The goal of this trial is to evaluate the safety and tolerability of lithium in people with progressive supranuclear palsy or corticobasal degeneration.

Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are progressive, adult-onset neurodegenerative disorders characterized by the accumulation of hyperphosphorylated tau. Symptomatic treatment is of minimal benefit to individuals with PSP or CBD, and there are no effective disease modifying agents.

Tau phosphorylation is regulated in part by the enzyme GSK-3β (glycogen synthase kinase-3 beta ). Inhibition of this enzyme may benefit individuals with PSP or CBD by decreasing the levels of phosphorylated tau. Lithium is known to inhibit GSK-3β and, thus, may be a rational therapeutic approach.

The primary objective of this study is to determine the safety and tolerability of lithium in people with PSP or CBD. Additionally, this study will evaluate potential biomarkers and clinical outcome measures as well as assess study drug compliance.

In this multicenter, open label study, 45 eligible participants with PSP or CBD will receive the study drug, lithium. The dosage of lithium will be titrated over a 5-week period, and participants will then be followed prospectively for 6 months. Participants will be evaluated at the screening visit, baseline visit, and weeks 2 and 5 during the titration phase. Clinic study visits will then occur on alternate months through week 28. Telephone visits will occur between clinic study visits.

Inclusion Criteria:

1. Able to give informed consent

2. Able to comply with the study protocol, including ability to attend follow-up study visits for the duration of the study

3. Diagnosis of PSP or CBD based on the following criteria:

   1. Probable PSP:

      • Gradually progressive akinetic disorder
      • Unequivocal and prominent slowing of vertical saccades or vertical supranuclear gaze palsy
      • Early prominent postural instability or early falls
      • Poor or absent response to levodopa

   2. Probable CBD:

      • Chronic progressive course
      • Asymmetric onset
      • Presence of higher cortical dysfunction (apraxia, apraxia of speech, non-fluent aphasia, cortical sensory loss, or alien limb)
      • Movement disorder: rigid/akinetic syndrome resistant to levodopa and either dystonic limb posturing or focal myoclonus in limb (spontaneous or stimulus sensitive)

4. If psychotropic or anti-parkinsonian medications are taken (e.g., anxiolytics, hypnotics, benzodiazepines, antidepressants, levodopa, amantadine), the dosage must be stable for 28 days prior to the screening visit and should be maintained at constant dosages throughout the study, as possible

5. If NSAIDs, ACE-Is, ARBs, thiazide diuretics, COX-2 inhibitors or theophylline are taken by the subject, the dosage must be stable for 28 days prior to the screening visit and should be maintained at constant dosages throughout the study, as possible.

6. Creatinine clearance > 50 ml/min

7. Able to take oral medication

8. Women must not be able to become pregnant (e.g., post menopausal, surgically sterile or using adequate birth control methods for the duration of the study.)

9. Able to identify a study partner

Exclusion Criteria:

1. Evidence of other diseases that could explain the clinical presentation
2. History of known sensitivity or intolerability to lithium or to other known ingredients in the study drug
3. Exposure to any investigational agent within 28 days of the screening visit
4. Clinically significant cardiac disease or EKG findings
5. Other serious illness, including psychiatric illness ("serious illness" is defined as an illness that is unstable enough that it might jeopardize the subject's ability to complete the study)
6. Moderate to severe ongoing depression
7. Family history of "PSP" or "CBS"
8. Clinically significant abnormalities on the screening visit laboratory results
9. Any AE ≥ Grade 3 as listed on the CTCAE, version 3.0
10. Women who are pregnant or breastfeeding
11. History of brain surgery
12. Use of other potential GSK-3β inhibitors (e.g., valproic acid)
13. Use of iodide salts [e.g., calcium iodide, hydrogen iodide (hydriodic acid), iodide, iodinated glycerol (Organidin), iodine, potassium iodide (SSKI), and sodium iodide]
14. Previous use of lithium
15. Use of Coenzyme Q10 at a dosage greater than 600 mg a day or NanoQuinon at a dosage greater than 150mg a day or 2.5 mg/kg a day
16. Active psoriasis

The Publication Policy for the National Institute of Neurological Disorders and Stroke (NINDS) Pilot Therapeutic Trials Network (NPTUNE) outlines procedures for the development and review of concept sheets, abstracts, publications, presentations. Investigators must submit an application to the NPTUNE Publications Committee for the use of data. A Writing Committee, appointed by the Publications Committee, is responsible for initiating, coordinating, and approving publications and presentations.