HDClarity will seek at least 2500 research participants at different stages of Huntington's disease (HD). The primary objective is to collect a high quality CSF sample for evaluation of biomarkers and pathways that will enable the development of novel treatments for HD. The secondary objective is to generate a high quality plasma sample collection matching the CSF collections, which will also be used to evaluate biomarkers and pathways of relevance to HD research and development.

This is a longitudinal open-ended observational study. Participants will attend two annual study visits, an Annual Screening Visit followed by an Annual Sampling Visit, and may also attend an optional visit during the first year of enrollment, an Optional Repeat Sampling Visit.

During the Annual Screening Visit, medical history, and clinical and phenotypic data will be obtained. Participants who meet the eligibility requirements of the study and are willing to continue in the study, will return for an Annual Sampling Visit. During that visit, biosamples will be collected following a fast of at least 6 hours, or overnight: blood will be obtained via venipuncture and CSF will be obtained via lumbar puncture. Some participants may be invited to return for an Optional Repeat Sampling Visit approximately 4-8 weeks after the Annual Sampling Visit during their first year of enrolment.

The annual visits are at regular intervals after the first Annual Screening Visit (i.e. at 1, 2, 3 years and so on) ± 2 months. Participants will be encouraged to complete all annual visits; however, they are under no obligation to take part and will be able to skip annual visit without being discontinued from the study. Participants who do not come for an Annual Sampling Visit for three consecutive years will be discontinued from the study, but they may enrol again at a later date, if they so consent. Participants who have already completed HDClarity Sampling Visits under earlier versions of this protocol may also participate in the longitudinal study if they meet the eligibility criteria.

Inclusion Criteria:

• Age (18-75 years controls, early/late premanifest HD and incomplete penetrance HD, 21-75 years early/moderate/advanced manifest HD, ≥11 years juvenile HD)
• Enroll HD participant
• Capable of consenting or have a legal representative (parent/guardian for juveniles)
• Capable of complying with study procedures
• All participants other than family and community controls must have had a genetic test for HD

Exclusion Criteria:

• Drug trial within 30 days of any sampling visit
• Changes in medication (antidepressant, psychoactive, psychotropic or other medications or nutraceuticals used to treat HD within 30 days)
• Antiplatelet or anticoagulant therapy within 14 days
• Significant comorbidity
• Needle phobia, headache, spinal surgery / deformity
• Clotting or bruising disorder
• Screening blood test abnormalities >10% outside normal range
• Drug / alcohol abuse
• Positive urine pregnancy test at any screening or sampling visit for females of childbearing potential
• Predictable non compliance or unwillingness
• Serious adverse event related to HDClarity study procedures or any lumbar puncture procedure performed for any reason in the previous 30 days

Participants across 8 clinical cohorts will be enrolled at multiple sites up to an estimated minimum of 2500 participants or until the study is terminated by either the Funding Source or Sponsor

The cerebrospinal fluid (CSF) and plasma samples collected in this study will be the basis of future biomarker analysis studies. A Scientific Advisory Committee which will decide how the samples will be analysed.