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

All participants will attend a screening and sampling visit. During the screening visit,
medical history, and clinical and phenotypic data will be obtained. Participants who meet the
eligibility requirements are willing to continue in the study, will return for a sampling
visit during which ≤20ml CSF and approximately 50ml blood will be collected following an
overnight fast: blood will be obtained via venipuncture and CSF will be obtained via lumbar
puncture using local anaesthetic if required. Approximately 120 participants (including 20
controls) will be invited to attend an optional repeat sampling visit 4-6 weeks after the
original sampling visit.

Inclusion Criteria:

1. All eligible participants

1. Are 21-75 years of age, inclusive; and

2. Are capable of providing informed consent or have a legal representative
authorized to give consent on behalf of the participant; and

3. Are capable of complying with study procedures, including fasting, blood sampling
and lumbar puncture; and

4. Are participating in the Enroll-HD study; and

5. Will have had an Enroll-HD visit within three months of the Sampling Visit.

2. For the Early 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) × age, < 250.

3. 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.

4. 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 ≥ 36; and

3. Have Stage I or Stage II HD, defined as UHDRS Total Functional Capacity (TFC)
scores between 7 and 13 inclusive.

5. 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 ≥ 36; and

3. Have Stage III HD, defined as UHDRS TFC scores between 4 and 6, inclusive.

6. 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 ≥ 36; and

3. Have Stage IV HD, defined as UHDRS TFC scores between 0 and 3, inclusive.

7. For the Healthy Control group, subjects eligible are persons who meet the following
criteria:

1. Have no known family history of HD; or

2. Have known family history of HD but have been tested for the huntingtin gene
glutamine codon (CAG) expansion and are not at genetic risk for HD (CAG < 36).

Exclusion Criteria:

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

1. Current 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 antidepressant, psychoactive, psychotropic or other medications or
nutraceuticals used to treat HD, the use of inappropriate (e.g., non-therapeutically
high) 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

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 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

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