Huntington’s Disease: Pathogenic Mechanisms and Implications for Therapeutics

Huntington's disease (HD) is one of the most common dominantly inherited neurodegenerative disorders, characterized by a clinical trial of movement disorder, cognitive deficits, and psychiatric symptoms. Huntington’s Disease: Pathogenic Mechanisms and Implications for Therapeutics, reviews the most up-do-date content on HD pathogenic mechanisms and cutting-edge testing of therapeutic strategies for HD. Chapters explore areas such as, normal huntingtin biology in brain development and function, genetic modifiers of HD in patients, molecular pathogenic mechanism in HD, and mechanisms underlying selective neuronal vulnerability

• Reviews the clinical course and genetics of HD
• Reviews the biology of human huntingtin and HD-relevant cell types
• Reviews the wide range of pathobiology associated with mutant huntingtin
• Reviews genetic studies of HD and how these studies are informing the development of new therapeutic approaches
• Reviews new tools and model systems for basic and translational research in HD, including new human-derived model systems, as well as systems biology and artificial intelligence–driven approaches
• Provides an overview of new therapeutic approaches and current clinical programs in HD

• Language: English
• Publisher: Academic Press
• Release date: Feb 7, 2024
• ISBN: 9780323956734

Book preview

Preface

Huntington's disease (HD) is one of the most common dominantly inherited neurodegenerative disorders with an estimated worldwide prevalence of 2.71 per 100,000 people. HD symptoms typically begin at around 40 years of age (with rare cases begin at juvenile ages), and include a triad of a movement disorder, cognitive deficits, and psychiatric symptoms. The clinical course of HD is a continuous decline of motor and cognitive function with patients suffering from premature death approximately 15 years after onset. Despite its monogenic etiology, currently there are no effective therapies to prevent the onset or slow the progression of HD.

The study of HD started about 150 years ago, when George Huntington presented his treatise describing the salient clinical and genetic features of the hereditary chorea. Ever since, HD has been considered a model neurodegenerative disorder that is in the forefront of deciphering the genetic bases of brain diseases, dissecting pathogenic mechanisms, and testing innovative targeted therapeutics. Indeed, 2023 marks the 40th anniversary of the discovery of DNA marker for HD, the first genetic disease mapped by DNA polymorphisms; and 30th anniversary of the cloning of the HD gene itself, i.e. the elucidation of the pathogenic mutation as an expansion of CAG repeats encoding an elongated polyglutamine stretch in the Huntingtin gene. These landmark discoveries, in large part resulting from the study of Venezuelan HD patients by a group of pioneering scientists and clinicians lead by Dr. Nancy Wexler, have positioned HD in the leading edge of genetic brain disease research. With its unequivocal genetic etiology and well-delineated and highly selective neuropathology (e.g. massive degeneration of the medium spiny neurons in the striatum and to a lesser extent, the loss of pyramidal neurons in the cortex), HD is deemed a more tractable neurodegenerative disorder. Its monogenic nature facilitates charting a rationale path from a detailed mechanistic understanding of the disease in patients and model systems to ultimately translating such discoveries into novel and effective therapies for HD and possibly other neurodegenerative disorders.

The journey of HD research thus far has taught us about the complexity of brain disorders and how embracing such complexity with focused efforts and advanced technologies can turn challenges into opportunities. The clinical presentation of HD is variable in onset and progression, but large-scale analyses of the genetic bases of such variability have led to the discoveries of disease modifier genes and new candidate therapeutic targets. HD affects multiple brain regions and cell types, and studies into the basis of this pattern of vulnerability and resilience have uncovered the roles of different neuronal and nonneuronal cell types as well as their pathological communications in eliciting HD phenotypes. The holy grail for HD research is to discover the molecular mechanism(s) most proximal to the CAG repeat expansion in mutant Huntingtin that drive the cascade of events leading to striatal and cortical neuronal dysfunction and degeneration underlying the clinical manifestation of HD. The cumulative knowledge thus far suggests that HD pathogenesis likely involves multiple molecular players acting at different subcellular locations (e.g. nuclei, mitochondria, axons, synapses) in several brain cell types. To study the HD molecular and cellular pathogenesis and test candidate therapeutics, the HD field has developed a series of genetic rodent and large animal models as well as cellular models derived from patient cells. Many recent technological advances, including DNA sequencing and proteomics, systems biology, and artificial intelligence, have provided new avenues to disentangle the complexity of HD to provide molecular targets and therapeutic readouts. Finally, revolutionary advances in genome editing and delivery of gene-targeting therapies into the brain have propelled HD to the forefront among CNS diseases as a model to test many innovative therapeutic modalities and gene therapy/drug delivery tools to the brain.

In this book, an eminent group of active HD researchers provide the most up-do-date knowledge on key topics in HD and their insights into the implications of various research topics to therapeutics. Chapters explore areas that include the clinical features and genetic studies of HD, the cellular and molecular biology of huntingtin, a range of HD cellular and animal models, the diverse pathogenic mechanisms linked to the CAG repeat expansion, new systems biology and machine learning approaches to study HD pathogenesis, as well as emerging therapeutic approaches, a novel clinical staging paradigm, and the current landscape of HD clinical trials.

This book is unique in providing a comprehensive, up-to-date, and authoritative resource to learn about HD pathogenesis and therapeutics. It should be of primary interest to those who are actively pursuing HD basic or translational research in academia and industry, directly working with HD patients and families, HD funding agencies, and HD advocacy and educational groups. With each chapter written in accessible language and inclusion of historical as well as therapeutic perspectives, this book is particularly suitable for trainees (students, postdoctoral or clinical fellows, research scientists) new to the HD research field. This book will also be informative to those who study other neurodegenerative disorders (e.g. repeat expansion disorders, Alzheimer's disease, Parkinson's disease, frontotemporal dementia, and amyotrophic lateral sclerosis), and are interested in the latest HD research findings, tools, and therapeutic approaches that could apply to the other brain disorders. In the industry sector, this book may serve as a reference not only for HD translational and clinical researchers but also for investors who are interested in HD therapeutic development. Finally, this book may be helpful to provide cutting-edge knowledge to members of the HD patient community who seek advanced knowledge in HD-relevant brain biology and disease research.

The inception of this book was during the height of the COVID-19 pandemic. We have witnessed, for the first time in human history, how an incapacitating pandemic can be overcome using tools of modern science that have emerged from the powerful combination of basic and clinical research. George Huntington once prophetically stated that ‘science, which has accomplished such wonder through the never-tiring devotion of its votaries, may yet overturn and overturn, and overturn it, until it is laid open to the light of day.’ When working remotely together on this HD book, we (the three coeditors) share the nuanced optimism of George Huntington that science will lead to the light of day for HD.

We are indebted to the HD patients and their families who provide us constant inspiration and support. We would like to thank all our book chapter authors for taking on the extra work to write their chapters and do so with the utmost excellence and dedication. We would like to thank our Elsevier editor, Joslyn T. Chaiprasert-Paguio, and senior editorial project manager, Patricia Gonzalez, for their exceptional professionalism and support. We would also like to thank the following individuals for their contribution to the book cover: Chang Sin (Chris) Park from the X. William Yang lab at UCLA; Eric Christiansen and Steven Finkbeiner at Google and the Gladstone Institutes, respectively; and Mitsuko Nakajima and Sarah Tabrizi from the HD Centre at University College London.

X. William Yang

Leslie M. Thompson

Myriam Heiman

Chapter 1: Huntington's disease: Clinical features, genetic diagnosis, and brain imaging

Carlos Estevez-Fragaa, Mitsuko Nakajimaa, and Sarah J. Tabrizi     Huntington's Disease Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom

Abstract

Huntington's disease (HD) is caused by a CAG repeat expansion in the HTT gene. Genetic testing can be used to prevent the transmission of the disease and to precisely identify individuals that could benefit from potential disease-modifying treatments. HD causes a decline in the cognitive, psychiatric, and motor areas progressing slowly over 2 decades after starting, usually, during mid-adulthood. However, rare individuals with very large CAG repeat expansions develop symptoms before 20 years of age, with a more aggressive phenotype.

The progression of adult-onset patients is slow, being challenging to detect changes over a clinical trial period. However, imaging biomarkers can precisely quantify disease progression and neuronal loss in vivo decades before clinical motor diagnosis. Moreover, newer imaging analysis techniques provide in-depth information about the biological underpinnings of atrophy in HTT expansion carriers and are used to evaluate the efficacy and safety of therapies targeting core disease mechanisms.

Keywords

Genetic counseling; Huntington's disease; Juvenile Huntington's disease; Neurogenetics; Neuroimaging; Symptoms

Introduction

Huntington's disease (HD) is the most common autosomal dominant genetic dementia, with an estimated worldwide prevalence of 2.71/100.000 (Pringsheim et al., 2012). HD causes a triad of motor, behavioral, and cognitive symptoms, usually starting around 40 years of age (Oosterloo et al., 2021).

Traditionally, HD patients were classified into premanifest/presymptomatic (preHD) or manifest/symptomatic depending on the presence of unequivocal motor symptoms during neurological exam, while the term prodromal was used for patients with mild motor symptoms insufficient for diagnosis (Wild & Tabrizi, 2014). Although widely used in HD literature, these words are equivocal, vague, and subjective. In consequence, different studies have used various definitions for these concepts, being difficult to standardize previous research.

The new Huntington's disease–Integrated Staging System (HD-ISS) is an evidence-based staging system encompassing the entire disease course since birth (Tabrizi, Schobel, et al., 2022). The HD-ISS is centered on biological, clinical, and functional assessments. This system classifies HD into four different stages using objective cut-offs in landmark variables and includes a new standard biological case definition based on the HTT CAG expansion. Therefore, this classification overcomes the defects of previous classifications and is already being used for clinical research. Instead of the equivocal previous nomenclature, the HD-ISS supports the use of the more precise before clinical motor diagnosis and after clinical motor diagnosis (Tabrizi, Schobel, et al., 2022). In this chapter, we have followed this terminology whenever possible, except when referring to groups defined in previous studies or in published figures using the old terms. The new HD-ISS will be described in detail in the Chapter 2, Huntington's disease clinical research advances and challenges.

Patients with HD have a disease-causing cytosine-adenine-guanine (CAG) trinucleotide expansion in the HTT gene on chromosome 4p encoding for the toxic mutant Huntingtin (mHTT) protein (Ross & Tabrizi, 2011). The HTT gene has 67 exons and encodes a 348 kDa HTT protein (The Huntington's Disease Collaborative Research Group et al., 1993). The CAG repeat tract within exon 1 of HTT is translated into a polyglutamine stretch (polyQ) at the N-Terminal domain of the HTT protein (Bates, 2003).

The wild-type HTT protein is a ubiquitous protein located in both the nucleus and the cytoplasm. It interacts with numerous proteins and is implicated in diverse cellular processes such as vesicular transport, cell division, ciliogenesis, autophagy, and transcriptional regulation (Cattaneo et al., 2005). Its large size, together with its numerous interactions and involvement in multiple functions, argues in favor of its role as a scaffold protein, coordinating a broad range of cellular processes (Saudou & Humbert, 2016).

All cases of HD carry the same mutation in the HTT gene (The Huntington's Disease Collaborative Research Group et al., 1993) encoding the toxic mHTT protein (McColgan & Tabrizi, 2018). The length of the polyQ repeat is inversely associated with age at clinical motor diagnosis and rate of progression (Duyao et al., 1993; Keum et al., 2016). Patients with more than 39 CAG repeats invariably develop HD if they have a normal lifespan, while the penetrance is reduced between 36 and 39 repeats (McColgan & Tabrizi, 2018). The gene is meiotically unstable in the sperm, with the possibility of larger repeat sizes being transmitted to the offspring, particularly when the mutation is inherited from the paternal side (McColgan & Tabrizi, 2018). Somatic instability of the CAG repeat tract is also prominent in neural tissue, and especially in the striatum, where very large expansions have been observed in postmortem brain tissue from HD brains (Kennedy, 2003) being also associated with earlier age at clinical motor diagnosis (Tabrizi et al., 2020).

The chronic expression of mHTT causes protein aggregation in the nucleus and the cytosol (Fig. 1.1). Ultimately, these aggregates exceed the degradation mechanisms leading to disruption of homeostasis, forming the characteristic inclusions present in the brain of HD patients and possibly resulting in cellular death (Jimenez-Sanchez et al., 2017). However, the toxicity of these aggregates has not been completely established. The aggregates do not correlate with atrophy (Arrasate & Finkbeiner, 2012) while neuronal death can also result from oligomeric stages of aggregation, and there is evidence suggesting that the formation of inclusions may even be protective in animal and cell models (Nucifora et al., 2012).

These alterations in neuronal physiology translate into cerebral atrophy. A study of 163 HD brains by Vonsattel et al. performed before the discovery of the HTT mutation showed that the striatum was the preferential location for neuronal loss, leading to the neuropathological grading system of HD (Vonsattel et al., 1985). Atrophy begins in medial, caudal, and dorsal regions of the striatum and spreads gradually toward rostral, ventral, and lateral areas. As the disease progresses there is widespread involvement of white matter and extrastriatal gray matter eventually affecting the entire brain (Rüb et al., 2016) with HD brains weighting approximately 300 g lighter than those of controls (Vonsattel et al., 1985).

Magnetic resonance imaging (MRI) studies allow noninvasive, in vivo investigation into the progression of brain atrophy, white matter disorganization, and changes in brain activity that are associated with HD neuropathology (Estevez-Fraga, Scahill, et al., 2020; Johnson & Gregory, 2019; Scahill et al., 2017). Therefore, MRI studies are an essential tool to monitor safety outcomes and disease progression in clinical trials. In consequence, large multicentric studies using volumetric MRI imaging techniques have shown robust decreases in striatal volume and peristriatal white matter in HD participants compared to controls (Georgiou-Karistianis et al., 2013; Paulsen et al., 2008; Tabrizi et al., 2009). These changes are present before clinical motor diagnosis (Paulsen et al., 2010; Scahill et al., 2020) and progress linearly over the course of the disease (Aylward et al., 2004) in line with previous neuropathological studies (Vonsattel et al., 1985).

Figure 1.1  Pathogenetic cellular mechanisms in Huntington's disease. (1) HTT is translated to produce the full-length huntingtin protein as well as an amino-terminal HTT exon1 fragment (the result of aberrant splicing). The length of the polyglutamine (polyQ) tract in these proteins depends on the extent of somatic instability. (2) Full-length native huntingtin is cleaved through proteolysis to generate additional protein fragments. (3) Protein fragments enter the nucleus. (4) Fragments are retained in the nucleus through self-association, oligomerization, and aggregation—leading to the formation of inclusions, a process that causes transcriptional dysregulation through the sequestration of other proteins and through other incompletely defined mechanisms. (5) Huntingtin fragments oligomerize and aggregate in the cytoplasm. (6) The aggregation of huntingtin is exacerbated through the disease-related impairment of the proteostasis network, which also leads to global cellular impairments. (7) The aberrant forms of huntingtin result in additional global cellular impairments, including synaptic dysfunction, mitochondrial toxicity, and a decreased rate of axonal transport. PRD , proline-rich domain; Ub , ubiquitin. Credit: Reproduced with permission from Bates et al. (2015).

In contrast, diffusion-weighted imaging (DWI) MRI sequences measure the movement of water molecules in the tissue, reflecting their interaction with biological barriers such as myelin or cell membranes and thus, revealing information about the microstructural architecture of the brain (Hagmann et al., 2006; Mori & Zhang, 2006). In HD (Fig. 1.2), diffusion imaging studies have shown detectable loss of white matter organization before clinical motor diagnosis (Gómez-Tortosa et al., 2001; Paulsen et al., 2010; Tabrizi et al., 2009; Xiang et al., 2011) along an anterior to posterior gradient of changes in the sensorimotor network and corticostriatal tracts (Bohanna et al., 2011; McColgan, Gregory, et al., 2017). These changes affect initially the connections between sensori-motor cortex and the corpus callosum, extending to adjacent tracts as the disease progresses (Dumas et al., 2012; Poudel et al., 2014). Interestingly, together with increased diffusivity there is increased anisotropy in the basal ganglia of HD expansion-carriers suggesting increased reorganization in this area compared to controls (Estevez-Fraga, Scahill, et al., 2020).

Symptoms appear, on average, during mid-adulthood, when many patients have already started a family and seen the devastating course of the disease in their affected parent. Thereafter, there is a slow decline in physical and psychological health resulting in patients eventually requiring 24-hour care (Fig. 1.3).

Multiple symptoms emerge in response to the neuronal death triggered by the presence of the mHTT protein. Cognitive disturbance is characterized by a subcortical pattern with alterations in emotion recognition, psychomotor speed, executive function, and visuomotor integration (Paulsen & Long, 2014; Stout et al., 2012; Tabrizi et al., 2009). These changes can be detected years before clinical motor diagnosis (Stout et al., 2011) eventually evolving to severe impairment of affected cognitive domains and invariably progressing to dementia during late phases (Peavy et al., 2010).

Diverse neuropsychiatric symptoms also emerge during the disease course (van Duijn et al., 2014) with patients being at increased risk of suicide compared to healthy controls (Schoenfeld et al., 1984). Apathy is the most frequent neuropsychiatric symptom being present in 70% of HD patients, while anxiety, depression, or irritability occur in around 50% (Craufurd et al., 2018; Paulsen, 2001).

Since the seminal description of the disease in 1872, movement disorders have been the most identifiable characteristic of HD for many clinicians (Huntington, 1872) with motor symptoms being the core clinical feature for the clinical diagnosis of HD (Huntington Study Group, 1996; Reilmann et al., 2014). Patients initially present with hyperkinetic movements followed by parkinsonism (Bates et al., 2015; Reilmann, 2019). Patients with large CAG expansions, however, develop prominent parkinsonism early on (Fusilli et al., 2018). This phenotype may be related to a different topographical pattern of neuronal loss in the developing basal ganglia of juvenile HD patients (Vonsattel et al., 2011).

The CAG repeat length in HTT can be measured to confirm the genetic diagnosis of HD in an individual showing motor symptoms (diagnostic testing) or to predict whether an at-risk subject will develop the disease (predictive testing) (Macleod et al., 2013). In both cases, careful management is required from the first clinical visit. Importantly, the implications of a positive or negative result should be discussed with the patient and their family from the outset, and screening for psychiatric symptoms is essential. Predictive testing requires a particularly meticulous process involving several visits prior to testing as well as rigorous follow-up after the results are given to the patient. Adequate counseling should be provided to patients and their families before, during, and after testing, ideally in centers with experience in the genetic diagnosis of HD.

Figure 1.2  Summary of cross-sectional diffusion studies in HD. ↑, increase; ↓, decrease; ↑↑, marked increase; ↓↓, marked decrease; FA , fractional anisotropy; HD , Huntington's disease. Credit: Reproduced with permission from Estevez-Fraga, Scahill, et al. (2020)

Individuals carrying the expanded CAG repeat in HTT are asymptomatic at birth and achieve normal developmental milestones. Over time, subtle clinical signs emerge, affecting the cognitive, behavioral, and motor domains. Initially, the features are not specific to HD, however, with time, unequivocal motor signs of HD appear (McColgan & Tabrizi, 2018).

Figure 1.3  The impact of various life events and disease milestones on different domains of quality of life in a hypothetical person with Huntington's disease. The impact of the disease on an individual's quality of life begins long before the person has any symptoms of the disease. Quality-of-life domains are differentially affected by these events and milestones. Credit: Reproduced with permission from Bates et al. (2015).

In this chapter, the most recent evidence about the clinical characteristics of HD and genetic testing methods will be reviewed. We will also review available research about brain imaging studies in HD, centering on imaging biomarkers used to include participants in clinical trials and monitor the effect of therapeutic interventions.

Clinical course

Conventional diagnostic classification: The terms prodromal, premanifest, and manifest Huntington's disease

Carriers of the expansion in HTT are asymptomatic at birth, and there are no clinical abnormalities during infancy or adolescence in the vast majority of expansion carriers (Fig. 1.4). This phase has been classically referred to as premanifest or presymptomatic HD. The emergence of mild cognitive, motor, and psychiatric symptoms, often during mid-adulthood, defines the prodromal phase (Duff et al., 2007; Stout et al., 2011) while the time point when motor symptoms can be unequivocally attributed to HD is referred to as motor diagnosis. Beyond this timepoint patients have been classified as having manifest HD. This conventional system continues to be valuable in specialist HD clinics where it can be used to guide consultation, coordinate care, and determine management approach.

However, the use of this system in HD research, particularly in therapeutic trials, has been challenged by lack of standardization as well as biological evidence showing that there are pathological changes years before the emergence of symptoms (Scahill et al., 2020). As a consequence, newer staging systems incorporate objective measures to classify patients into different categories (Tabrizi, Schobel, et al., 2022), and the use of the terms premanifest, prodromal, or manifest HD is discouraged. This is described in more detail in the next chapter.

Figure 1.4   Natural history of clinical Huntington disease . The normalized CAG age product (CAP) score enables progression of many individuals with different CAG expansion lengths to be plotted on the same graph. Mean disease onset is at CAP score ∼100 (typically ∼45 years of age), but there is substantial interindividual variability. Without normalization, the CAP score at onset exceeds 400. The period before diagnosable signs and symptoms of Huntington disease occur is termed ‘premanifest’. During the ‘presymptomatic’ period, no signs or symptoms are present. In ‘prodromal’ Huntington disease, subtle signs and symptoms are present. Manifest Huntington disease is characterized by slow progression of motor and cognitive difficulties, and chorea is often prominent early but plateaus or even decreases later. Fine motor impairments (incoordination, bradykinesia and rigidity) progress more steadily. Credit: Reproduced with permission from Bates et al. (2015).

The concept of motor diagnosis

Motor features are the hallmark of HD. These are assessed with the Total Motor Score (TMS) part of the Unified Huntington's Disease Rating Scale (UHDRS), comprising 15 areas of clinical assessment including oculomotor function, dysarthria, chorea, dystonia, gait, and postural stability (Huntington Study Group, 1996).

The presence of unequivocal motor symptoms of HD with >99% confidence has been traditionally used to define the clinical motor diagnosis of the disease. However, motor diagnosis is typically made relatively late in the lifetime.

Clinical characteristics before clinical motor diagnosis

Motor features

Motor symptoms in HD typically appear gradually, being mild and usually nonspecific prior to clinical motor diagnosis (Paulsen, Long, Ross, et al., 2014; Tabrizi et al., 2011). PREDICT-HD was a longitudinal study lasting 10 years, designed to document the natural history of premanifest individuals (Paulsen, Long, Ross, et al., 2014). These participants were stratified using the CAG Age Product (CAP) score, a measure of exposure to the effects of expanded CAG repeat lengths, being calculated from CAG repeat length, and the age of the individual. Participants were divided into low, medium, and high CAP groups (Zhang et al., 2011). During the 10-year study period, there were statistically significant differences in TMS scores between the control/medium groups (predicted to be 7.58–12.78 years from clinical motor diagnosis) and the high (predicted to be less than 7.59 years away from clinical motor diagnosis) CAP groups. However, these differences were not specific to any subsection within the TMS (e.g., oculomotor, chorea).

TRACK-HD was designed to evaluate measures of motor, cognitive, oculomotor, and psychiatric progression that could be used as outcome measures in clinical trials. Controls, premanifest, and manifest individuals were evaluated annually during a time frame of 36 months with brain MRI, blood tests, and clinical evaluations including quantitative motor assessments. Participants were classified as premanifest based on a TMS ≤5, being further divided into two groups based on the median years to clinical motor diagnosis of 10.8 years. Premanifest HD and controls had differences in speed tapping variability and tongue protrusion force, particularly in participants closer to motor diagnosis (Tabrizi et al., 2013). Moreover, three quantitative motor items were found to be significant in the group of individuals who progressed to clinical motor diagnosis during the follow-up period: rates of deterioration in the chorea orientation index, speeded-tapping tap duration variability, and grip force variability.

Evidence suggests that nonspecific motor symptoms gradually evolve into the unequivocal signs of HD. However, the magnitude of motor changes depends on proximity to clinical motor diagnosis, with motor scores demonstrating large effect sizes close to motor diagnosis but being insensitive to detect changes during earlier stages.

Cognitive features

There are mild cognitive signs in premanifest individuals 10 years before clinical motor diagnosis (Stout et al., 2011) probably caused by early alterations in fronto-striatal circuits (Papoutsi et al., 2014). Also, early deficits have been found in executive function, visuomotor integration, emotion recognition, and psychomotor speed (Harrington et al., 2014; Stout et al., 2011, 2012; Tabrizi et al., 2013). Among the cognitive rating scales, the symbol-digit modalities test (SDMT) and the Stroop word reading (SWR) test have been used in multiple studies showing differences between premanifest HD and controls as well as detecting longitudinal change (Paulsen, Long, Ross, et al., 2014; Tabrizi et al., 2012, 2013).

TRACK-HD demonstrated that, in premanifest participants, there were measurable changes over the follow-up period in the scores of SDMT, which measures visuomotor integration and executive function. The low, medium, and high CAP groups in PREDICT-HD all displayed increasing rates of cognitive decline, whereas the control group improved over time, probably because of practice effects. The rate of change differed across the groups, while the high CAP group had significant decline in all cognitive measures, the medium CAP group declined significantly in nine out of 10 scales, and the low CAP group show significantly decreased scores only in four cognitive measures (SDMT, SWR, Smell-ID, and Trail-Making) (Paulsen, Long, Ross, et al., 2014).

The HD-YAS study investigated differences between premanifest HD 25 years on average prior to clinical motor diagnosis, and healthy controls. It included 64 HTT expansion carriers and 67 healthy controls. Participants underwent a comprehensive cognitive evaluation with the Cambridge Neuropsychological Test Automated Battery (CANTAB), however, there were no significant differences between expansion carriers and controls in any cognitive feature (Scahill et al., 2020).

In summary, cognitive features, similar to motor features, declined slowly before clinical motor diagnosis over a long period of time. Changes can only be detected by using exhaustive standardized evaluations in expansion carriers close to clinical motor diagnosis.

Psychiatric features

There are clear psychiatric traits associated with the HTT mutation. Some psychiatric symptoms clearly deteriorate with disease progression, whereas others remain stable over time. This may be related to the availability of symptomatic medications for certain manifestations (e.g., depression) but not for others (e.g., apathy). In addition, it is difficult to disentangle the psychiatric effects caused by the biological effects derived from the presence of mHTT, from those caused by the sociopsychological impact of growing up in an HD family.

Apathy is one of the most characteristic psychiatric symptoms in HD, being present in up to 32% of premanifest HD. In addition, premanifest patients are 15 times more likely to have apathetic symptoms compared to healthy controls (Martinez-Horta et al., 2016). Moreover, apathy is associated with faster cognitive decline over a 2-year period, accounting for 16.1% of the variance in cognitive decline (Andrews et al., 2021).

Obsessive compulsive traits are less frequent than apathy but more specific to HD (Paulsen, 2001; Sellers et al., 2020; van Duijn et al., 2014). In PREDICT-HD, significant changes of psychiatric symptoms over time were observed in premanifest participants relative to controls, and the strongest effect was observed in obsessive-compulsive symptoms (likelihood ratio test statistic for obsessive-compulsive trait = 100.54; for apathy = 80.71) (Paulsen, Long, Johnson, et al., 2014).

Increased scores in depression and anxiety have also been found in premanifest individuals, although not showing significant longitudinal changes (Epping et al., 2016). In contrast, a small study showed longitudinal changes in irritability and hostility over the study period (Kirkwood et al., 2002).

However, the HD-YAS study also included detailed neuropsychiatric testing with emotion, motivation, impulsivity, and social cognition tests. Similar to cognitive testing, no significant difference was found between HTT expansion carriers and controls (Scahill et al., 2020).

In conclusion, psychiatric symptoms are frequent in HD before clinical motor diagnosis. However, scores in psychiatric scales do not track disease progression of the disease prior to this stage.

Other symptoms

Sleep disturbance is frequently reported after clinical motor diagnosis (see next section), but fragmented sleep profile has also been reported in one study including premanifest participants, being correlated with disease burden score and cognitive function (Lazar et al., 2015).

Functional capacity

Functional capacity is typically preserved in individuals who are more than 10 years away from a clinical motor diagnosis. However, after this period, there is a gradual decline in the total functional capacity (TFC) scale, which is associated with disease burden (Paulsen, Long, Ross, et al., 2014).

In summary, there is robust evidence supporting the presence of pathological changes prior to clinical motor diagnosis (Rüb et al., 2015). However, available knowledge about the clinical phenotype in participants before clinical motor diagnosis is not as comprehensive.

Perhaps one of the most challenging limitations in HD research is the difficulty of recruiting participants with known genetic status long before clinical motor diagnosis. It is estimated that the majority (>80%) of the at-risk population do not undergo predictive testing (Baig et al., 2016). However, this scenario may change if effective treatments become available.

Far from clinical motor diagnosis, disease progression is slow and the biomarkers are limited in their ability to detect HTT expansion carriers (Byrne et al., 2018; Scahill et al., 2020). This is particularly challenging among participants more than 10 years to clinical motor diagnosis and remains an important area of research as this is exactly the group of HTT expansion carriers who are most likely to experience larger benefit in response to effective disease-modifying therapies.

Further studies in participants before clinical motor diagnosis are underway, including the HD YAS 2.0 investigating longitudinal changes in participants long before clinical motor diagnosis. These studies are expected to fill in a crucial gap in the knowledge of the disease, providing the conceptual framework to develop efficient clinical trials in populations before clinical motor diagnosis.

Clinical characteristics after clinical motor diagnosis

Motor features

Patients with HD usually follow a course of hyperkinetic movement disorders with chorea and dystonia that typically plateau, followed by the emergence of parkinsonism which becomes the predominant motor symptom during late stages of the disease (Bates et al., 2015; Reilmann, 2019). These findings mirror evidence from pathological studies with selective vulnerability of medium spiny neurons of the indirect pathway while there is a relative preservation of the direct pathway during early stages of the disease (Galvan et al., 2012). Patients with very large CAG expansions, in contrast, develop motor symptoms before 20 years of age, where parkinsonism is the prominent feature at clinical motor diagnosis in 17% (Cronin et al., 2019). This may be related to a different topographical pattern of neuronal loss in the developing basal ganglia of juvenile HD patients (Vonsattel et al., 2011) (see Juvenile Huntington's Disease).

However, movement disorders in patients with adult-onset HD are also varied, with features such as gait disturbance, abnormal eye movements, dysarthria, or swallowing dysfunction being present and frequently causing significant disability (Dorsey et al., 2013; Kirkwood et al., 2001).

Motor symptoms are associated with disease duration, especially shortly after clinical motor diagnosis (Tabrizi et al., 2013) and have been used as a primary outcome in numerous clinical trials (Reilmann & Schubert, 2017) investigating symptomatic and potentially disease-modifying therapies (Frank et al., 2016; Huntington Study Group, 2006; Reilmann et al., 2019; Rodrigues & Wild, 2018).

Cognitive features

Cognitive symptoms in HD are initially subtle, usually preceding the emergence of motor features. However, these symptoms tend to increase as the disease progresses, ultimately leading to dementia, which dominates the clinical picture during late stages of the disease (Bates et al., 2015).

The classical cognitive syndrome in manifest HD is characterized by a subcortical pattern that includes alterations in executive function, emotion recognition, psychomotor speed, and visuomotor integration (Stout et al., 2012; Tabrizi et al., 2009). In contrast, cortical functions such as orientation, semantic memory, or language comprehension are not affected, at least in early HD patients (Papoutsi et al., 2014).

The main cognitive hallmark after clinical motor diagnosis is a dysexecutive syndrome, dependent on the malfunction of the frontostriatal circuits. However, deficits in visuomotor and visuospatial domains support the involvement of other regions, such as posterior cortical areas, and there is increasing evidence suggesting that posterior cortical involvement plays a decisive role in the development of dementia (Martinez-Horta et al., 2020).

Within-group variability is a challenge when measuring longitudinal changes in the cognitive function (Papoutsi et al., 2014). However, significant declines in the SDMT and SWR were shown after a 24-month follow-up in the TRACK-HD study. Although no treatment has been shown to improve cognitive symptoms in HD (Cubo et al., 2006; Fernandez et al., 2000; Rot et al., 2002), cognitive scales are among the most sensitive clinical outcomes, and have been included as primary endpoints in clinical trials with possible disease-modifying therapies (Estevez-Fraga et al., 2021).

Psychiatric features

Diverse neuropsychiatric symptoms are present in HD (van Duijn et al., 2014) with patients being at increased risk of suicide compared to healthy controls (Schoenfeld et al., 1984). Apathy is the most frequent neuropsychiatric symptom and is present in 70% of manifest HD patients, while anxiety, depression, or irritability occur in around 50%. Obsessive-compulsive disorder, aggressiveness, or psychosis, although rarer, lead to severe disability when present (Craufurd et al., 2018; Paulsen, 2001).

In observational studies, psychiatric features were more common as the first major feature of HD in youngerpatients compared to olderpatients, while motor features were more frequent later. For those developing symptoms over 60 years of age, 68.6% had initial motor symptoms, while 11.5% had psychiatric, and 6.7% had initial cognitive symptoms (McAllister et al., 2021).

The evolution of different psychiatric symptoms is not uniform throughout disease progression. Depression and irritability are not correlated with disease severity, while scores in apathy scales tend to increase gradually with time (Tabrizi et al., 2013). These divergent trajectories in the evolution of different psychiatric symptoms may be related to their different neuroanatomical substrates (De Paepe et al., 2019; McColgan, Razi, et al., 2017) as well as to the absence of effective treatments for apathy.

Other symptoms

Progressive weight loss and reduced BMI are commonly reported in manifest HD (Djoussé et al., 2002; Sanberg et al., 1981). The exact mechanism is not yet clear, however, defective metabolism (Mochel et al., 2007) and expression of mHTT in peripheral tissues (Lakra et al., 2019) have been reported to cause a hypermetabolic state. Furthermore, acceleration of weight loss has been reported to begin about 5.6 years after clinical motor diagnosis (Ogilvie et al., 2021).

In a postal survey, sleep disturbance was reported in 90% of the responders (Taylor & Bramble, 1997). Disturbed sleep pattern has been demonstrated with sleep electro-encephalography (EEG), specifically increased time to sleep onset, reduced sleep efficiency and significant reduction of deep sleep (Wiegand et al., 1991). Sleep efficiency is also associated with increased severity of motor symptoms and caudate atrophy in manifest HD (Wiegand et al., 1991).

Functional capacity

As a result of neuronal loss and subsequent motor, cognitive, and psychiatric symptoms, patients with HD experience a decline in their ability to perform the activities of daily living. Patients commonly report difficulties in maintaining employment at first, frequently needing adaptations such as being assigned less complex or fewer tasks. Over time, patients ultimately need to give up work. Next, complex tasks such as using public transport independently or managing finances are affected. Eventually, patients develop difficulties with housework and require assistance with self-care.

These deficits can be measured through the TFC showing gradual increases from 13 (completely independent) to 0 (requiring full-time care) (Shoulson & Fahn, 1979).

Juvenile Huntington's disease

Juvenile Huntington's disease (JHD) refers to subjects with symptoms of HD prior to 20 years of age, while the term pediatric HD is applied to patients with clinical manifestations before turning 18 years old (Bakels et al., 2022). Pediatric HD can be further subclassified into childhood (<10 years) and adolescent onset (10–18 years). The median CAG repeat of JHD patients is 60, although it can vary from 50 to more than 100 CAG repeats. The mutation is usually inherited from the paternal side as a consequence of meiotic variability with increases in CAG length during spermatogenesis (Fusilli et al., 2018; Went et al., 1984; Zühlke et al., 1993).

Although rare in the general population, JHD can represent up to 10% of patients with HD (Quarrell et al., 2012) and their clinical characteristics may make them a suitable population for the development of therapies that could later be applied to adult patients. The main symptoms of JHD affect areas comparable to these altered in adult-onset HD, but there is faster progression and shorter disease duration in JHD, with a mean survival of approximately 11 years from motor diagnosis (Fusilli et al., 2018). Patients with JHD present frequently with symptoms such as behavioral disturbance, falls, gait disturbance, and cognitive impairment. Parkinsonism is present at clinical motor diagnosis in 17% of JHD patients although eventually almost all JHD patients develop parkinsonism in the course of disease (Cronin et al., 2019). Chorea can be present during disease progression, particularly in JHD patients with clinical motor diagnosis after 16 years of age. Ataxia, although classically considered to be a typical manifestation of JHD, is rare; its low frequency could be related to difficulties identifying cerebellar dysfunction in the complex clinical setting of JHD (Fusilli et al., 2018).

Cognitive deficits are commonly reported as the initial signs of JHD, with patients developing poor school performance before clinical motor diagnosis (Cronin et al., 2019). However, JHD patients also develop cognitive features analogous to those described in adult forms with executive dysfunction and decreased psychomotor speed (Bakels et al., 2022).

The proportion of patients presenting with psychiatric symptoms is similar to adult-onset HD and there is frequent presence of irritability and affective disorders including higher risk of suicide (Ribaï et al., 2007). However, obsessive compulsive behaviors and psychotic symptoms, rare in the adult-onset HD, are common in the JHD population (Fusilli et al., 2018; Moser et al., 2017).

Similar to adult-onset HD, sleep problems and weight loss develop in patients with juvenile forms of the disease (Bakels et al., 2022), although these may become more severe and appear earlier in JHD patients.

Another distinctive characteristic of JHD is epilepsy. Approximately 37.5% of patients with JHD have seizures during the course of the disease (Achenbach et al., 2020), while these are rarely present in adult-onset participants. When present, generalized tonic-clonic seizures are the most frequent, although absences, tonic and myoclonic seizures can also occur. In most cases seizures are easily controlled with a single antiepileptic drug (Cloud et al., 2012).

Importantly, the number of CAG repeats determines the characteristics of the disease. Fusilli et al. categorized 36 JHD patients into two categories using hierarchical clustering, resulting in a highly expanded group (median CAG 86, interquartile range [IQR]: 83–104) and a low expansion group (median CAG of 60.5, IQR: 54–65). In this study, participants with low expansions were more similar to adult HD patients with more frequent chorea at clinical motor diagnosis and comparable survival rates. In contrast, patients with higher expansions had higher rates of developmental delay, severe gait impairment, seizures, and shorter survival rates (Fusilli et al., 2018).

There are few neuropathologic studies in patients with JHD, most having been performed prior to the discovery of the gene. However, certain histological features are characteristic of juvenile patients. On one side, striatal atrophy tends to be more severe, with higher Vonsattel grades and more marked neuronal loss. In addition, there is predominant frontal and parietal atrophy alongside marked neurodegeneration in the thalamus and globus pallidus (Vonsattel et al., 2011). Cerebellar atrophy has also been described in JHD, while it is rare in adult-onset patients. However, most patients with cerebellar atrophy were also epileptic (Latimer et al., 2017) and the administration of antiepileptic drugs is independently associated with cerebellar atrophy (Crooks et al., 2000). Therefore, it is unclear whether the presence of neuronal loss in the cerebellum is secondary to the HTT mutation or to an adverse effect from the medication.

Recent evidence from the Kids-JHD study has also shown that neuropathological findings translate into significant changes in structural MRI metrics. Patients with JHD had decreased total intracranial volume alongside white matter atrophy and neuronal loss in subcortical nuclei compared with controls. There were no abnormalities in cortical thickness, perhaps suggesting that these occur at late stages, however, insufficient sensitivity of the available software to detect change in cortical thickness should also be considered. Interestingly, cerebellar volume was not decreased in structural MRI studies, while it was proportionally enlarged in JHD as a fraction of the total intracranial volume, possibly as a consequence of neuronal loss in supratentorial regions (Tereshchenko et al., 2019). Unfortunately, to the best of our knowledge there are no published studies evaluating diffusion imaging or functional MRI (fMRI) in JHD.

In addition, juvenile patients have significantly increased concentrations of neurofilament light proteins (NfL) (Fig. 1.5) in plasma compared to age-matched controls and premanifest HD, and there seems to be a correlation between caudate and putamen volume with NfL in JHD, as well as with disease burden score (Byrne et al., 2022).

The characteristics of JHD patients are relevant for the development of disease-modifying therapies. The progression of adult-onset HD is usually slow, spanning 2 decades on average from clinical motor diagnosis to death (Rodrigues et al., 2017), with only minor changes in clinical scales over a 2-year timeframe (Tabrizi et al., 2013). In contrast, the rapid slope of decline in JHD may make it easier to demonstrate clinical benefit over a clinical trial period in response to a disease-modifying therapy. However, the severe neuronal loss at clinical motor diagnosis and relatively late diagnosis of JHD, delay treatment initiation until there is excessive neuronal loss, making it difficult to intervene early during the course of the disease.

Figure 1.5  Plasma NfL is elevated in juvenile HD and children within 20 years to clinical motor diagnosis. HD , Huntington's disease; JOHD , juvenile onset HD; NfL , neurofilament light protein. Credit: Reproduced with permission from Byrne et al. (2022).

Finally, most HD animal models have repeat lengths similar to these present in JHD patients, with CAG repeat lengths usually above 100 (Pouladi et al., 2013). Disease-modifying therapies are initially tested in these animal models prior to moving into human participants. Therefore, clinical trials in the JHD population would be, from a genetic perspective, more similar to preclinical studies with experimental drugs (Kordasiewicz et al., 2012; Southwell et al., 2018; Zeitler et al., 2019).

Genetic diagnosis and genetic counseling

Genetic testing for HD may be indicated to confirm the diagnosis in the presence of unequivocal clinical features, or as a predictive test for individuals before clinical motor diagnosis. Information about all four possible outcomes (i.e., normal, intermediate, reduced, and full penetrance) should always be included in the assessment and evaluation of patients at-risk of carrying the HTT expansion (Semaka & Hayden, 2014). Similarly, genetic testing may also be indicated during reproductive counseling in patients at-risk or with confirmed CAG expansions in HTT. Genetic counseling, predictive genetic testing, and reproductive counseling for HD are usually conducted by a clinical geneticist.

Diagnostic genetic testing

A diagnostic genetic test is performed when an individual is symptomatic. The symptoms must include unambiguous motor signs and require a thorough neurological assessment by a trained doctor (Craufurd et al., 2015). Presence of other symptoms, such as mood disturbance, cognitive impairment, or personality changes, without evident motor signs are not sufficiently specific to perform a diagnostic genetic test. Genetic testing in such circumstances would be considered predictive and a referral to genetic counseling is recommended.

Shortly after the HTT mutation was discovered in 1993, direct sequencing of the gene quantifying the number of CAG repeats was made available, making it possible to counsel patients prior to clinical motor diagnosis (The Huntington's Disease Collaborative Research Group et al., 1993). Pretest counseling should be provided even in cases presenting with unequivocal motor signs. The optimal timing needs to be assessed for each patient, and exploration of patient's insight is paramount. Although some patients may be aware of their symptoms, others may have impaired insight, which is a recognized feature of HD (Jankovic & Roos, 2014). Furthermore, due to the inherited nature of HD, there may be wide implications across the family. Therefore, it is advisable that the patient is accompanied to the appointments by a spouse, partner, or close relative when available (Craufurd et al., 2015). Posttest counseling is also recommended independently of the result, during which available treatment options may be discussed.

Predictive genetic testing

Individuals at-risk for inheriting the HTT mutation but currently asymptomatic, or with nonspecific symptoms, may seek predictive testing. Initial guidelines on performing predictive molecular testing were published soon after the discovery of the responsible gene (International Huntington Association and the World Federation of Neurology Research Group on Huntington's Chorea, 1994) being updated in 2013 (Macleod et al., 2013). However, despite its availability, the uptake rate of predictive test has remained low (Nance, 2017).

The predictive test should only be performed in adults freely and voluntarily, after informed consent. A predictive test should not be performed on minors. In the process of the predictive test, a climate of trust must be created with the individual at-risk and it is recommended to conduct it over several visits. During the first visit the family history of the patient should be collected and the patient should be provided with detailed information about the disease (Semaka & Hayden, 2014). The understanding about the disease and motivations to take the test alongside a careful assessment of the mental status should be performed during the second visit, followed by a third visit when the DNA sample is collected. During the fourth visit the patient is advised to attend with a companion to receive the result in a closed envelope. A close follow-up during a fifth visit should be provided after the result is delivered, particularly in case of a positive result as during this period there is increased risk of suicide, and psychological support should be available (Macleod et al., 2013).

Reproductive planning

Genetic testing has a key role in reproductive counseling. Preconception counseling is recommended for couples where one partner is either at-risk of HD or is a carrier of the expanded CAG repeat (Macleod et al., 2013). Reproductive options include:

• Carrying out no additional testing and accepting the 50% risk that each child will develop HD

• Choosing not to have children

• Adoption

• Use of gamete donors

• Prenatal diagnosis, which is performed during pregnancy

• Preimplantation genetic diagnosis (PGD), performed through in vitro fertilization (IVF).

Prenatal diagnosis

Prenatal diagnosis has been available for more than 20 years (Nance, 2017). It involves testing the fetus' DNA, acquired by chorionic villous sampling (CVS) from 11 weeks, or by amniocentesis from 15 weeks of gestation. If the fetus is found to carry the HD gene, the pregnancy can be terminated.

A retrospective study in the United Kingdom reported that a small proportion of parents continue with pregnancy following a positive test result after PND (Piña-Aguilar et al., 2019). Therefore, it is critical to inform potential parents about the implications of not terminating the pregnancy if the fetus is found to have a positive genetic test. Firstly, the procedure would add an unnecessary risk to maternal and fetal health. Secondly—and crucially—the test would be effectively a predictive test for an individual that has not consented to it, and will therefore be a violation of their autonomy.

Both CVS and amniocentesis are invasive, as they require samples from the developing fetus. In consequence, there is a small but significant risk of miscarriage (Alfirevic et al., 2017). However, a recent systematic review and metaanalysis found that the procedure-related risk of miscarriage is smaller than previously thought (Salomon et al., 2019).

Preimplantation genetic diagnosis

Preimplantation genetic diagnosis (PGD) involves extracting DNA from a polar body obtained from an oocyte, or one or more cells biopsied from a developing embryo, performing genetic tests, and using the results to select the desired embryos for uterine transfer (Brezina & Kutteh, 2015). PGD is only performed as part of IVF. One of the advantages of PGD over PND is that it is noninvasive, and there is no risk of induced abortion.

Usually, the blastocyst is biopsied on day five or six removing five to eight trophoectodermal (TE) cells. At this stage cellular loss is less dangerous to the embryo, as the inner cell mass that forms the fetus is undisturbed (De Rycke & Berckmoes, 2020). In a randomized control trial, biopsy at cleavage stage led to maintenance in 30%, whereas nonbiopsy led to 50% live-born infants. In contrast, biopsy at blastocyst stage led to similar levels of live-born infants (51% in biopsy group vs. 54% in control group) (Scott et al., 2013). TE biopsy increases the amount of DNA available for testing, however, there is a low rate of karyotypic discordance between the TE cells and the inner cell mass of 2%–4% (Johnson et al., 2010). TE cells originate from trophoblast, thus PGD using TE cells is analogous to CVS in prenatal diagnosis. Therefore, both approaches share a similar proportion misdiagnoses (Brezina & Kutteh, 2015).

Prenatal testing in patients at-risk

For potential parents at-risk of HD, if they do not wish to undergo predictive testing but want to have children unaffected by HD, they may require PGD with exclusion testing. This involves indirect testing using the genetic markers to identify haplotypes. The embryos that have inherited either of the affected grandparent's haplotype would be discarded (De Rycke & Berckmoes, 2020). However, these embryos also have 50% chance of being unaffected. Consequently, half of the couples will undergo unnecessary IVF/PGD with exposure to adverse events and risks for the female and embryos. Therefore, PGD with exclusion testing is prohibited in certain countries.

In summary, there are multiple options to have children without the disease-causing mutation. The different procedures are subject to ethical implications and local legal regulations, with many techniques not being universally available. Newer, more advanced techniques will provide more precise and less invasive diagnosis. However, comprehensive information should be made available to potential parents with sufficient time, to take the most suitable decision for their individual circumstances.

Imaging

Introduction to neuroimaging techniques

Unlike other neurodegenerative diseases, neuroimaging is not mandatory for the diagnosis of HD, as genetic testing enables precise identification of HD expansion carriers prior to clinical motor diagnosis. However, neuroimaging allows noninvasive visualization and quantification of the impact of pathology across the disease course and has been important in clinical research mapping the trajectory of the natural history of disease. Most recent neuroimaging studies have used 3-Tesla (3T) MRI, as it can capture different tissue properties with good spatial resolution and tissue contrast. MRI also has a favorable safety profile, as it does not rely on ionizing radiation; and it is widely available. Several types of MRI sequences have been applied in HD research, which can be broadly categorized into structural, DWI, and fMRI studies.

In structural imaging, T1-weighted images are used to estimate structural brain volumes as they provide the best contrast between gray matter (GM) and white matter (WM), facilitating the delineation of structures of interest (Zeun et al., 2019). In HD, T1-weighted imaging has been used to characterize the course and pattern of atrophy across the whole brain, including subcortical GM structures, macroscopic WM, as well as cortical thinning. It has demonstrated prominent volume decreases in the striatum, peristriatal WM, and cortex starting years before clinical motor diagnosis. These findings mimic results from postmortem histological studies where atrophy in the same areas has been shown to be the pathological hallmark of the disease (Vonsattel & Difiglia, 1998).

Diffusion-weighted imaging (DWI) measures the movement of water molecules—diffusion—in different tissues, reflecting their interaction with biological barriers such as myelin or cell membranes and thus, also revealing information about the microstructural architecture of the brain (Hagmann et al., 2006; Mori & Zhang, 2006). If there is no structure preventing motion, the displacement of water molecules is isotropic, following a three-dimensional distribution. However, when there are structures, such as axons, that hinder water motion, the distribution of water movement in the tissue becomes restricted in one direction, or anisotropic. These characteristics can be used to infer the orientation and integrity of WM tracts. In neurodegenerative conditions, such as HD, WM tracts become less coherent and more disorganized, resulting in decreased anisotropy and increased diffusivity (Basser & Pierpaoli, 1996).

More recently, newer methods to model DWI data have become available. Neurite orientation dispersion and density imaging (NODDI) differentiates between signal arising from the intracellular, extracellular, and CSF compartments providing a more comprehensive understanding of the biological mechanisms underlying changes in WM microstructure (Berlot et al., 2014; Zhang et al., 2012).

Novel imaging techniques examine subtle microstructural changes that may be undetectable with conventional methods. Multiparametric maps (MPMs) can be used to estimate myelin and iron content within the tissue using magnetization transfer, proton density, longitudinal relaxation (R1), and effective transverse relaxation (R2∗) sequences (Weiskopf et al., 2013). Specifically, R1 has been shown to be more sensitive to myelin than to iron (Stüber et al., 2014), whereas R2∗ is more sensitive to iron content (Edwards et al., 2018; Kirilina et al., 2020). Interpretation of MPMs is dependent on the region being investigated: in subcortical GM, changes in R1 or R2∗ suggest modifications in iron composition. In contrast, in cortex or WM, the same findings indicate changes in iron or myelin. Quantification of iron and myelin content is important in the context of HD, as iron accumulation has been found in the striatum from post-mortem studies of HD brains (Dexter et al., 1991; Simmons et al., 2007). Evidence of myelin damage is less conclusive; although aberrant myelination (de La Monte et al., 1988; Dunlap, 1927; Vonsattel & Difiglia, 1998), and increased oligodendrocyte density has been found in brains from premanifest HD (Gómez-Tortosa et al., 2001).

Lastly, fMRI measures brain activity. Under the assumption that increased neuronal activity is accompanied by an increase in blood flow, fMRI evaluates the increases in signal intensity caused by the changes in the ratio between oxygenated and deoxygenated hemoglobin (Johnson & Gregory, 2019). MRI studies investigate functional connectivity, a descriptive measure of temporal correlations between regional activities or across the whole brain (Gregory & Scahill, 2018). Task-based fMRI is used to assess the spatial distribution of brain activity associated with a specific task. Resting-state fMRI, in contrast, examines the brain at rest, focusing on network connectivity and evaluating the temporal relationship of regions within a network (Rosas et al., 2008).

In this section, we will discuss the key neuroimaging features in carriers of the HTT expansion before and after clinical motor diagnosis. However, as previously mentioned, it is important to note that previous studies classified participants into premanifest, prodromal, and manifest using distinct definitions for clinical motor diagnosis and therefore limiting their comparison. This limitation has been overcome with the HD-ISS which can be used to standardize future clinical trials and observational cohorts (see Chapter 2 Huntington's disease clinical research advances and challenges) (Bates et al., 2015).

MRI features before clinical motor diagnosis

There has been an increasing interest during recent years to investigate imaging biomarkers before clinical motor diagnosis. Atrophy, indicative of irreversible neuronal death, is pronounced by the time of motor diagnosis, particularly in the caudate and putamen, but also evident in striatal WM. Thus, the likelihood of changing the course of HD is possibly higher if patients are treated before clinical motor diagnosis. However, demonstrating an improvement in the natural history of clinical findings in response to treatments will be challenging in this population. Therefore, detailed characterization of imaging biomarkers is crucial.

Figure 1.6  Regional distribution of brain volume change over 12 months. Statistical parametric maps demonstrating significantly higher gray matter (A) and white matter (B) changes between different HD groups and controls. Credit: Reproduced with permission from Tabrizi et al. (2011).

Subcortical MRI features before clinical motor diagnosis

Prominent atrophy in the basal ganglia is one of the pathological hallmarks of HD (Vonsattel et al., 1985). The HD-YAS cross-sectional study including premanifest participants approximately 24 years from clinical motor diagnosis showed that putaminal volume is smaller in HTT expansion carriers than in controls, being the only imaging metric surviving correction for multiple comparisons (Scahill et al., 2020). Other studies including premanifest participants with higher disease burden, hence closer to predicted clinical motor diagnosis, have similarly shown that striatal volumes tend to be smaller in HTT expansion carriers than in controls, and striatal atrophy increases gradually toward clinical motor diagnosis (Fig. 1.6) (Aylward et al., 2000, 2004, 2011; Paulsen et al., 2006, 2008; Ross & Tabrizi, 2011; Tabrizi et al., 2009). Finally, at the time of clinical motor diagnosis, the volume of putamen is 43%–67% of normal volume, and caudate is 59%–60% compared to the volume in healthy controls (Georgiou-Karistianis et al., 2013).

There are volumetric decreases in the caudate and putamen nuclei of premanifest participants (Aylward et al., 2011). Significant longitudinal atrophy in the caudate nucleus was found over a 30-month follow-up in premanifest participants on average 16 years before clinical motor diagnosis (Dominguez et al., 2016). Similarly, greater reduction in the caudate volume was found in those who progressed to clinical motor diagnosis during a 3-year period (Tabrizi et al., 2013). In contrast, other studies have found putaminal volume to be a better predictor of motor phenoconversion (Coppen et al., 2018). The different atrophy rates between caudate and putamen atrophy are possibly related to the anatomical boundaries of the striatal nuclei. There are marked differences in intensity between caudate/CSF and caudate/surrounding WM. These marked differences result in more reliable delineation. In contrast, it is more challenging to accurately define the anatomical boundaries of the putamen (Scahill et al., 2017), since the continuous GM/WM boundary of the putamen is often not well defined on T1 MRI. Therefore, atrophy rates between structures depend on how reliant imaging analysis software is on the different anatomical boundaries and on field strength. In consequence, better definition of subcortical structures with ultra-high field 7T MRI may make it possible in the near future to detect the earliest changes in striatal volume (McColgan et al.,