod did not show a clinical improvement (UHDRS-TMS, p=0.26; UHDRS-TFC, p=0.86). No change was seen in the placebo group (UHDRS-TMS, p=1.00; UHDRS-TFC, p=0.10).

Conclusion: The data from the PET arm of LEGATO-HD study indicate that laquinimod treatment in HD may not affect regional microglia activation, as reflected by ¹¹C-PBR28 striatal DVR values.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/a-longitudinal-pet-study-to-assess-the-state-of-microglia-activation-in-a-phase-2-study-of-laquinimod-as-a-treatment-for-huntingtons-disease-legato-hd/