New pharmacological options for treating advanced Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) affects about 1% of the over 60 population and is characterized by a combination of motor symptoms (rest tremor, bradykinesia, rigidity, postural instability, stooped posture and freezing of gait [FoG]) and non-motor symptoms (including psychiatric and cognitive disorders). Given that the loss of dopamine in the striatum is the main pathochemical hallmark of PD, pharmacological treatment of the disease has focused on restoring dopaminergic neurotransmission and thus improving motor symptoms. However, the currently licensed medications have several major limitations. Firstly, dopaminergic medications modulate all the key steps in dopamine transmission other than the most powerful determinant of extracellular dopamine levels: the activity of the presynaptic dopamine transporter. Secondly, other monoaminergic neurotransmission systems (ie noradrenergic, cholinergic and glutamatergic systems are altered in PD and may be involved in a variety of motor and non-motor symptoms. Thirdly, today's randomized clinical trials are primarily designed to assess the efficacy and safety of treatments for motor fluctuations and dyskinesia. Fourthly, there is a need for disease- modifying treatments (DMTs) that slow disease progression and reduce the occurrence of the very disabling disorders seen in late-stage PD.

OBJECTIVE: To systematically review a number of putative pharmacological options for treating the main impairments in late-stage PD (ie gait disorders, cognitive disorders and behavioural disorders such as apathy).

METHODS: We searched the PubMed database up until July 2013 with logical combinations of the following search terms: "Parkinson's disease", "gait", "cognition", "apathy", "advanced stage", "modulation", "noradrenergic", "cholinergic", "glutamatergic" and "neurotransmission".

RESULTS: In patients undergoing subthalamic nucleus stimulation, the potentiation of noradrenergic and dopaminergic transmission by methylphenidate improves gait and FoG and may relieve apathy. However, the drug failed to improve cognition in this population. Potentiation of the cholinergic system by acetylcholinesterase inhibitors (which are licensed for use in dementia) may reduce pre-dementia apathy and falls. Modulation of the glutamatergic system by an N-methyl-D-aspartate receptor antagonist did not improve gait and dementia but may have reduced axial rigidity. A number of putative DMTs have been reported.

DISCUSSION: Novel therapeutic strategies should seek to reduce the appearance of the very disabling disorders observed in late-stage PD. Dopamine and/or noradrenaline transporter inhibitors, anticholinesterase inhibitors, Peroxisome-proliferator-activated-receptor-agonists and iron chelators should at least be investigated as putative DMTs by applying a delayed-start clinical trial paradigm to a large population

CONCLUSIONS: There is a need for more randomized clinical trials of treatments for late-stage PD.