title: New pharmacological options for treating advanced Parkinson's disease.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Medical Pharmacology, EA 1046, Lille Nord de France University, Lille, France. Electronic address: david.devos@chru-lille.fr.
authors.forename: David
authors.initials: D
authors.lastname: Devos
authors.forename: Caroline
authors.initials: C
authors.lastname: Moreau
authors.forename: Kathy
authors.initials: K
authors.lastname: Dujardin
authors.forename: Ioav
authors.initials: I
authors.lastname: Cabantchik
authors.forename: Luc
authors.initials: L
authors.lastname: Defebvre
authors.forename: Regis
authors.initials: R
authors.lastname: Bordet
mesh_terms: D057565:Apathy / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D046690:Deep Brain Stimulation; D050483:Dopamine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D018765:Dopamine Uptake Inhibitors / Q000627:therapeutic use; D055808:Drug Discovery; D005684:Gait / Q000187:drug effects; D006801:Humans; D007502:Iron Chelating Agents / Q000627:therapeutic use; D008774:Methylphenidate / Q000627:therapeutic use*; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D010300:Parkinson Disease / Q000188:drug therapy / Q000628:therapy*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*
chemical_list: D002800:Cholinesterase Inhibitors; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D007502:Iron Chelating Agents; D050484:Norepinephrine Plasma Membrane Transport Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D008774:Methylphenidate
keywords: apathy; cognition; dementia; disease-modifying treatment; gait; non-dopaminergic treatment