Editors' ChoiceNeurodegenerative Disease

Measuring the cart before the horse: A new biomarker for Huntington’s disease

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Science Translational Medicine  05 Aug 2015:
Vol. 7, Issue 299, pp. 299ec134
DOI: 10.1126/scitranslmed.aac9321

Huntington’s disease (HD) causes fatal neurodegeneration, with gradual deterioration of motor, cognitive, and neuropsychiatric function—and no cure or therapy. Detection of disease prior to onset of symptoms could help accelerate drug development. To this end, Niccolini and colleagues have imaged the brains of presymptomatic HD patients and revealed alterations in phosphodiesterase 10A (PDE10A), an enzyme highly expressed in the striatum that has direct links to HD pathology.

The authors performed a prospective, cross-sectional association study comparing 12 individuals who carried the HD gene mutation with 12 age- and gender-matched healthy volunteers. The mutation carriers were clinically asymptomatic but on average had a 90% probability of developing symptoms 25 years later. PDE10A was imaged with positron emission tomography and a PDE10A-specific tracer in brain regions that were identified with multimodal magnetic resonance imaging. They found significant reductions in PDE10A levels in the caudate and globus pallidus, and increased levels in the motor thalamic nuclei. PDE10A was also decreased in sensorimotor cortico-striatal pathways and the striatal output tracts. Alterations in PDE10A occurred prior to any loss of neurons, as brain volumes were not different between HD and healthy volunteers. The presymptomatic PDE10A decreases seen here were consistent with similar changes in PDE10A reported previously in symptomatic HD patients; the increased PDE10A activity in the thalamic motor nuclei may be compensatory. Alterations in PDE10A activity were the only strong predictors of future HD symptomatic conversion.

The investigators conclude that both anatomical and functional alterations in PDE10A activity are found in presymptomatic HD gene carriers and that alterations in PDE10A function are an early, measureable in vivo pathological markers. These results will need to be validated in a longitudinal study, but because PDE10A levels may already be decreased early in HD, they suggest that currently proposed therapies designed to inhibit PDE10A function may not be beneficial.

F. Niccolini et al., Altered PDE10A expression detectable early before symptomatic onset in Huntington's disease. Brain 10.1093/brain/awv214 (2015).[Abstract]

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