IMarkHD: in Vivo Longitudinal Imaging of HD Pathology

Inclusion Criteria: PwHDs and HC participants: * Female and male adults, aged 21-75 years old, inclusive. * Adequate visual (Snellen chart) and auditory (Rinne and Weber tests) acuity to complete the psychological testing as determined by the investigator. * Capable of giving informed consent. * Willing to comply with highly effective contraceptive measures following informed consent (for Cohort 2 only). * Vital signs within certain set ranges. * Considered by the investigator to be in good health as judged by the absence of clinically significant diseases, laboratory values, physical examination, and able to travel to imaging and clinical assessment centers in London, UK. * Suitable physically and psychologically to travel (with a companion if requested) and undergo the assessments as judged by the investigator. PwHDs without symptoms: (approximately HD-ISS stage 0 or 1) * HDGECs with ≥ 40 CAG repeats * TMS ≤ 6 AND TFC ≥ 12 AND CAP \> 70 PwHDs with symptoms in early disease: (approximately HD-ISS stage 2) * HDGECs with ≥ 40 CAG repeats * If one of the following criteria is met: 1. TMS ≤ 6 AND TFC = 11 2. TMS is between 7 and 23 inclusive AND TFC is between 11 and 13 inclusive 3. TMS is between 24 and 33 inclusive AND SDMT \> 50 AND TFC is between 11 and 13 inclusive PwHDs with symptoms in late disease (approximately HD-ISS stage 3) * HDGECs with ≥ 40 CAG repeats * If one of the following criteria is met: 1. TMS ≤ 6 AND TFC is between 7 and 10 inclusive 2. TMS is between 7 and 23 inclusive AND TFC is between 8 and 10 inclusive 3. TMS is between 24 and 33 inclusive AND SDMT \> 50 AND TFC is between 7 and 10 inclusive 4. TMS is between 7 and 23 inclusive AND TFC = 7 5. TMS \> 23 AND SDMT ≤ 50 AND TFC is between 7 and 13 inclusive 6. TMS \> 33 AND SDMT \> 50 AND TFC is between 7 and 13 inclusive Healthy Controls (HC): * Age- and sex-matched, and balanced (±8 years) with PwHDs. * No known family history of HD or 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: PwHD and HC participants: * Presence or history of other neurological condition (including brain surgery, intracranial hematoma, stroke/cerebrovascular disorders, demyelinating conditions, epilepsy) likely to interfere with imaging or PET studies or abnormal neurologic examination finding suggestive of a central nervous system pathology (for PwHDs - other than HD). * Presence or history of primary psychiatric disorders unrelated to HD. * Participants using any medications with known actions on cannabinoid type 1 receptors (CB1R), phosphodiesterase 10A (PDE-10A), 5-hydroxytryptamine-2A receptor (5-HT2AR), histamine type-3 receptors (H3R), or any other PET targets used in iMarkHD. * Pregnancy confirmed by a positive urine pregnancy test. * Participants who are currently breastfeeding or intend to breastfeed during the study. * Contraindication to MRI, such as presence of metal devices or implants (e.g. pacemaker, vascular- or heart- valves, stents, clips), metal deposited in the body (e.g. bullets or shells), or metal grains in the eyes. * History of alcoholism or substance abuse within 3 years prior to study entry. * Failure of drug screen for substances of abuse such as amphetamines, barbiturates, benzodiazepines, methadone, opiates, cocaine, cannabinoids, phencyclidine, and creatine. * History of cancer. * Claustrophobia. * Significant back pain that makes prolonged laying on the PET or MRI scanner intolerable. * Contraindication for arterial cannulation as judged by the Allen test and the laboratory blood screening for coagulopathy (Cohort 2 only). * Inability to communicate or cooperate with the principal investigator/iMarkHD team for any reason. * Participants who are currently enrolled in or participated in clinical trials testing the efficacy of novel therapeutics with action on the specific PET targets being tested within 3 months of screening. * Any concurrent conditions that could interfere with the safety and/or tolerability measurements.