HDClarity: a Multi-site Cerebrospinal Fluid Collection Initiative to Facilitate Therapeutic Development for Huntington's Disease (HDClarity)

Inclusion Criteria:

1. All eligible participants:

   a. Are 21-75 years of age, inclusive; and b. Are capable of providing informed consent or have a legal representative authorized to give consent on behalf of the participant; and c. Are capable of complying with study procedures, including fasting, blood sampling and lumbar puncture; and d. Are participating in the Enroll-HD study; and e. Will have had an Enroll-HD visit within two months of the Screening Visit.

2. For the Healthy Control group, participants eligible are persons who meet the following criteria:

   a. Have no known family history of HD; or b. Have known family history of HD but have been tested for the huntingtin gene CAG expansion and are not at genetic risk for HD (CAG < 36).

3. For the Early Pre-manifest HD group, participants eligible are persons who meet the following criteria:

   a. Do not have clinical diagnostic motor features of HD, defined as Unified Huntington's Disease Rating Scale (UHDRS) Diagnostic Confidence Score < 4; and b. Have CAG expansion ≥ 40; and c. Have burden of pathology score, computed as (CAG - 35.5) × age, < 250.

4. For the Late Pre-manifest HD group, participants eligible are persons who meet the following criteria:

   1. Do not have clinical diagnostic motor features of HD, defined as Unified Huntington's Disease Rating Scale (UHDRS) Diagnostic Confidence Score < 4; and
   2. Have CAG expansion ≥ 40; and
   3. Have burden of pathology score, computed as (CAG - 35.5) x age, ≥ 250.

5. For Early Manifest HD group, participants eligible are persons who meet the following criteria:

   1. Have clinical diagnostic motor features of HD, defined as UHDRS Diagnostic Confidence Score = 4; and
   2. Have CAG expansion ≥ 40; and
   3. Have Stage I or Stage II HD, defined as UHDRS Total Functional Capacity (TFC) scores between 7 and 13 inclusive.

6. For Moderate Manifest HD group, participants eligible are persons who meet the following criteria:

   1. Have clinical diagnostic motor features of HD, defined as UHDRS Diagnostic Confidence Score = 4; and
   2. Have CAG expansion ≥ 40; and
   3. Have Stage III HD, defined as UHDRS TFC scores between 3 and 6, inclusive.

7. For Advanced Manifest HD group, participants eligible are persons who meet the following criteria:

   1. Have clinical diagnostic motor features of HD, defined as UHDRS Diagnostic Confidence Score = 4; and
   2. Have CAG expansion ≥ 40; and
   3. Have Stage IV HD, defined as UHDRS TFC scores between 0 and 2, inclusive.

Exclusion Criteria:

1. For all groups, participants are ineligible if they meet any of the following exclusion criteria:

1. Use of investigational drugs or participation in a clinical drug trial within 30 days prior to Sampling Visit; or
2. Current intoxication, drug or alcohol abuse or dependence; or
3. If using any medications or nutraceuticals, the use of inappropriate (e.g., non prescribed) or unstable dose within 30 days prior to Sampling Visit; or
4. Significant medical, neurological or psychiatric co-morbidity likely, in the judgment of the Site Principal Investigator, to impair participant's ability to complete study procedures, or likely to reduce the utility of the samples and data for the study of HD; or
5. Needle phobia, frequent headache, significant lower spinal deformity or major surgery; or
6. Antiplatelet or anticoagulant therapy within the 14 days prior to Sampling Visit, including but not limited to: aspirin, clopidogrel, dipyridamole, warfarin, dabigatran, rivaroxaban and apixaban; or
7. Clotting or bruising disorder; or
8. Screening blood test results more than 10% outside the lab's normal range for the following: white cell count, neutrophil count, lymphocyte count, hemoglobin (Hb), platelets, prothrombin time (PT) and activated partial thromboplastin time (APTT), or any combination of blood test results that the Site Principal Investigator deems to be of clinical significance; or
9. Screening blood test results for C-reactive protein (CRP)>2× upper limit of normal; or
10. Predictable non-compliance as assessed by Site Principal Investigator; or
11. Inability or unwillingness to undertake any of the study procedures; or
12. Exclusion during history or physical examination, final decision to be made by the Site Principal Investigator; including but not limited to:

i. any reason to suspect abnormal bleeding tendency, e.g. easy bruising, petechial rash; or ii. any reason to suspect new focal neurological lesion, e.g. new headache, optic disc swelling, asymmetric focal long tract signs; or iii. any other reason that, in the clinical judgment of the Site Principal Investigator, it is felt that lumbar puncture performed per this protocol and associated manuals is unsafe without brain imaging.

m. Serious Adverse Event (SAE) related to study procedures during or following any previous HDClarity Sampling Visit (if applicable), or SAE related to any other lumbar puncture in the previous 12 months.