Longitudinal assessment of PDE10 in Huntington disease (HD) using [¹⁸F]MNI-659 PET imaging.

Objectives To further evaluate the feasibility of [¹⁸F]MNI-659 PET, a striatal PDE10A imaging tracer, as a biomarker for progression of HD. [¹⁸F]MNI-659 is a selective PET tracer for phosphodiesterase PDE10A, an enzyme specifically and highly expressed in striatal neurons (see Barret, O, et al. J Nucl Med. 2014). Prior studies demonstrated a strong correlation between extent of loss of [¹⁸F]MNI-659 striatal uptake and clinical and molecular indices of manifest (mHD) and premanifest (preHD) HD severity (see Figure and Russell, D, et al. JAMA Neurol. 2014).

Methods All subjects completed baseline clinical assessments, including UHDRS rating, and brain MRI. PET imaging was acquired over 90 minutes following injection of ~5 mCi [¹⁸F]MNI-659. Standard uptake values were determined for the basal ganglia and component subnuclei. Binding potentials (BPnd) were estimated with SRTM (cerebellum as reference). Subjects underwent clinical assessments and [¹⁸F]MNI-659 PET imaging at 1 and 2 years following baseline.

Results Eight HD subjects (6 mHD [Stage 1 (n=2), Stage 2 (n=4)]; and 2 preHD) participated. At baseline, HD subjects demonstrated reduced striatal [¹⁸F]MNI-659 uptake of ~50% compared to existing an healthy control cohort (n=7). At 1 year, [¹⁸F]MNI-659 uptake declined in the basal ganglia in all 8 subjects with mean annualized rates of signal reduction in caudate, putamen, and globus pallidus (GP) of 16.6%, 6.9% and 5.8%, respectively. A decline in clinical status assessed by UHDRS was also observed in this cohort. To date, 3 subjects have completed year 2 imaging with continued mean annualized reduction in [¹⁸F]MNI-659 uptake at a rate comparable to year 1 (caudate 15.5%, putamen 7.2%, and GP 9.4%).

Conclusions [¹⁸F]MNI-659 appears to be an excellent striatal imaging biomarker for early HD. Also, annual decrements in striatal PDE10A binding in longitudinal studies of early mHD and preHD are observed over 2 years. Additional studies are currently underway.