Altered phosphodiesterase 10A (PDE10A) expression in the brain could be a very early pathophysiological marker of Huntington disease (HD), and also seems to correlate with disease severity and progression in Parkinson disease (PD), according to a pair of new studies published in Brain.

A team led by Marios Politis at King's College London, UK used PET scanning with the radioligand 11C-IMA107 to measure PDE10A levels in the brains of presymptomatic huntingtin (HTT) mutation carriers and patients with PD. The overall aim of the research was to investigate the molecular mechanisms of neurodegeneration in basal ganglia disorders.

“PDE10A is a dual substrate enzyme mainly expressed in the striatal GABAergic medium spiny neurons, where it regulates the cAMP–PKA–DARPP-32 signalling cascade, which has a key role in the regulation of movement and promotion of neuronal survival,” explains Politis. “Therefore, we hypothesized that PDE10A levels could be altered in movement disorders such as HD and PD.”

A precedent for the current research was set by the results of animal studies. HD is caused by a trinucleotide repeat expansion in the HTT gene, and experiments in a transgenic model of the disease indicated that mutant huntingtin affected PDE10A expression. In addition, in a rat model of PD, lesioning of midbrain dopaminergic neurons led to reduced PDE10A expression in the striatum and globus pallidus.

For the first study, Politis and colleagues recruited 12 HTT mutation carriers who were, on average, 25 years away from the predicted age of symptomatic onset of HD (range 17–43 years), along with 12 healthy controls. As a group, the mutation carriers exhibited reduced PDE10A levels in the striatum and globus pallidus and elevated PDE10A levels in motor thalamic nuclei compared with the controls. Moreover, the ratio of motor thalamic to striatal PDE10A expression correlated with the probability of conversion to symptomatic HD.

PDE10A availability, visualized by 11C-IMA107 binding, in the striatum of a healthy control, a presymptomatic Huntington disease mutation carrier, and a patient with Parkinson disease. Image courtesy of M. Politis.

“Our findings represent a major breakthrough by reporting the earliest biochemical abnormality identified in HD to date, and showing bidirectional alteration of PDE10A signalling within neuropathologically salient networks in HD gene carriers up to 43 years before the development of overt clinical symptoms,” says Politis. “The altered balance of PDE10A signalling between motor thalamic nuclei and striatopallidal internal projecting segments of the striatum is the strongest reported association with predicted risk of symptomatic conversion.”

In the second study, 11C-IMA107 PET scans were performed in 24 patients with moderate to advanced levodopa-treated PD, and 12 healthy controls. The Unified Parkinson's Disease Rating Scale and the Unified Dyskinesia Rating Scale (UDysRS) were used to assess the severity of motor symptoms and levodopa-induced dyskinesias (LIDs), respectively.

The researchers found that loss of PDE10A from the striatum and globus pallidus correlated strongly with both disease duration and motor symptom severity. In addition, striatal PDE10A levels showed an inverse relationship with UDysRS scores. However, it was unclear whether this further depletion of PDE10A in patients with LIDs was merely a consequence of advanced disease.

“PDE10A expression could be a biomarker for the integrity of striatal medium spiny neurons, and 11C-IMA107 PET may be a useful tool for future trials of disease-modifying therapeutics aimed at delaying the onset and slowing the progression of HD and PD,” concludes Politis. “PDE10A could also be targeted with novel pharmacotherapy, which may help improve dopaminergic signalling and striatal output, and promote neuronal survival.”