Huntington disease is characterized by difficulties in movement and thinking. Psychological disturbances including irritability, aggression, loss of interest, depressed mood, obsessions and compulsions, also represent common symptoms of HD. These symptoms are distressing both for HD patients and their caregivers, contribute to the loss of ability to carry out activities of daily living, and present a major treatment challenge for physicians. The goal of this study is to determine the effect of memantine on movement, thinking and emotional difficulties in HD patients. Memantine is a medication originally approved for the treatment of aggression and agitation in patients with moderate-to-severe Alzheimer's disease (AD), which has also recently been shown to improve the behavioural and neuropathological symptoms in a mouse model of Huntington Disease (HD).

TRACK-HD was a multi-centre, multi-national, prospective, observational study of pre-manifest and early Huntington's disease (HD) with a control group of volunteers not carrying the HD mutation. The goal of the project was to contribute essential methodology that will form the basis for clinical trials in pre-manifest and early HD. TRACK-HD complemented existing observational studies (e.g., Predict-HD, PHAROS, COHORT), sharing some features, but also having areas of unique emphasis.

The UBC site recruited 90 subjects including 30 control subjects, 30 asymptomatic pre-manifest HD gene carriers and 30 subjects with early symptoms of HD (stage 1 or 2). All subjects were assessed using the TRACK-HD battery at baseline, 1 year, 2 years, and 3 years. Following the fourth visit (3 year assessment), the TRACK-HD study will be completed, and the 30 subjects with early symptoms of HD will be invited to enroll in the MITIGATE-HD Study.

The MITIGATE-HD study is a single center Phase IIb,out-patient,randomized, double-blind, placebo-controlled trial of memantine treatment in subjects with Huntington disease (HD). The study will evaluate Memantine 10 mg two times daily (BID) administered orally (PO) for six months (24 weeks) compared with matching placebo BID. Safety and tolerability will be assessed by recording of adverse events and by monitoring of vital signs, physical examinations, and suicidality risk scores.

The TRACK-HD assessment battery will be administered to all subjects after six months of study drug administration. The effects of memantine will be evaluated both against placebo as well as compared to the previous 3 years of observational data from the TRACK-HD Study.

Inclusion Criteria:

To be eligible for the study, a subject must be enrolled in the early HD cohort of the TRACK-HD study and:

• be at least 18 years of age and not older than 65
• able to provide written consent
• carry the abnormal HD gene and show early symptoms of HD
• be able and willing to comply with study requirements, including travel to study center
• have no metal implants to be suitable for MRI scans and able to tolerate them
• able to tolerate blood draws
• be of stable medical, psychiatric and neurological health at the time of enrollment
• not have a history of significant head injury
• not have a history of significant hand injury that would prevent either writing or performing rapid computer tasks
• not be abusing drugs and/or alcohol that may cause failure to comply with study procedures
• not be currently participating in PREDICT-HD or a clinical drug trial.

Exclusion Criteria:

Prospective subjects will be excluded if:

• they are younger than 18 years of age and older than 65
• they are unable to provide written consent
• they show advanced symptoms of HD if they are HD gene carriers
• they are unwilling to comply with study requirements, including travel to study center
• they are unsuitable for MRI (e.g, claustrophobia, metal implants) or unable to tolerate them
• they are unable to tolerate blood draws; or,
• they have a major psychiatric disorder, concomitant significant neurological disorder or concomitant significant medical illness at the time of enrollment
• they have a history of CNS disease or significant head injury; or,
• they have a history of significant hand injury that would prevent either writing or performing rapid computer tasks; or,
• they are likely to be non-compliant with study procedures due to drug and/or alcohol abuse; or,
• they are participating in PREDICT-HD or a clinical drug trial at the time of enrollment.
• they are not sighted
• English is not their first language
• they are currently or treated within the last 6 months with antipsychotic medications, including the traditional neuroleptics such as haloperidol as well as the atypical antipsychotics risperidone, clozapine, quetiapine and olanzapine
• they are use phenothiazine-derivative antiemetic medications such as prochlorperazine, metoclopramide, promethazine and Inapsine on a regular basis (greater than 3 times per month)
• they have a history of learning disability and/or mental retardation.