This is a prospective investigation which aims to address key challenges to the design of clinical trials to prevent the onset of Huntington's disease (HD). The project will provide necessary psychometric data for clinical outcome assessments (COAs) and biomarkers (BMs) in the cerebral spinal fluid (CSF) to address questions of central importance to the success of these measures for premanifest clinical trials. Of the 258 participants: 52 will be low risk of motor diagnosis, 102 high risk of motor diagnosis, 52 with diagnosed HD (stages I or II), and 52 healthy controls. Participants can expect to be in the study for up to 2 years.

This is a prospective investigation which aims to address key challenges to the design of clinical trials to prevent the onset of Huntington's disease (HD). The project will provide necessary psychometric data for clinical outcome assessments (COAs) and biomarkers (BMs) in the cerebral spinal fluid (CSF) to address questions of central importance to the success of this measure for premanifest clinical trials such as:

1. How reliable the measure is in the same person when repeated over time;
2. how reliable the measure is in the same person when analyzed by two different labs/sites;
3. how well the measure reflects disease symptoms;
4. how well the measure predicts meaningful disease outcomes;
5. how well the measure tracks disease progression or severity; AND
6. how many research subjects are required to test that an intervention is delaying/slowing the onset of HD?

Answers to these questions will better position the field to more effectively test new interventions to prevent HD such as gene therapies and new drugs.

Neurocognitive, motor and behavioral data, blood, CSF, and genetic samples, and MRI measures will be collected from 258 participants at baseline. Of the 258 participants: 52 will be low risk of motor diagnosis, 102 high risk of motor diagnosis, 52 with diagnosed HD (stages I or II), and 52 healthy controls. Neurocognitive and behavioral data, blood and CSF samples, and MRI will be repeated 2 years (18-24 months) after the baseline visit. Remote assessments of clinical outcome measures (neurocognitive, motor and behavioral data) will be conducted as needed.

Specific Study Aims and Methods

Aim 1: To evaluate Clinical Outcome Assessments (COAs) currently being used in premanifest HD. In accordance with the FDA, all types of COAs (a) Clinician-reported; (b) Observer-reported; (c) Patient-reported; and (d) Performance-based outcomes will be evaluated as appropriate for each phenotypic domain (motor, cognitive, psychiatric/behavioral, functional activity, quality of life). Specific outcomes of this aim will follow those recommended by the FDA including:

• a) Cross-sectional evaluation (critical for sample selection) of currently used COA instruments according to the following recommended criteria: mode of administration; format and scoring criteria; content validity; internal consistency reliability; test-retest reliability; floor and ceiling effects; construct validity; convergent validity; and strength of each COA expressed in terms of effect sizes.
• b) Longitudinal evaluation (critical for endpoint selection and responsiveness) of each COA to detect change using effect sizes across the premanifest and early HD disease continuum with documentation of the responder definition(s) of construct validity.
• c) Identification and documentation of the context of use (COU) and concept of interest (COI) for clinical trials in premanifest HD to position available COAs within a preliminary conceptual model.

Aim 2: To assess the psychometric properties of various biomarkers obtained from cerebral spinal fluid when compared between groups (premanifest HD, HD, NC) and over time (baseline and 2 years). Specific outcomes of this aim will include:

• a) CSF mHTT collected at baseline and 2 years in 100 premanifest HD, 25 diagnosed HD, and 25 healthy controls (HC) will be analyzed (blind to gene status) by two independent labs. Safety, feasibility, cost efficiency, and inter-site reliability will be obtained.
• b) Validity of CSF mutant huntingtin (mHTT) will be examined in HD groups for association with cross-sectional and longitudinal (a) phenotypic severity and decline using measures of the primary triad of clinical manifestation and progression (motor, cognitive, psychiatric/behavioral); (b) meaningful clinical outcome measures such as diagnosis in premanifest subjects and patient-reported outcomes, functional capacity and disability in all HD patients; and (c) available disease burden measures calculated as the product of Cytosine-Adenine-Guanine (CAG) repeat length and current age (considered a reflection of genetic toxicity by time survived; AKA disease burden). The investigators hypothesize that the candidate biomarkers will show appropriate association reflecting concurrent and predictive validity (types of criterion-related validity) with the most widespread "benchmarks" of HD phenotype, the Unified HD Rating Scale in diagnosed and advanced prodromal HD. Data from this Aim will immediately inform the interpretation of ongoing clinical trials that show biomarker levels in "some", but not "all", premanifest. Although it is unknown whether the biomarkers will demonstrate any predictive validity or concurrent validity for the entire premanifest HD group, data will immediately be useful to develop an evidence threshold for when in the premanifest HD prodrome, the biomarker will be detectable and tracked over time. The evidence threshold is immediately useful to the design of disease modifying trials in HD, particularly when the paramount goal is to prevent diagnosis, or manifestation.
• c) Biological criterion-related validity for biomarkers will be examined in HD groups for association with (a) microglial biomarkers; (b) inflammatory biomarkers; (c) neuronal death biomarkers; and (d) mHTT HD-specific protein. The investigators hypothesize that mHTT will show detection at the earliest point in the prodrome, followed by microglial markers, then inflammatory markers and, finally, neuron death markers in diagnosed HD.

Inclusion Criteria for HD Participants:

• Estimated at low or high probability of motor diagnosis based on the multivariate risk score (MRS)
• Willing to commit to two in-person assessment visits (baseline and 2-year follow-up) and remote assessments as needed
• No active comorbidities (i.e. receiving stable treatment)
• All medications will be allowed although the protocol will mandate documentation of medications and analyses will particularly assess potential impact of medications on outcomes (i.e., sedation of abnormal movements)
• If previously measured, CAG results must be 36 or above (previous CAG is not a requirement, but this threshold will be upheld for those participants who have their CAG scores and/or have them in their medical record).

Inclusion Criteria for Healthy Controls (HC):

• Willing to commit to two in-person assessment visits (baseline and 2-year follow-up) and remote assessments as needed
• In generally good health
• IQ > 70
• Able to undergo an MRI scan

Exclusion Criteria (for all Participants):

• Evidence of unstable medical or psychiatric illness (including substance abuse)
• History of severe learning disability, mental retardation, or other central nervous system (CNS) disease or event (e.g., seizures, head trauma, additional neurological diagnoses)
• Treatment with phenothiazine-derivative antiemetic medications such as prochlorperazine, metoclopramide, promethazine and Inapsine greater than 3 times per month
• History of serious alcohol or drug abuse within the past year
• Unable (determined by patient's prescribing doctor) to not take tryptophan, leucine, niacin or niacinamide-containing dietary supplements, anti-inflammatory medications, anti-coagulants (such as warfarin and heparin) or anti-platelets (such as aspirin) in the past 14 days to assure safety during lumbar puncture
• Unable to fast (no food or drink, only water) overnight before the lumbar puncture

At baseline 258 male and female participants between the ages of 18 and 80 years will be enrolled in the study. Of the 258: 52 will be low risk of motor diagnosis, 102 high risk of motor diagnosis, 52 with diagnosed HD (stages I or II), and 52 age-, ethnicity-, and education-matched healthy controls.

All clinical research data collected as part of this study is also stored in the NIH database for genotype and phenotypes (dbGaP) and the NIH National Data Archives for sharing with approved researchers worldwide. dbGaP provides two levels of access - open and controlled - in order to allow broad release of non-sensitive data, while providing oversight and investigator accountability for sensitive data sets involving personal health information. Summaries of studies and the contents of measured variables as well as original study document text are generally available to the public, while access to individual-level data including phenotypic data tables and genotypes require varying levels of authorization.

conclusion of study

institutional certificate of professional degree