Kate Johnson

June 17, 2015

BALTIMORE — In patients with Parkinson's disease, neurochemical changes seen on molecular imaging could open the door to better treatment of motor dysfunction, new research shows.

Specifically, the decreased expression of protein phosphodiesterase 10A (PDE10A) was seen in patients with Parkinson's disease on PET scans that used the radioligand carbon 11 IMA107 (¹¹C-IMA107), said investigator Flavia Niccolini, MD, from King's College London, United Kingdom.

Moreover, decreased PDE10A expression is significantly linked to disease progression and the severity of motor symptoms, she reported.

"Our study is the first in vivo demonstration of loss of PDE10A expression in patients with middle-stage and advanced Parkinson's disease," said investigator Marios Politis, MD, also from King's College London.

Because PDE10A, a protein expressed primarily in the basal ganglia, "is critical in dopaminergic neuron function, it is possible that novel treatments targeting PDE10A could help improve Parkinson's symptoms and complications," he told Medscape Medical News.

Dr Niccolini presented the study results here at the Society of Nuclear Medicine and Molecular Imaging 2015 Annual Meeting.

Study Details

The study involved 24 patients with Parkinson's disease who had been receiving stable treatment with levodopa for at least 6 months. Mean age was 61.7 years. These patients were compared with 12 healthy control subjects with no history of psychiatric or neurologic disorders.

At baseline, all study participants underwent PET scans with ¹¹C-IMA107 and a structural MRI scan. The patients with Parkinson's disease were on their medications during these scans.

In addition, motor symptoms and complications were assessed with the motor examination section of the Unified Parkinson Disease Rating Scale (UPDRS) and the Unified Dyskinesia Rating Scale.

Patients with Parkinson's disease had less PDE10A binding in the striatum than control subjects (mean decrease, 22.8%; P < .001), as well as less caudate (mean decrease, 28.4%; P < .001) and less putamen (mean decrease, 25.5%, P < .001).

Decreases in the striatum were strongly associated with longer disease duration (P = .027) and worse motor symptoms, assessed with the UPDRS (P = .011). Decreases in the globus pallidus were also strongly associated with longer disease duration (P = .030) and worse motor symptoms (P = .003).

These findings provide evidence of a novel neurochemical change in patients with Parkinson's disease; a 14% to 28% loss of striatal and pallidal PDE10A expression was linked to disease progression and severity, Dr Niccolini reported.

 
PDE10A could serve as a novel therapeutic target for Parkinson's disease.
 

"PDE10A could serve as a novel therapeutic target for Parkinson's disease, and PDE10A-modulating drugs — by acting independent of or synergistically with levodopa — could have a therapeutic role in the alleviation of motor symptoms and motor complications," she explained.

"Phosphodiesterases, as key regulators of cyclic nucleotides, and their inhibitors have been emerging as new pharmacological targets for many diseases, including central nervous system pathologies," write Carmen Gil, PhD, from the Centro de Investigaciones Biológicas in Madrid, and colleagues in a recent review (Curr Med Chem. 2014;21:1171-1187).

Because "PDE10A is highly expressed in the striatum, the pharmacologic modulation of this enzyme could be a promising approach for neurodegenerative disorders, such as Parkinson's and Huntington's disease," Dr Gil told Medscape Medical News.

"As a consequence of the growing interest in PDE10A, there is a search for different PET radioligands for imaging PDE10A in the human brain in vivo, which could lead to a better understanding of its role in the diseases," she explained. In this study, ¹¹C-IMA107 was used "to demonstrate the important role of PDE10A in the pathophysiology of Parkinson's disease," she added.

Dr Niccolini and Dr Gil have disclosed no relevant financial relationships.

Society of Nuclear Medicine and Molecular Imaging (SNMMI) 2015 Annual Meeting: Abstract 32. Presented June 7, 2015.

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