Huntington's Disease Biomarkers Research Articles

Optical Coherence Tomography in Huntington's Disease-A Potential Future Biomarker for Neurodegeneration?

Huntington's disease (HD) is a progressive neurodegenerative disorder for which, until now, only symptomatic treatment has been available. Lately, there have been multiple ongoing clinical trials targeting therapeutic agents for preventing disease onset or slowing disease progression in HD. These studies are in constant need of reliable biomarkers for neurodegeneration in HD. In recent years, retinal biomarkers have attracted significant attention in neurodegenerative disorders. Likewise, optical coherence tomography (OCT) is being evaluated as a potential biomarker in HD. In this article, we review the existing literature on OCT as a biomarker for neurodegeneration in HD.

Interplay between Sex and Disease Burden in Huntington's Disease: Clinical and Neuroimaging Perspectives.

Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a cytosine-adenine-guanine (CAG) repeat expansion in the hungtintin gene. The disease exhibits sex-related differences in symptomatology and disease progression, but the effect on brain structural biomarkers and the interaction between sex and disease burden remain underexplored. To investigate the interplay between sex and disease burden on clinical measures and neuroimaging biomarkers in HD. We retrospectively analyzed data from Enroll-HD, TRACK-HD/ON, PREDICT-HD, and IMAGE-HD studies, including a combined dataset of 19,738 participants with CAG>=40. Linear mixed models were employed to evaluate the influence of sex and the sex-disease burden interaction on clinical evaluations (Unified Huntington's Disease Rating Scale and Problem Behaviors Assessment) and neuroimaging biomarkers (striatal volumes and cortical thickness), with CAG-Age Product Score (CAPS) used as a proxy for disease burden, while controlling for covariates. Female participants exhibited less pronounced striatal atrophy and cortical thinning with increasing CAPS (caudate: β male/female =-3.462/-2.935, p<0.05; putamen: β male/female =-4.775/-3.908, p<0.01). Regarding clinical measures, females experience greater motor decline with increasing CAPS (Total Motor Score: β male/female =3.024/3.244, p<0.0001), greater cognitive decline (Symbol Digit Modalities Test : β male/female =-34.89/-38.91, p<0.0001), and greater functional decline (Total Functional Capacity: β male/female =-6.449/-6.817, p<0.05; Independence Scale: β male/female =-32.44/- 34.99, p<0.001). The sex-CAPS interaction significantly impacts both clinical and neuroimaging biomarkers of HD, underscoring the importance of incorporating sex-specific considerations into the clinical staging and management of HD.

Glymphatic influx and clearance are perturbed in Huntington's disease.

The accumulation of mutant huntingtin protein aggregates in neurons is a pathological hallmark of Huntington's disease (HD). The glymphatic system, a brain-wide perivascular network, facilitates the exchange of interstitial fluid and cerebrospinal fluid (CSF), supporting interstitial solute clearance of brain wastes. In this study, we employed dynamic glucose-enhanced (DGE) MRI to measure d-glucose clearance from CSF as a tool to predict glymphatic function in a mouse model of HD. We found significantly diminished CSF clearance efficiency in HD mice before phenotypic onset. The impairment of CSF clearance efficiency worsened with disease progression. These DGE MRI findings in compromised glymphatic function were further verified with fluorescence-based imaging of CSF tracer influx, suggesting an impaired glymphatic function in premanifest HD. Moreover, expression of the astroglial water channel aquaporin-4 in the perivascular compartment, a key mediator of glymphatic function, was significantly diminished in both HD mouse brain and human HD brain. Our data, acquired using a clinically translatable MRI, indicate a perturbed glymphatic network in the HD brain. Further validation of these findings in clinical studies will provide insights into the potential of glymphatic clearance as a therapeutic target as well as an early biomarker in HD.

Elevated plasma and CSF neurofilament light chain concentrations are stabilized in response to mutant huntingtin lowering in the brains of Huntington’s disease mice

BackgroundTherapeutic approaches aimed at lowering toxic mutant huntingtin (mHTT) levels in the brain can reverse disease phenotypes in animal models of Huntington's disease (HD) and are currently being evaluated in clinical trials. Sensitive and dynamic response biomarkers are needed to assess the efficacy of such candidate therapies. Neurofilament light chain (NfL) is a biomarker of neurodegeneration that increases in cerebrospinal fluid (CSF) and blood with progression of HD. However, it remains unknown whether NfL in biofluids could serve as a response biomarker for assessing the efficacy of disease-modifying therapies for HD.MethodsLongitudinal plasma and cross-sectional CSF samples were collected from the YAC128 transgenic mouse model of HD and wild-type (WT) littermate control mice throughout the natural history of disease. Additionally, biofluids were collected from YAC128 mice following intracerebroventricular administration of an antisense oligonucleotide (ASO) targeting the mutant HTT transgene (HTT ASO), at ages both before and after the onset of disease phenotypes. NfL concentrations in plasma and CSF were quantified using ultrasensitive single-molecule array technology.ResultsPlasma and CSF NfL concentrations were significantly elevated in YAC128 compared to WT littermate control mice from 9 months of age. Treatment of YAC128 mice with either 15 or 50 µg HTT ASO resulted in a dose-dependent, allele-selective reduction of mHTT throughout the brain at a 3-month interval, which was sustained with high-dose HTT ASO treatment for up to 6 months. Lowering of brain mHTT prior to the onset of regional brain atrophy and HD-like motor deficits in this model had minimal effect on plasma NfL at either dose, but led to a dose-dependent reduction of CSF NfL. In contrast, initiating mHTT lowering in the brain after the onset of neuropathological and behavioural phenotypes in YAC128 mice resulted in a dose-dependent stabilization of NfL increases in both plasma and CSF.ConclusionsOur data provide evidence that the response of NfL in biofluids is influenced by the magnitude of mHTT lowering in the brain and the timing of intervention, suggesting that NfL may serve as a promising exploratory response biomarker for HD.

Differential microRNA expression in the SH-SY5Y human cell model as potential biomarkers for Huntington's disease.

Huntington's disease (HD) is caused by an expansion of CAG trinucleotide repeat in the HTT gene; the exact pathogenesis of HD currently remains unclear. One of the promising directions in the study of HDs is to determine the molecular mechanism underlying the development and role of microRNAs (miRNAs). This study aimed to identify the profile of miRNAs in an HD human cell line model as diagnostic biomarkers for HD. To study HD, the human SH-SY5Y HD cell model is based on the expression of two different forms: pEGFP-Q23 and pEGFP-Q74 of HTT. The expression of Htt protein was confirmed using aggregation assays combined with immunofluorescence and Western blotting methods. miRNA levels were measured in SH-SY5Y neuronal cell model samples stably expressing Q23 and Q74 using the extraction-free HTG EdgeSeq protocol. A total of 2083 miRNAs were detected, and 354 (top 18 miRNAs) miRNAs were significantly differentially expressed (DE) (p < 0.05) in Q23 and Q74 cell lines. A majority of the miRNAs were downregulated in the HD cell model. Moreover, we revealed that six DE miRNAs target seven genes (ATN1, GEMIN4, EFNA5, CSMD2, CREBBP, ATXN1, and B3GNT) that play important roles in neurodegenerative disorders and showed significant expression differences in mutant Htt (Q74) when compared to wild-type Htt (Q23) using RT-qPCR (p < 0.05 and 0.01). We demonstrated the most important DE miRNA-mRNA profiles, interaction binding sites, and their related pathways in HD using experimental and bioinformatics methods. This will allow the development of novel diagnostic strategies and provide alternative therapeutic routes for treating HD.

Dark Adaptometry and Optical Coherence Tomography Angiography in Huntington Disease.

Huntington's Disease (HD) is a fully penetrant neurodegenerative disease leading to cognitive and motor disturbances. The retina may serve as a structural and functional extension of the central nervous system to identify biomarkers of HD using noninvasive imaging technology such as optical coherence tomography angiography (OCTA) and dark adaptometry. This case-control study included 12 HD participants (24 eyes) recruited from the Huntington's Disease Society of America Center of Excellence at Washington University in St. Louis along with 16 control participants (31 eyes). Disease-positive participants underwent imaging testing of retinal capillary density and foveal avascular zone utilizing OCTA along with dark adaptometry testing. Data were collected from November 2020 to February 2022. Individuals with HD had a lower mean age-adjusted superficial foveal capillary density and a higher mean deep foveal capillary density compared to control subjects. There was no significant difference in the mean foveal avascular zone or in dark adaptometry testing between the two groups. This study suggests that changes in retinal biomarkers may exist in patients with HD and that additional investigations using multimodal techniques are warranted.

No optical coherence tomography changes in premanifest Huntington's disease mutation carriers far from disease onset

BackgroundSpectral‐domain optical coherence tomography (OCT) may detect retinal changes as a biomarker in neurodegenerative diseases like manifest Huntington's disease (HD). We investigate macular retinal layer thicknesses in a premanifest HD (pre‐HD) cohort and healthy controls (HC).MethodsPre‐HD mutation carriers underwent standardized ratings and a preset macular OCT scan. Thickness values were determined for each sector of all macular retinal layers, the mean of all sectors and the mean of the inner ring (IR, 3 mm) after segmentation (Heyex segmentation batch). HC were retrospectively included from an existing database. The IR thickness of the ganglion cell layer (GCL), retinal nerve fiber layer (RNFL), GCL + inner plexiform layer (GCIPL), and total retina were included in the exploratory correlation analyses with paraclinical ratings and compared to HC.ResultsThe analyses comprised n = 24 pre‐HD participants (n = 10 male, n = 14 female) and n = 38 HC (n = 14 male, n = 24 female). Retinal layer parameters did not correlate with paraclinical ratings. Expected correlations between established HD biomarkers were robust. The IR thicknesses of the GCL, GCIPL, and total retina did not differ between pre‐HD and HC. The IR thickness of the RNFL was significantly higher in pre‐HD participants (pre‐HD: 23.22 μm (standard deviation 2.91), HC: 21.26 μm (1.90), p = .002).DiscussionIn this cross‐sectional cohort of genetically determined pre‐HD participants, neurodegenerative features were not detected with retinal layer segmentation. Since our pre‐HD collective was more than 16 years before disease onset, OCT may not be sensitive enough to detect early changes.

Disordered Decision Making: A Cognitive Framework for Apathy and Impulsivity in Huntington's Disease.

A caregiver's all‐too‐familiar narrative ‐ “He doesn't think through what he does, but mostly he does nothing.” Apathy and impulsivity, debilitating and poorly understood, commonly co‐occur in Huntington's disease (HD). HD is a neurodegenerative disease with manifestations bridging clinical neurology and psychiatry. In addition to movement and cognitive symptoms, neurobehavioral disturbances, particularly apathy and impulsivity, are prevalent features of HD, occurring early in the disease course, often worsening with disease progression, and substantially reducing quality of life. Treatments remain limited, in part because of limited mechanistic understanding of these behavioral disturbances. However, emerging work within the field of decision‐making neuroscience and beyond points to common neurobiological mechanisms underpinning these seemingly disparate problems. These insights bridge the gap between underlying disease pathology and clinical phenotype, offering new treatment strategies, novel behavioral and physiological biomarkers of HD, and deeper understanding of human behavior. In this review, we apply the neurobiological framework of cost‐benefit decision making to the problems of apathy and impulsivity in HD. Through this decision‐making lens, we develop a mechanistic model that elucidates the occurrence of these behavioral disturbances and points to potential treatment strategies and crucial research priorities. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.

Validation of biomarkers in Huntington disease to support the development of disease-modifying therapies: A systematic review and critical appraisal scheme

BackgroundThere are promising novel genetic-based therapies under development intended to modify the disease trajectory in Huntington disease (HD). Valid biomarkers that can facilitate the development of such disease-modifying therapies are urgently needed. There are currently no studies that appraise the quality of research for validation of biomarkers in HD. ObjectiveTo review studies for disease progression biomarkers in HD and evaluate their methodological quality. MethodsA systematic review of all HD biomarker studies up to June 2020 was conducted. Each study was assessed for methodological quality using a 24-item standardized checklist. We completed a subgroup analyses based on year of publication and biomarker type. ResultsWe included 218 HD biomarker studies, 76 (34.9%) were longitudinal and 161 (74%) included premanifest HD. On average, 10 ± 3 items (out of 24) were rated as good quality. The items more commonly rated as poor quality were: reporting of validity and reliability of assessments, sampling method, report of adverse events associated with the biomarker test, power calculation and appropriateness of study enrolment. Publications from 2016 to 2020 (mean score = 11.2 ± 2.3) had a better methodological quality than publications prior to 2016 (mean score = 9.8 ± 3.1; p = 0.018). ConclusionOverall, the reported methodological quality of the existing research on biomarkers for disease progression is low, which undermines the confidence of biomarkers use in drug development studies. It will be important to invest in better designed studies to support the use of biomarkers as valid drug development tools.

Seasonal variation in fluorescence characteristics of dissolved organic matter in wastewater and identification of proteins through HRLC-MS/MS

In the present study, wastewater samples acquired from five wastewater treatment plants (WWTPs), located in western India were characterized using fluorescence spectroscopy, and resin-based fractionation was conducted to fractionate DOM into hydrophobic and hydrophilic base, acid, and neutral fractions. Among several fractions, the hydrophilic acid (HIA) and hydrophilic neutral (HIN) fractions were present in higher abundance (more than 50% of DOC) compared to the hydrophilic base (HIB) fraction in both influent and effluent wastewater stream obtained from WWTPs. Tryptophan-like and tyrosine-like substances were also abundant in the influent and effluent stream of WWTPs. Further, LC-MS/MS analysis could identify 235 and 288 DOM proteins in the influent and effluent stream of WWTP-1, respectively. These proteins revealed varying percentage of tryptophan and tyrosine residues. The tryptophan residues primarily contributed to protein-like fluorescence in wastewater. The proteins were further classified based on their role in biological processes, location in the cell, and molecular function. Among several proteins, Alzheimer's and Huntington disease biomarkers were identified at WWTP-1. Their presence in the surface water can serve as an early warning system for wastewater-based epidemiology.

Mutant huntingtin and neurofilament light have distinct longitudinal dynamics in Huntington's disease.

The longitudinal dynamics of the most promising biofluid biomarker candidates for Huntington's disease (HD)-mutant huntingtin (mHTT) and neurofilament light (NfL)-are incompletely defined. Characterizing changes in these candidates during disease progression could increase our understanding of disease pathophysiology and help the identification of effective therapies. In an 80-participant cohort over 24 months, mHTT in cerebrospinal fluid (CSF), as well as NfL in CSF and blood, had distinct longitudinal trajectories in HD mutation carriers compared with controls. Baseline analyte values predicted clinical disease status, subsequent clinical progression, and brain atrophy, better than did the rate of change in analytes. Overall, NfL was a stronger monitoring and prognostic biomarker for HD than mHTT. Nonetheless, mHTT has prognostic value and might be a valuable pharmacodynamic marker for huntingtin-lowering trials.

Cerebrospinal Fluid Levels of Prodynorphin-Derived Peptides are Decreased in Huntington's Disease.

Huntington's disease (HD) is a devastating neurodegenerative disorder characterized by a selective loss of striatal medium spiny projection neurons (MSNs). Prodynorphin (PDYN) is enriched in a subpopulation of striatal MSNs. Postmortem brains of HD patients and rodent models have been demonstrated to have reduced levels of PDYN transcripts and the neuropeptide dynorphin. Given the unmet need for novel pharmacodynamic HD biomarkers in the context of experimental huntingtin (htt)-lowering therapies, we investigated the levels of PDYN-derived peptides and neurofilament light (NfL) chain in the cerebrospinal fluid (CSF) from HD patients (n = 16), matched controls (n = 55), and patients with other neurodegenerative disorders (n = 70). PDYN-derived peptide levels were found to be substantially decreased in HD patients (P < 0.0001 in comparison to controls), whereas the NfL levels were elevated in all neurodegenerative disorders. Our study suggests decreased PDYN-derived peptide levels in the CSF as a more specific biomarker for HD in comparison to NfL. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Deficit in Motor Skill Consolidation-Dependent Synaptic Plasticity at Motor Cortex to Dorsolateral Striatum Synapses in a Mouse Model of Huntington's Disease.

Huntington's disease (HD) is a neurodegenerative disease notably characterized by progressive motor symptoms. Although the loss of medium spiny neurons (MSNs) in the striatum has been associated with motor deficits, premanifest patients already present cognitive deficiencies and show early signs of motor disabilities. Here, in a YAC128 HD mouse model, we identified impairment in motor skill consolidation at the age of 11-14 weeks. Using optogenetic stimulation, we found that excitatory synaptic transmission from motor cortex to MSNs located in the dorsolateral part of the striatum (DLS) is altered. Using single pellet reaching task, we observed that while motor skill consolidation is accompanied by a dynamic change in AMPA/NMDA ratio in wild-type (WT) mice, this form of synaptic plasticity does not occur in YAC128 mice. This study not only proposes new meaningful insight in the synaptopathic mechanisms of HD, but also highlights that deficit in motor skill consolidation-dependent synaptic plasticity at motor cortex to DLS synapses represents an early biomarker for HD.

Sex-dependent impaired locomotion and motor coordination in the HdhQ200/200 mouse model of Huntington's Disease

Huntington's Disease (HD) is a fatal neurodegenerative disease characterized by severe loss of medium spiny neuron (MSN) function and striatal-dependent behaviors. We report that female HdhQ200/200 mice display an earlier onset and more robust deterioration in spontaneous locomotion and motor coordination measured at 8 months of age compared to male HdhQ200/200 mice. Remarkably, HdhQ200/200 mice of both sexes exhibit comparable impaired spontaneous locomotion and motor coordination at 10 months of age and reach moribund stage by 12 months of age, demonstrating reduced life span in this model system. Histopathological analysis revealed enhanced mutant huntingtin protein aggregation in male HdhQ200/200 striatal tissue at 8 months of age compared to female HdhQ200/200. Functional analysis of calcium dynamics in MSNs of female HdhQ200/200 mice using GCaMP6m imaging revealed elevated responses to excitatory cortical-striatal stimulation suggesting increased MSN excitability. Although there was no down-regulation of the expression of common HD biomarkers (DARPP-32, enkephalin and CB1R), we measured a sex-dependent reduction of the astrocytic glutamate transporter, GLT-1, in female HdhQ200/200 mice that was not detected in male HdhQ200/200 mice when compared to respective wild-type littermates. Our study outlines a sex-dependent rapid deterioration of striatal-dependent behaviors occurring in the HdhQ200/200 mouse line that does not involve alterations in the expression of common HD biomarkers and yet includes impaired MSN function.

Handwriting Movement Abnormalities in Symptomatic and Premanifest Huntington's Disease.

Kinematic measures of handwriting movements are sensitive to mild subclinical motor abnormalities stemming from a wide range of disorders involving the basal ganglia including Huntington's disease (HD). Prior research has not investigated handwriting movements in at-risk individuals in the premanifest stage of HD. The purpose of this study was to examine whether handwriting movement abnormalities are present prior to clinically manifest chorea in HD. A total of 38 symptomatic HD, 30 gene-positive premanifest, and 25 healthy control participants completed handwriting tasks consisting of circles, loops, sentences, and spirals with a noninking pen on a digitizing tablet. Multiple measures of pen stroke kinematics and pressure were measured along with the cognitive and motor status of each participant. Burden of pathology and CAG × age product scores were obtained from each participant with HD. Participants with HD exhibited significantly longer and more variable stroke durations, decreased handwriting smoothness, and increased and more variable pen pressures when compared with the healthy controls. We found significant positive associations between stroke duration and both burden of pathology and CAG × age product. Results from a discriminant function analysis revealed a 7-factor model that distinguished premanifest from healthy controls with 85% accuracy. Factors in the model included greater variability in stroke amplitude, velocity and pen pressure, higher levels of pen pressure, longer stroke durations, and lower velocities for combinations of handwritten circles, sentences, and spirals. These findings support the clinical utility of dynamic measures of handwriting kinematics as a potential early behavioral biomarker in HD.

Circadian dysfunction in the Q175 model of Huntington's disease: Network analysis.

Disturbances in sleep/wake cycle are a common complaint of individuals with Huntington's disease (HD) and are displayed by HD mouse models. The underlying mechanisms, including the possible role of the circadian timing system, have been the topic of a number of recent studies. The (z)Q175 mouse is a knock-in model in which the human exon 1 sequence of the huntingtin gene is inserted into the mouse DNA with approximately 190 CAG repeats. Among the numerous models available, the heterozygous Q175 offers strong construct validity with a single copy of the mutation, genetic precision of the insertion and control of mutation copy number. In this review, we will summarize the evidence that this model exhibits disrupted diurnal and circadian rhythms in locomotor activity. We found overwhelming evidence for autonomic dysfunction including blunted daily rhythms in heart rate and core body temperature (CBT), reduced heart rate variability, and almost a complete failure of the sympathetic arm of the autonomic nervous system to function during the baroreceptor reflex. Mechanistically, the Q175 mouse model exhibits deficits in the neural output of the central circadian clock, the suprachiasmatic nucleus along with an enhancement of at least one type of potassium current in these neurons. Finally, we report a novel network analysis examining the phase coherence between activity, CBT, and cardiovascular measures. Such analyses found that even young Q175 mutants (heterozygous or homozygous) show coherence degradation, and suggests that loss of phase coherence is a variable that should be considered as a possible biomarker for HD.

DNA damage signatures in peripheral blood cells as biomarkers in prodromal huntington disease.

Easily accessible biomarkers in Huntington disease (HD) are actively searched. We investigated telomere length and DNA double-strand breaks (histone variant pγ-H2AX) as predictive disease biomarkers in peripheral blood mononuclear cells (PBMC) from 25 premanifest subjects, 58 HD patients with similar CAG expansion in the huntingtin gene (HTT), and 44 healthy controls (HC). PBMC from the pre-HD and HD groups showed shorter telomeres (p < 0.0001) and a significant increase of pγ-H2AX compared to the controls (p < 0.0001). The levels of pγ-H2AX correlated robustly with the presence of the mutated gene in pre-HD and HD. The availability of a potentially reversible biomarker (pγ-H2AX) in the premanifest stage of HD, negligible in HC, provides a novel tool to monitor premanifest subjects and find patient-specific drugs. Ann Neurol 2018;00:1-6 ANN NEUROL 2019;85:296-301.

Platelet-derived extracellular vesicles in Huntington's disease.

The production and release of extracellular vesicles (EV) is a property shared by all eukaryotic cells and a phenomenon frequently exacerbated in pathological conditions. The protein cargo of EV, their cell type signature and availability in bodily fluids make them particularly appealing as biomarkers. We recently demonstrated that platelets, among all types of blood cells, contain the highest concentrations of the mutant huntingtin protein (mHtt)-the genetic product of Huntington's disease (HD), a neurodegenerative disorder which manifests in adulthood with a complex combination of motor, cognitive and psychiatric deficits. Herein, we used a cohort of 59 HD patients at all stages of the disease, including individuals in pre-manifest stages, and 54 healthy age- and sex-matched controls, to evaluate the potential of EV derived from platelets as a biomarker. We found that platelets of pre-manifest and manifest HD patients do not release more EV even if they are activated. Importantly, mHtt was not found within EV derived from platelets, despite them containing high levels of this protein. Correlation analyses also failed to reveal an association between the number of platelet-derived EV and the age of the patients, the number of CAG repeats, the Unified Huntington Disease Rating Scale total motor score, the Total Functional Capacity score or the Burden of Disease score. Our data would, therefore, suggest that EV derived from platelets with HD is not a valuable biomarker in HD.

A Critical Evaluation of Wet Biomarkers for Huntington's Disease: Current Status and Ways Forward.

There is an unmet clinical need for objective biomarkers to monitor disease progression and treatment response in Huntington’s disease (HD). The aim of this review is, therefore, to provide practical advice for biomarker discovery and to summarise studies on biofluid markers for HD. A PubMed search was performed to review literature with regard to candidate saliva, urine, blood and cerebrospinal fluid biomarkers for HD. Information has been organised into tables to allow a pragmatic approach to the discussion of the evidence and generation of practical recommendations for future studies. Many of the markers published converge on metabolic and inflammatory pathways, although changes in other analytes representing antioxidant and growth factor pathways have also been found. The most promising markers reflect neuronal and glial degeneration, particularly neurofilament light chain. International collaboration to standardise assays and study protocols, as well as to recruit sufficiently large cohorts, will facilitate future biomarker discovery and development.

An image-based model of brain volume biomarker changes in Huntington's disease.

ObjectiveDetermining the sequence in which Huntington's disease biomarkers become abnormal can provide important insights into the disease progression and a quantitative tool for patient stratification. Here, we construct and present a uniquely fine‐grained model of temporal progression of Huntington's disease from premanifest through to manifest stages.MethodsWe employ a probabilistic event‐based model to determine the sequence of appearance of atrophy in brain volumes, learned from structural MRI in the Track‐HD study, as well as to estimate the uncertainty in the ordering. We use longitudinal and phenotypic data to demonstrate the utility of the patient staging system that the resulting model provides.ResultsThe model recovers the following order of detectable changes in brain region volumes: putamen, caudate, pallidum, insula white matter, nonventricular cerebrospinal fluid, amygdala, optic chiasm, third ventricle, posterior insula, and basal forebrain. This ordering is mostly preserved even under cross‐validation of the uncertainty in the event sequence. Longitudinal analysis performed using 6 years of follow‐up data from baseline confirms efficacy of the model, as subjects consistently move to later stages with time, and significant correlations are observed between the estimated stages and nonimaging phenotypic markers.InterpretationWe used a data‐driven method to provide new insight into Huntington's disease progression as well as new power to stage and predict conversion. Our results highlight the potential of disease progression models, such as the event‐based model, to provide new insight into Huntington's disease progression and to support fine‐grained patient stratification for future precision medicine in Huntington's disease.