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Huntington disease
Introduction
George Huntington published his essay “On Chorea” in 1872 (Huntington, 1872), 1 year after graduating from Columbia College of Physicians and Surgeons and while practicing general medicine with his father on Long Island, New York. In this paper, he described many of the clinical features associated with the entity later to carry his name. These features included onset in adulthood, hereditary nature, presence of abnormal movements and behavioral changes, risk for suicidality, and a relentlessly progressive course ( ). The eponym Huntington’s chorea was adapted in the literature to draw attention to chorea (derived from the Latin choreus, meaning “dance” and Greek choros, meaning “chorus”) because it is the clinical hallmark of this neurodegenerative disorder. However, the term Huntington disease (HD) (OMIM 143100) is more appropriate (Penney and Young, 1998; ; ) because chorea is one of several clinical features and may not be present in some.
Although chorea (known as the “dancing mania”) has been recognized since the Middle Ages, the origin of the affected families described by Huntington was traced to the early seventeenth century in the village of Bures in southeast England. The inhabitants of this area later migrated to various parts of the world, accounting for the marked variation in the regional prevalence of HD.
HD is a model neurobehavioral and neurodegenerative disease in which the discovery of a gene mutation is being gradually translated into improved understanding of the mechanisms of cell death and pathogenesis-targeted treatments. Because of availability of predictive testing, the disease has the potential to be amenable to disease-modifying therapies that can be initiated long before the manifestation of symptoms. According to one criterion ( ) “Onset is defined as the point when a person who carries a CAG-expanded Htt allele develops the unequivocal presence of an otherwise unexplained extrapyramidal movement disorder (e.g., chorea, dystonia, bradykinesia, rigidity)” and cognitive impairment.
This chapter will focus on HD; other diseases, such as HDL1, HDL2, and HDL3; dentatorubral-pallidoluysian atrophy; and spinocerebellar ataxia type 17 (SCA17), which may manifest as an HD-like phenotype are discussed in the chapter on chorea and in other reviews ( ; , ; ; ; ; ).
Epidemiology
The prevalence of HD is geographically heterogeneous, probably based on diaspora from southeast England after the founder mutation. Thus, in certain regions of the world, the prevalence is as high as 560 per 100,000 (Moray Firth, Scotland) and 700 per 100,000 (Lake Maracaibo, Venezuela) ( ; Morrison et al., 2010). Based on a meta-analysis of 13 studies, the worldwide prevalence of HD was found to be 2.71 per 100,000 (95% confidence [CI], 1.55–4.72) and the overall incidence was 0.38 per 100,000 per year (95% CI, 0.16–0.94). ( ). The estimated prevalence of HD in the United States is about 6 per 100,000 population ( ), which translates to about 30,000 people with HD and another 200,000 at risk for developing the disease. A detailed study in Northern Ireland found the prevalence of HD to be 10.6 per 100,000, a figure that is based on the affected cases with confirmed molecular diagnosis, because older prevalence figures before 1990 were based on family history and clinical diagnosis only (Morrison et al., 2010). The figure of 10 in 100,000 is consistent with the reported world-wide estimates of prevalence of HD. Although the reason for the higher prevalence of HD in North American and European White populations compared with Asian and black populations is not known, this difference may be partly explained by differences in CAG tract size and Htt haplotypes ( ). There is convincing evidence that the average CAG tract size in European populations (18.4 ± 6 3) is larger than that in Asian and African populations (16.4–16.6 ± 1.5) (Squitieri et al., 2004).
Americo Negrette, a Venezuelan physician, first observed the “dancing mania” of Maracaibo in the 1950s, and his findings later led to seminal expeditions to this region, the discovery of the gene locus (1983), and identification of the gene mutation for HD (1993) ( ). Because many epidemiologic studies were done before the advent of genetic testing, the true prevalence of the HD gene is not known. DNA testing has largely replaced other tests, such as magnetic resonance imaging (MRI) of the brain, in the evaluation of patients with HD.
Clinical Aspects
HD is represented by a broad array of motor, psychiatric, and cognitive features ( ). In a study involving 1901 patients with HD, the following were considered the most frequent presenting symptoms, in descending order: chorea, trouble walking, unsteadiness, irritability, depression, clumsiness, speech difficulty, memory loss, dropping of objects, lack of motivation, paranoia, intellectual decline, sleep disturbance, hallucination, weight loss, and sexual problems ( ). Motor features of HD can include chorea, dystonia, gait and balance impairment, falls, rigidity, and bradykinesia. In addition, motor changes can manifest as abnormal saccades and eye movements, dysarthria and speech abnormalities, and dysphagia. Cognitive features frequently affect executive function, attention, verbal fluency, memory, and judgment. Psychiatric symptoms include depression, anxiety, irritability, apathy, obsessions-compulsions, perseveration, and in some, psychosis and suicidality. Sleep, circadian, and autonomic dysfunction may also accompany HD ( ; ; ).
Motor features
The motor signs and symptoms of HD are highly diverse, with many different phenomenologies of movement disorders represented. Commonly associated with HD, chorea can be present in various bodily regions from face, to extremities, to trunk. Chorea may affect fine and gross motor function, activities of daily living (ADLs), and gait and balance, which can affect quality of life, lead to falls, and affect employability and independence. In addition, chorea may contribute to weight loss with increased energy expenditure, social isolation, increased morbidity, and dependence on others, and eventually lead to institutionalization ( ). In one study, only the change in the Unified Huntington’s Disease Rating Scale (UHDRS) chorea score correlated with the change in the complex task performance, such as peg insertion (Andrich et al., 2007). Although diagnostically helpful, chorea is not a good marker of disease severity or progression ( ). Some patients “camouflage” their chorea by incorporating the involuntary movements into semipurposeful activities, called parakinesias ( ). Interestingly, many HD patients are either unaware of their chorea, deny any symptoms, or have poor insight into their symptoms, sometimes even in the presence of pronounced motor or behavioral problems that interfere with ADLs ( ). In one study of 38 patients with HD, 18 (47.4%) phenoconverted from a presymptomatic state to demonstrating clear evidence of the disease without being aware of their own signs, thus highlighting marked inaccuracy of self-reporting, particularly in early stages of the disease ( ). Unaware patients were less likely to be depressed. Patients with HD are more likely to report functional or motor consequences of chorea such as dropping objects, clumsiness, restlessness, or “twitching.” There is little or no relationship between direct experience or awareness of chorea and actual chorea scores ( ), which may explain why the presence and degree of chorea poorly correlates with functional decline ( ). 
Video 13.1 Huntington disease (HD).
HD also can manifest as hypokinetic (or akinetic)-rigid signs, in adults and more commonly its juvenile form, also termed Westphal variant (described later). Bradykinesia, usually evident in patients with the rigid form of HD, when it coexists with chorea, might not be fully appreciated on a routine examination ( ; ). When present, hypokinesia usually coexists with cognitive and global dysfunction ( ). Variability in isometric grip forces while grasping an object correlates well with UHDRS scores and with progressive motor deficits associated with HD ( ; ). Although bradykinesia was most pronounced in the rigid-akinetic patients, it was also evident in patients with the typical choreic variety of HD, and when bradykinesia predominates, patients exhibit parkinsonian findings. Assessing simple repetitive movements, such as tapping, correlates with UHDRS scores and may be used to follow progression of HD (Andrich et al., 2007). Variability in speeded and metronome tapping tasks was reported in premanifest and manifest HD in one cross-sectional study, with associations with not only later HD stages and UHDRS total motor scores (TMSs), but also gray matter atrophy and cortical thinning on brain MRI ( ). Such motor deficits may provide a possible outcome measure for use in future preventive clinical trials ( ). Micrographia also may be one manifestation of underlying parkinsonism ( ). Theories regarding bradykinesia in HD include an expression of postsynaptic parkinsonism invoking both direct and indirect pathways result from degeneration of the basal ganglia output to the supplementary motor areas concerned with the initiation and maintenance of sequential movements and failure of thalamocortical relay of sensory information ( ). These theories may explain why a reduction in chorea with antidopaminergic drugs rarely improves overall motor functioning and indeed can exacerbate motor impairment. Although bradykinesia associated with HD usually does not respond to dopaminergic therapy, late-onset levodopa-responsive HD presenting as parkinsonism has been documented ( ). Regarding the course of choreatic versus hypokinetic-rigid HD motor subtypes, a study from the European HD Network REGISTRY study investigated 4135 subjects who were classified at baseline as either predominantly choreatic (n = 891), hypokinetic-rigid (n = 916), or mixed-motor (n = 2328) and followed for up to 6 years ( ). Over the follow-up period, the predominantly choreatic group showed a significant decrease in chorea, whereas the predominantly hypokinetic-rigid group had a slight increase in hypokinesia and rigidity. Those with predominantly chorea, had significantly faster rates of change over time in their total functional capacity (TFC) and cognitive scores (Stroop and verbal fluency tests). In a study analyzing 7311 manifest HD participants from the Enroll-HD study, motor deficits were worse for those HD with late onset (onset at 60 years or older) at early stages of HD and for young onset HD (onset <30 years) at more advanced stages, who also had a faster functional decline as measured by TFC scores ( ).
Fine and gross motor functions are frequently affected in HD. Gait impairment and postural instability increase with disease progression. Gait changes in HD are characterized by slowness, reduced speed, and increased variability in measures of step length, stride time, and symmetry ( ). Balance impairment reflects dysfunction in ability to anticipate changes in the base of support and perturbation and difficulty with dual-task function, particularly in the setting of cognitive changes. In one study of 24 patients with HD, 14 (58.3%) reported at least 2 falls within the previous 12 months and the fallers had worse scores on Berg Balance Scale (BBS) and the Timed Up & Go (TUG) test ( ). Although loss of balance, postural instability, and falls are usually considered features of more advanced disease, computerized dynamic posturography detected impaired postural stability even in premanifest HD, suggesting that this abnormality may be a highly sensitive indicator of early motor impairment in HD ( ).
Other motor symptoms that can accompany HD include dystonia, ataxia, bruxism, myoclonus, tics and tourettism, dysarthria, dysphagia, and aerophagia ( ; ; ; ; ; ; ; Jankovic and Ashizawa, 2003; ) ( , , , ). Rarely, patients with HD present with tics and other features suggestive of adult-onset Tourette syndrome (tourettism) ( ) ( ). Dysphagia is one of the most troublesome and potentially life-threatening symptom of HD, particularly in advanced stages. A dysphagia scale has been developed to assess the severity of this symptom ( ). Another characteristic feature of HD is the inability to maintain tongue protrusion, representing motor impersistence (sometimes also referred to as “negative chorea”) ( , ). Motor impersistence, the inability to hold constant a voluntary muscle contraction, is also described regarding hand grip, or the so-called milkmaid grip. Hung-up and pendular reflexes are also typically present in patients with HD ( ) ( ).
Video 13.2 Huntington disease (HD).
Video 13.3 Huntington disease (HD).
Video 13.4 Huntington disease (HD).
Video 13.5 Huntington disease (HD).
Video 13.6 Huntington disease (HD).
Video 13.7 Huntington disease (HD).
Video 13.8 Huntington disease (HD).
Eye movements can be impaired in manifest HD and in its early stages or presymptomatic individuals. In a large Venezuelan kindred study (n = 593), generation of fine motor movements and rapid eye saccades was impaired in about 50% of at-risk individuals ( ). At-risk individuals with these findings were more likely than those without them to develop overt HD within several years; these abnormalities were thought to represent the earliest clinical manifestations of the disease. If the first examination was normal, there was only a 3% risk for developing symptomatic HD within 3 years. HD patients have greater defects in initiating internally than externally generated saccades ( ). In 215 individuals who were at risk for or recently diagnosed with HD, a high-resolution, video-based eye tracking system demonstrated three types of abnormalities while performing memory-guided and antisaccade tasks: increased error rate, increased saccade latency, and increased variability of saccade latency ( ). Abnormalities in saccadic latency have been demonstrated in premanifest HD patients ( ). In another study, initiation deficits of voluntary-guided, but not reflexive, saccades occurred in individuals with preclinical HD ( ). Voluntary-guided saccades in 25 presymptomatic HD individuals correlated with deficits in white matter tracts as determined by diffusion tensor brain MRI ( ). Antisaccade performance correlated with brain volume loss in the caudate and globus pallidus (GP) and with thinning of the occipital and parietal lobes. Oculomotor defects may be seen in presymptomatic patients with a predicted time to clinical onset of up to 10 years ( ). Additional neuro-ophthalmologic abnormalities in HD include increased blink rates ( ; ), irregular elevations of eyebrows as a result of frontalis muscle choreic contractions and eye closures with irregular narrowing of palpebral fissures, rarely leading to frank blepharospasm, and apraxia of eyelid opening and closure ( ).
Psychiatric features
A range of psychiatric features have been well documented in HD. These symptoms include personality changes, agitation, irritability, anxiety, apathy, social withdrawal, impulsiveness, depression, mania, paranoia, delusions, hostility, hallucinations, psychosis, and various sexual disorders (Fedoroff et al., 1994; Litvan et al., 1998; ; ; ; ). In a study of 52 patients with HD, Paulsen and colleagues (2001a) found the following neuropsychiatric symptoms in descending order of frequency as represented by greater than 65%: dysphoria, agitation, irritability, apathy, anxiety; in 20% to 50%: disinhibition, euphoria, and aggression; in 5% to 12%: delusions and compulsions; and in less than 5%: hypersexuality and hallucinations ( ). In HD mutation, carriers from the European HD Network REGISTRY study, the majority exhibited some type of neuropsychiatric symptoms, and four distinct behavioral patterns were identified: depression, irritability/aggression, psychosis, and dysexecutive (which included apathy and obsessive and compulsive behaviors) ( ; ). In a study using the Enroll-HD database, incidence of behavioral symptoms in individuals with manifest HD was highest with those with early onset symptoms (26%), compared to those with late onset (11%) or mid-adult onset (19%) ( ).
Video 13.9 Huntington disease (HD).
Depression represents the most frequent psychiatric symptom in HD patients ( ), with estimated prevalence rates of 40% to 50%, ranging from 9% to 63%. Depression may precede the onset of HD motor symptoms. In one study of presymptomatic individuals at risk for HD, gene carriers were 1.74 times (95% CI, 1–3.07) more likely to report depression than noncarriers, and the rate of depression increased when closer to clinical onset ( ). However, data from the PREDICT-HD study found that depressive symptoms were more prevalent in mutation carriers but did not increase with proximity to HD diagnosis ( ). In this study, increased depressive symptoms were associated with female gender, history of depression, and a slight decrease in functioning but not with time since genetic testing. Depression, poor impulse control, anxiety, and other socioeconomic factors associated with HD contribute to the markedly increased risk for suicide in patients with HD. Suicide rate in patients with HD is about 10 times greater than in the general population, that is, 138 per 100,000 person years compared with 12 to 13 per 100,000 person years in the general population ( ; ) and about 4 times the expected rate for corresponding U.S. White population in which a review of records of 452 deceased patients diagnosed with HD documented that 5.7% of deaths were attributed to suicide ( ). In a study of 506 individuals with documented or suspected HD, suicide represented the third most common cause of death, accounting for 12.7% of 157 ascertained deaths, after bronchopneumonia (31.8%) and heart disease (15.3%) ( ). In the REGISTRY study, 169 (8.0%) mutation carriers expressed suicidal ideation ( ), which was independently correlated with the following at baseline: disease duration, anxiety, aggression, previous suicide attempt, and a depressed mood. In a cross-sectional study of 2835 patients with “definite” diagnosis of HD with disease onset at age 20 years or later, mean age of 49.6 years, and duration of symptoms for a mean 7.6 years, 50.3% reported seeking treatment for depression and 10.3% reported at least on suicide attempt ( ). Patients endorsing current symptoms of depression were twice as likely to have attempted suicide in the past as those who deny symptoms of depression (15.7% versus 7.1%). In another study using UHDRS in 4171 patients with HD, the frequency of suicidal ideation doubled from 9.1% in at-risk persons with normal neurologic examination to 19.8% in at-risk individuals with soft neurologic signs and increased to 23.5% in persons with “possible” HD. In patients with diagnosed HD, the risk for suicidal ideation increased from 16.7% at stage 1 to 21.6% at stage 2 and decreased thereafter to 19.5%, 14.1%, and 9.8% in stages 3, 4, and 5, respectively ( ). Thus, the most critical periods of suicide risk are immediately before receiving a formal diagnosis of HD and in stage 2 of the disease, when activities, such as driving and taking care of personal finances, are beginning to be restricted and patients are becoming more dependent on others.
Other psychiatric symptoms include anxiety, which has been reported in 17% to 61% ( ). Anxiety, in contrast to depression, may be independent from the stage of illness. Irritability is commonly reported, with rates between 35% and 73% and potential increases during the disease course, associated with functional decline. Behaviors such as anxiety, irritability and agitation have been related to degeneration of striatal and orbitofrontal-subcortical circuitry (Litvan et al., 1998). Criminal behavior, closely linked to the personality changes, depression, and alcohol abuse, has been reported to be more frequent in patients with HD than in nonaffected first-degree relatives ( ). Such behavior might be a manifestation of an impulsive disorder as part of disinhibition, seen not only in HD, but also in other frontal lobe–basal ganglia disorders, particularly Tourette syndrome ( ). Obsessive and compulsive symptoms are less common than other psychiatric symptoms, with prevalence rates ranging from 7% to 50%, but can be associated with other psychiatric comorbidities ( ). Similarly, these behaviors and mental inflexibility and perseveration may result from corticostriatal dysfunction. Apathy, however, may overlap with mood dysfunction (e.g., depression) and cognitive impairment, with putative underlying anterior cingulated–subcortical circuit dysfunction. Apathy is thought to occur in about 50% to 70% of HD, with increasing rates in later disease stages ( ). Psychosis, including paranoia and delusions, occurs in about 3% to 11%; use of antidopaminergic/antipsychotic medications for treatment of hyperkinetic motor symptoms may influence prevalence rates of psychosis in HD.
Cognitive features
The cognitive profile of HD has been characterized by subcortical deficits such as executive dysfunction, attention deficits, cognitive slowing, and visuoperceptual and construction impairment, which are thought to reflect underlying frontostriatal disruption ( ; ). Executive dysfunction in HD manifests as poor planning and organizing, adapting to alternatives, and mental flexibility. Later in the disease, impaired episodic memory, learning, and spatial navigation may be impaired. Early studies demonstrated dementia was found in 66% of 35 HD patients ( ). In keeping with a subcortical dementia, the profile of HD cognitive impairment differs from that of Alzheimer dementia with more prominent executive dysfunction and with a memory impairment characterized by greater retrieval deficits than encoding dysfunction.
Cognitive decline may occur as an early symptom, as described by self-report or on neuropsychologic testing. From the REGISTRY study, 8.4% of 615 patients reported having cognitive features as first disease symptoms, with an additional 13.2% reporting a mixed onset of motor and/or cognitive and/or psychiatric symptoms ( ). Whereas some studies ( ) showed that cognitive deficits correlated with the number of CAG repeats in asymptomatic carriers of the HD gene, other studies found no correlation between cognitive decline and CAG repeats in symptomatic patients with HD ( ). Tasks requiring psychomotor or visuospatial processing, such as skills tested by the Trail Making B and Stroop Interference Test, are impaired early in the course of the disease and deteriorate at a more rapid rate than memory impairment (Bamford et al., 1995). Progressive decline in attention and executive function, consistent with frontostriatal pathologic findings, has been identified in early HD ( ). In the PREDICT-HD study, mild cognitive impairment was noted in nearly 40% of 575 patients before motor diagnosis of HD ( ). Furthermore, cognitive dysfunction has been linked to mobility impairments in HD. In a retrospective study of 70 HD patients, mobility as reported on gait and balance measures correlated with executive function cognitive measures (phonemic verbal fluency, Symbol Digit Modalities Test, and Stroop Test); the latter two cognitive tests were significant predictors of the Tinetti Mobility test scores ( ). Compared with age-matched controls, HD patients (n = 17) had worse postural control under dual-task conditions and decreased visuospatial performance that correlated with greater total sway and jerk balance measures ( ). In addition to deficits in visual and auditory perception, patients with HD have impaired recognition of emotional facial expression ( ). Social cognition may be impaired in symptomatic and premanifest HD (Bora et al., 2016), with a meta-analysis demonstrating that HD patients were significantly impaired on theory of mind and emotion recognition to both facial and vocal stimuli, particularly in negative emotional contexts. Speech and language also may be affected in HD, possibly as result of striatal degeneration ( ). One study showed that high levels of insulin-like growth factor I (IGFI) are associated with cognitive deficits in HD ( ).
Asymptomatic at-risk individuals who are positive for the HD gene or the marker do seem to differ in their cognitive performance from asymptomatic at-risk individuals who are negative for the HD gene or marker ( ; ; ). Most studies have found that neuropsychological tests do not differentiate between presymptomatic individuals who are positive for the HD gene and those who are negative ( ; ), but some studies have found that cognitive changes might be the first symptoms of HD ( ). In a longitudinal study by the Huntington Study Group of 260 individuals who were considered to be at risk for HD, Paulsen and colleagues (2001b) found that this group had worse scores on the cognitive section of the UHDRS at baseline, an average of 2 years before the development of motor manifestations of the disease.
Other features
In addition to motor, psychiatric, and cognitive changes, many HD patients lose weight during the course of their disease, despite increased appetite ( ). Weight loss in HD increases with higher CAG repeats ( ). Weight loss is not unique for HD among the neurodegenerative disorders; for example, it is typically seen in patients with Parkinson disease (PD) ( ). The pathogenesis of weight loss in HD is unknown, but one study showed that patients with HD have a 14% higher sedentary energy expenditure than that of controls and that this appears to be correlated with the severity of the movement disorder ( ). Although chorea and dystonia were not major determinants of disability, chorea was associated with weight loss. The lower body mass index in HD parallels the weight loss in transgenic mice, suggesting that it represents a clinical expression of the gene abnormality associated with HD ( ; ). Weight loss, alterations in sexual behavior, and changes in wake-sleep cycle in HD have been attributed to involvement of the hypothalamus even in early stages of HD as demonstrated by positron emission tomography (PET) and postmortem studies ( ).
Juvenile Huntington disease
About 10% of HD cases have their onset before age 20, termed juvenile HD. Juvenile HD is usually inherited from the father (paternal versus maternal inheritance for patients with onset before age 10 years is 3:1). Juvenile HD is associated with higher CAG repeats (Andresen et al., 2007; ), typically greater than 50 CAG reports. In one study, 54% of juvenile HD cases had 60 or more CAG repeats ( ). In one case of HD, associated motor neuron disease may have accounted for the progressive muscle atrophy ( ). Juvenile HD typically manifests with the combination of progressive parkinsonism, dementia, ataxia, myoclonus, and seizures and with less chorea than adult-onset HD. In one study of juvenile HD, 33% had seizures, generalized tonic-clonic being the most common, followed by tonic, myoclonic, and staring spells ( ). Myoclonus is particularly common in patients with juvenile HD ( ) ( ), and progressive myoclonic epilepsy has been reported as the initial presentation of juvenile HD ( ) ( , , ). Duration of illness is approximately 5 to 15 years. 
Video 13.10 Huntington disease (HD).
Video 13.11 Huntington disease (HD).
Video 13.12 Huntington disease (HD).
Assessments
The UHDRS was developed to assess and quantify various clinical features of HD, specifically motor function, cognitive function, behavioral abnormalities, and functional capacity (Huntington Study Group, 1996; ). A shortened version of the UHDRS has been validated ( ). When so-called “soft signs” are identified at the initial evaluation, the cumulative relative risk for HD diagnosis at 1.5 years is 4.68 times greater than in controls ( ). Although in contrast to other neurodegenerative diseases such as Alzheimer disease (AD) and PD, HD has an excellent “trait” biomarker, namely the genetic test for expanded CAG repeats; however, there is a need to develop a sensitive “state” biomarker that would reliably monitor the progression of the disease ( ). In a systematic review and meta-analysis of clinical variables, the UHDRS Motor, UHDRS Independence, and Trail B were found to be the best determinants of separation between HD stages ( ). In a meta-analysis of randomized controlled trials (RCTs) and cohorts to determine the most appropriate outcomes, the TFC score and the TMS of the UHDRS were considered the most appropriate outcomes ( ). The lowest number of subjects required per group in an RCT was 19 (for TFC) and 30 (for TMS). The verbal fluency test was most appropriate to assess cognition. To longitudinally assess patients at advanced stages of HD, a specifically designed instrument, UHDRS–For Advanced Patients (UHDRS-FAP), was developed and found to be more sensitive to change than the original UHDRS for both motor and cognitive domains ( ). An index, referred to as CAP, consisting of age × (CAG 30 – L), where age is the current age of the individual, CAG is the repeat length, and L is a constant near the threshold of CAG repeat expansions for disease seems to be a good predictor of clinical progression ( ).
Regarding early clinical detection, Siemers and colleagues (1996) found subtle but significant abnormalities in simple and choice movement time and reaction time in 103 truly presymptomatic carriers of the HD gene. These deficits correlated well with number of CAG repeats. In a follow-up longitudinal study of 43 at-risk individuals, Kirkwood and colleagues (1999) found that the following variables declined more rapidly among the presymptomatic gene carriers (n = 12) than among the noncarriers (n = 31): psychomotor speed (digit symbol subscale of the Wechsler Adult Intelligence Scale), optokinetic nystagmus, and rapid alternating movements. In contrast to the UHDRS, which is not very sensitive in detecting early clinical signs of HD, careful gait and balance analysis has detected gait bradykinesia and dynamic balance impairment in presymptomatic HD gene carriers with otherwise normal neurologic examination ( ). In the PREDICT-HD study, 505 at-risk individuals, 452 of whom had more than 39 CAG repeats, but have not yet met clinical criteria for the diagnosis of HD, the striatum MRI volume decreased from 17.06 cm 3 at diagnostic confidence level of 0 to 14.89 cm 3 at diagnostic confidence level of 3 (probable HD, with a mean CAG repeat number of 44 and mean motor UHDRS score of 16.92) ( ). The study found that smaller striatal volume, reduced finger tapping speed and consistency, and impaired odor identification were among the best markers of “preclinical” HD ( ). Additional analyses found that even subtle abnormalities in finger tapping (bradykinesia), tandem gait, Luria test, saccade initiation, and chorea were associated with high probability of disease diagnosis ( ). The Luria manual sequencing task, which consists of three steps (make a fist, tap ulnar aspect of open palm, palm down fingers extended) is often abnormal in patients with frontal dysfunction. Of the 1078 individuals with a CAG expansion included in the analysis of the PREDICT-HD, followed for up to 12 years (mean: of 5.1 years), 225 (21%) received a motor diagnosis of HD during the study ( ). The strongest predictors were in the motor, imaging, and cognitive domains: an increase of 1 SD in TMS (motor domain) increased the risk for a motor diagnosis by 3.1 times, a reduction of 1 standard deviation (SD) in putamen volume (imaging domain) increased risk by 3.3 times, and a reduction of 1 SD in Stroop word score (cognitive domain) increased risk by 2.3 times.
Several reviews from the International Parkinson’s Disease and Movement Disorder Society on rating scales used in HD have been published ( , , , , ). From six rating scales assessing motor features of HD, excluding performance testing and quantitative motor rating methods, only the UHDRS-TMS was classified as “recommended” ( ). Regarding behavioral symptoms, three rating scales were “recommended” for screening purposes, including the Irritability Scale for Irritability, Beck Depression Inventory–II, and Hospital Anxiety and Depression Scale for depression ( ). Assessment of behavioral symptoms can be challenging because multiple behavioral symptoms occur together, patients may have limited insight, and scales may be targeted to capture severity or change with intervention or time. Regarding cognition, the Montreal Cognitive Assessment (MoCA) was “recommended with caveats” for evaluating severity of cognitive impairment but “suggested” for screening ( ). Several other scales such as the UHDRS Cognitive Assessment, the UHDRS–For Advanced Patients cognitive section, the Alzheimer’s Disease Assessment Scale–Cognitive Subscale, the Frontal Assessment Battery, the Mattis Dementia Rating Scale, the Mini-Mental State Examination, and the Repeatable Battery for the Assessment of Neuropsychological Status were “suggested” for evaluating severity of cognitive impairment. Smartphone-based cognitive assessments for performance-based cognitive tasks have been explored in a pilot study of manifest and premanifest HD, demonstrating feasibility and medium to strong correlations with more “traditional” cognitive tasks; further investigation of mobile technologies for cognitive and other clinical features of HD will be needed ( ). Given the effects of HD on functional ability, several performance-based measures (e.g., balance, walking, and reaching/grasping) have been examined. In the review, three performance-based measures were rated as “recommended”: the Tinetti Mobility Test for screening of fall risk and for severity assessment of mobility in patients with manifest HD (up to stage III); the BBS for severity of balance impairment; and the Six-Minute Walk Test for assessment of walking endurance (severity) in HD subjects with preserved ambulation ( ). Quality of life, as reported by both patient- and caregiver-reported outcome measures, is recognized as an important determinant in HD. Studies have shown that the “work” and “alertness behavior” domains of the Sickness Impact Profile are affected the most ( ) and that depressive mood and functional disability as measured by the 36-Item Short-Form Health Survey are key factors in health-related quality of life in HD (Ho et al., 2009). In the recent critique, the Medical Outcomes Study 36-Item Short-Form Health Survey as “recommended” for patient-outcomes but that further validation of HD-specific health-related quality of life measures was needed.
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