Towards a Novel Treatment of Huntington´s Disease

Sammanfattning: The function of the human brain is based on complex interactions between billions of neurons. The brain function declines as a result of normal aging, but is also disturbed in neuropsychiatric and neurodegenerative disorders. Huntington’s disease is a hereditary autosomal-dominant neurodegenerative disorder that manifests with a complex range of symptoms resulting in severe motor deficiencies, cognitive decline, behavioral disturbances, and premature death. To date, no preventive, disease-modifying, or even symptomatic therapy exists. Normal function of the brain is maintained by different neurotransmitters, which act through their receptors. One such example is the monoamine neurotransmitter dopamine, which plays a central role in normal brain function. The dopamine system is involved in a wide range of functions such as motor function, reward, cognition and emotion, and is importantly connected to the modulation of glutamate functions in the brain. There is evidence that dopaminergic systems are disturbed in Huntington’s disease, and that the delicate balance between dopamine and glutamate interplay is disrupted in the disorder. Dopaminergic stabilizers belong to a novel class of CNS compounds that can both enhance and counteract psychomotor activity depending on the initial level. Such effects are believed to be mediated by state dependent modulation of monoaminergic and glutamatergic functions. One such compound, pridopidine (ACR16), is currently in development for the treatment of Huntington’s disease. The aim of this thesis was to better understand the physiopharmacology of dopaminergic stabilizers and to investigate their effects in healthy subjects and patients with Huntington’s disease. To explore the possibilities for this therapy in Huntington’s disease, three experimental studies using positron emission tomography were undertaken. These studies yielded a number of findings. It could be shown that the extrastriatal density of dopamine D2 receptors is well preserved in patients with Huntington’s disease. This finding has implications for pridopidine therapy since the D2 receptor is believed to be the primary target receptor for the compound. In addition, it was shown that in patients with Huntington’s disease, pridopidine treatment induced general state dependent changes in cerebral metabolic activity, and increases in cerebral metabolic activity in brain regions believed to be important for mediating compensatory mechanisms in the disorder. In another study elucidating the mechanisms of action of dopaminergic stabilizers in healthy subjects, it could be shown that a single dose of the compound produced modest reductions in the availability of striatal dopamine D2 receptors, and more marked fluctuations in the availability of cortical and striatal dopamine D1 receptors. The results from this mechanistic study suggest that dopaminergic stabilizers exert their glutamate modulating properties via indirect effects of dopamine D1 receptors. Moreover, in the framework of this thesis, an overview of available imaging biomarkers to study the progression of Huntington’s disease is presented, providing guidance for methods to be applied in studies aimed at modifying disease progression