Effects of Lithium Therapy on Blood-based Therapeutic Targets in Parkinson's Disease.
Condition: Parkinson Disease
MeSH terms: Parkinson Disease
Study type: Interventional
Phase: Phase 1

Summary: 
      This study aims to determine if one of three low doses of lithium therapy for 6 months can
      engage one or more blood-based therapeutic targets implicated in Parkinson's disease (PD)
      pathophysiology. Results of this study will help to determine if lithium therapy is
      worthwhile to further investigate as a potential disease-modifying therapy in PD, the optimal
      dose to study and the optimal PD subgroup most likely to benefit from lithium therapy.
    

Detailed description: 
      Lithium belongs to a class of kinase-targeting therapies, including the diabetes medication
      exenatide and the cancer medication nilotinib, that have demonstrated promise as
      disease-modifying therapies for Parkinson's disease (PD). Exenatide was recently shown to
      engage protein kinase B (Akt) and provide significant symptomatic and possible
      disease-modifying benefit in PD in a phase 2 randomized controlled trial (RCT). Nilotinib
      engages c-Abelson kinase (c-Abl) and its disease-modifying effects are currently being
      investigated in two, phase 2 PD RCTs. Lithium targets Akt, glycogen synthase kinase-3 beta
      (GSK-3B, a downstream target of Akt) and cyclin-dependent kinase 5 (cdk5, a downstream target
      of c-Abl) in manners that recapitulate those of exenatide and nilotinib. Also, lithium
      inhibits inositol monophosphate leading to enhanced autophagy and reduced intracellular
      levels of alpha-synuclein (a-synuclein), which is believed to be a primary mediator of the
      progressive neurodegeneration in PD. In addition to a-synuclein, genome-wide association
      studies (GWAS) have implicated oligomeric tau in the pathogenesis of PD. Pathological
      mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of a
      late-onset parkinsonism that is clinically indistinguishable from sporadic PD and very
      similar pathologically. Pathological LRRK2 mutations affect the activities of Akt, GSK-3B and
      cdk5 to greatly increase the formation of phosphorylated tau (p-tau) - the precursor to tau
      oligomer formation - and decrease the activity of the transcriptional cofactor B-catenin -
      which mediates the transcription of neuronal survival genes implicated in PD such as nuclear
      receptor related 1 (Nurr1). Through its ability to inhibit GSK-3B, lithium can enhance
      B-catenin-mediated activity and Nurr1 expression. Lithium was also effective in several PD
      animal models. Finally, both clinical trial and epidemiologic data suggest that lithium
      exposures of even <1mg a day may provide significant disease-modifying effects in
      neurodegenerative diseases including PD.

      The investigators propose to assess the effects of 3 lithium dosages for 6 months on the
      above targets measured in blood in a randomized, parallel design, proof of concept clinical
      trial among 18 PD patients. In addition, 2 PD patients will serve as controls and not receive
      lithium therapy.
    

Intervention name(s): Lithium
Intervention type(s): Drug
Intervention description(s): Lithium aspartate of lithium carbonate will be administered by mouth.
Intervention MeSH terms: Lithium Carbonate
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Randomized, parallel group, open-label trial
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Lithium; Alpha-synuclein