The Neuropsychology of Huntington's Disease

Archives of Clinical Neuropsychology 32 (2017) 876–887

The Neuropsychology of Huntington’s Disease Julie S. Snowden* Greater Manchester Neuroscience Centre, Salford Royal NHS Trust, Salford, UK Downloaded from https://academic.oup.com/acn/article/32/7/876/4161107 by guest on 27 September 2021 Division of Neuroscience and Experimental Psychology, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK

*Corresponding author at: Cerebral Function Unit, Greater Manchester Neuroscience Centre, Salford Royal NHS Trust, Salford M6 8HD, UK. Fax: +44-161-206-0388; Tel.: +44-161-206-2561. E-mail address: [email protected] (J.S. Snowden). Editorial Decision 25 August 2017; Accepted 4 September 2017

Abstract Huntington’s disease is an inherited, degenerative brain disease, characterized by involuntary movements, cognitive disorder and neuropsychiatric change. Men and women are affected equally. Symptoms emerge at around 40 years, although there is wide variation. A rare juvenile form has onset in childhood or adolescence. The evolution of disease is insidious and structural and functional brain changes may be present more than a decade before symptoms and signs become manifest. The earliest site of pathology is the striatum and neuroimaging measures of striatal change correlate with neurological and cognitive markers of disease. Chorea and other aspects of the movement disorder are the most visible aspect of the disease. However, non-motor features have greatest affect on functional independence and quality of life, so require recognition and management. The evidence-base for non-pharmacological treatments in Huntington’s disease is currently limited, but recent intervention studies are encouraging.

Keywords: Huntington’s disease; Movement disorders; Subcortex; Basal ganglia; Congenital/genetic Disorders; Executive functions

Introduction and Epidemiology

Huntington’s disease (HD) is an inherited degenerative disorder of the brain, caused by an expansion in the number of CAG repeats in the huntingtin gene on chromosome 4 (Huntington’s Disease Collaborative Research Group, 1993). The mode of inheritance is autosomal dominant and is fully penetrant. Thus, children of an affected parent, both male and female, have a 50% risk of inheriting the faulty gene and gene carriers will develop symptoms of disease during a normal life span. The mean age at which symptoms and signs appear is around 40 years (Harper, 1991), but there is wide variation. In around 5% of cases onset is in childhood or teenage years, referred to as juvenile HD (Quarrell, 2014). At the other extreme, people may remain symptom-free until the seventh or eighth decade of life, referred to as late onset HD. The course of disease is insidiously progressive, the duration of illness from diagnosis to death being about 15–20 years. The insidious evolution of disease is important. Structural and functional brain changes and subtle cognitive, behavioral, and motor changes may begin years before the characteristic physical symptoms and signs are sufficiently manifest to warrant a clinical diagnosis of HD (Brandt, Shpritz, Codori, Margolis, & Rosenblatt, 2002; Paulsen et al., 2008; Paulsen, Smith, & Long, 2013; Stout et al., 2011; Tabrizi et al., 2009, 2012, 2013). The term “manifest HD” refers to “clinically evident” HD, which is not equivalent to “onset of the disease process”, which may be more than a decade earlier. HD occurs worldwide. The overall incidence and prevalence of disease is difficult to determine with accuracy. Like any strongly genetic condition there is geographical clustering so that epidemiological studies that sample from a limited geographical area can result in underestimation or overestimation of overall prevalence. Nevertheless, it is clear that HD is most common in populations of European descent (Kay, Fisher, & Hayden, 2014), and genealogical studies have identified foun- ders from northern Europe, particularly the United Kingdom (Harper, 1992). Current figures for the UK, where prevalence has been most intensively investigated, suggest a prevalence rate in excess of 10 cases per 100,000, with higher than average

© The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: [email protected]. doi:10.1093/arclin/acx086 Advance Access publication on 18 September 2017 J.S. Snowden / Archives of Clinical Neuropsychology 32 (2017); 876–887 877 prevalence in Scotland and northeastern England (Evans et al., 2013). The highest prevalence estimate reported in North America is 13.7 per 100,000 in the Canadian province of British Columbia (Fisher & Hayden, 2013), with substantially higher prevalence in Caucasians than in other ethnic groups.

Neuropathology

HD is a degenerative brain disease, involving progressive atrophy of the brain. The major and earliest site of pathology is the neostriatum, which encompasses the caudate nucleus and putamen (Vonsattel & DiFiglia, 1998; Vonsattel, et al., 1985). The mutated huntingtin protein—the CAG repeat mutation—is assumed to have a toxic function causing neuronal death, the striatum being particularly vulnerable. More widespread brain atrophy is found over the disease course, reﬂecting loss of structural and functional connectivity between striatum and other parts of the brain. HD has provided a model for understand- Downloaded from https://academic.oup.com/acn/article/32/7/876/4161107 by guest on 27 September 2021 ing the role of the basal ganglia in cognition.

Clinical Characteristics

HD gives rise to a triad of clinical features: motor, cognitive, and neuropsychiatric. The movement disorder is distinctive and is the hallmark of the disease. The most characteristic feature is chorea, rapid involuntary movements of the face, trunk, and limbs. Until recent years HD was known as Huntington’s chorea, reﬂecting that aspect of the movement disorder empha- sized by the eponymous George Huntington in his seminal description of the disease (Huntington, 1872). However, chorea is not the sole motor characteristic (Roos, 2014). People with HD also show dystonia, slow twisting movements of the limbs, as well as bradykinesia, slowed execution of movements, and limb rigidity, akin to that seen in Parkinson’s disease. These different motor features may co-occur, albeit with variable prominence in different individuals. Notably, juvenile HD is more often associated with prominent bradykinesia than with chorea (Hayden, 1981; Van Dijk, van der Velde, Roos, & Bruyn,1986). Choreiform movements may be striking to the external observer. Yet such movements are rarely a source of complaint to people affected with HD. Indeed, affected individuals report chorea to be less of a problem than do their caregivers (Simpson, Lovecky, Kogan, Vetter, & Yohrling, 2016) and studies have consistently shown reduced awareness of chorea in people with HD (Sitek et al., 2011; Snowden, Craufurd, Grifﬁths, & Neary,1998; Vitale et al., 2001). The cognitive and neuropsychiatric characteristics of disease are less immediately evident but their recognition is crucial. They contribute greatly to the affected person’s loss of functional independence and they have greatest impact on families (Beglinger et al., 2010; Hamilton et al., 2003; Marder et al., 2000; Mayeux, Stern, Herman, Greenbaum, & Fahn,1986; Nehl, Paulson, & Huntington Study Group, 2004; Ready, Mathews, Leserman, & Paulsen, 2008; Rothlind, Bylsma, Peyser, Folstein, & Brandt,1993; Simpson et al., 2016; Tabrizi et al., 2013). These features are considered below.

Neuropsychological Features

The salient changes in HD are in the domains of psychomotor and executive skills, memory, emotion processing, and social cognition.

Psychomotor Slowing

The earliest change and best predictor of disease progression is psychomotor slowing (Snowden, Craufurd, Griffiths, & Thompson, 2001; Snowden, Craufurd, Thompson, & Neary, 2002; Stout et al., 2011; Tabrizi et al., 2009, 2012, 2013). Slowing is demonstrated most commonly on timed tasks such as Stroop, Digit symbol substitution and Trail making (Snowden et al., 2001; Starkstein et al., 1992; Stout et al., 2012; Tabrizi et al., 2012, 2013). Cognitive slowing is found in the “pre-manifest” stages of HD (Foroud et al., 1995; Kirkwood et al., 1999; Maroof, Gross, & Brandt, 2011; Snowden et al., 2002; Stout et al., 2012; Tabrizi et al., 2012, 2013), and is reported to be a significant predictor of functional capacity in daily life (Eddy & Rickards, 2015a). Interestingly, the word reading component of the Stroop test is a more sensitive marker of change than the more demanding Interference component (Snowden et al., 2001; Tabrizi et al., 2012), attributed to a failure to “automatize” the simpler psychomotor task (Snowden et al., 2001). Psychomotor slowing has considerable practical impact in daily life. It has been found, for example, to be a significant predictor of driving cessation (Beglinger et al., 2012). 878 J.S. Snowden / Archives of Clinical Neuropsychology 32 (2017); 876–887

Executive Skills

Executive difficulties in HD include problems in planning (Lawrence et al.,1996; Unschuld et al., 2013; Watkins et al., 2000), organization and sequencing (Snowden et al., 2001), cognitive flexibility and set shifting (Lawrence et al., 1996; Paulsen et al., 1995b; Watkins et al., 2000). In early studies, the Wisconsin Card Sorting test was commonly used to measure cognitive flexibility (Josiassen, Curry, & Mancall, 1983; Paulsen et al., 1995b; Pillon, Dubois, Ploska, & Agid, 1991; Weinberger, Berman, Iadarola, Driesen, & Zec, 1988), although its use has diminished in recent years. People with HD commonly also show reduced performance on verbal fluency tasks (Henry, Crawford, & Phillips, 2005; Rohrer, Salmon, Wixted, & Paulsen,1999; Rosser and Hodges, 1994). Cognitive slowing as well as executive difficulties in strategic search are likely to contribute to low scores (Henry et al., 2005; Rohrer et al., 1999). A common practical difficulty observed in HD is in multi-tasking. In keeping with this, there is neuropsychological evidence of problems in attention (Georgiou, Bradshaw, Phillips, Bradshaw, & Chiu, 1995; Sprengelmeyer, Lange, & Homberg, Downloaded from https://academic.oup.com/acn/article/32/7/876/4161107 by guest on 27 September 2021 1995). It is worth highlighting, however, that dual task difficulty in HD extends to tasks that in healthy individuals would be considered relatively undemanding of attention, such as bimanual motor tapping (Thompson et al., 2010) and walking concur- rently with carrying out a cognitive task (Delval et al., 2008). Such findings indicate that ostensibly “automatic” tasks require more conscious attention in people with HD.

Memory

Memory difficulties are commonly reported in HD and may be noticed by the affected person as well as by their relatives (Cleret de Langavant et al., 2013). Memory studies have shown proportionally poorer free recall than recognition memory and cued recall (Butters, Salmon, & Heindel,1994; Butters, Wolfe, Martone, Granholm, & Cermak,1985; Lundervold, Reinvang, & Lundervold,1994; Pillon, Deweer, Agid, & Dubois, 1993), more passive learning strategies in HD than controls (Lundervold et al., 1994), problems in source memory (Brandt, Bylsma, Aylward, Rothlind, & Gow, 1995) and in prospective memory (Nicoll et al., 2014) and relative preservation of retention from immediate to delayed recall. The profile of memory disturbances suggests a strong executive contribution to memory failures, in keeping with disruption to striatal-frontal pathways. Aside from problems in declarative memory (i.e. explicit memory for material previously presented), people with HD show problems in procedural memory (i.e. skill and habit learning). Difficulties have been demonstrated on tasks involving motor skill learning (Gabrieli, Stebbins, Singh, Willingham, & Goetz, 1997; Heindel, Butters, & Salmon, 1988), serial reaction time (Knopman & Nissen, 1991), and sequence learning (Thompson et al., 2010; Willingham & Koroshetz, 1993; Willingham, Koroshetz, & Peterson, 1996). Problems in procedural memory are consistent with the findings of difficulties in simultaneous execution of relatively low level, “automatic” tasks. The study of HD has been key to understanding of the role of the basal ganglia in memory (Salmon & Butters, 1995).

Emotion Processing and Social Cognition

There is substantial evidence that people with HD have difficulty processing facial expressions of emotion. Early reports suggested that the difficulty was particularly prominent for the emotion of disgust (Sprengelmeyer et al., 1996, 1997), although more recent studies have found deficits at least as great for other negative emotions, in particular anger and fear (Aviezer et al., 2009; Calder et al., 2010; Henley et al., 2008, 2012; Snowden et al., 2008). Impairments are cross modal, affecting recognition of vocal as well as facial emotions (Calder et al., 2010; Snowden et al., 2008). Difficulties in emotional expression as well as recognition have also been demonstrated (Trinkler, Cleret de Langavant, & Bachoud-Lévi, 2013). Emotion processing is important in HD, firstly because deficits appear at a very early stage of disease, including the preclinical phase (Johnson et al., 2007; Labuschagne et al., 2013; Tabrizi et al., 2009) and secondly, because they potentially contribute to the social breakdown and reduction in sympathy and empathy that are common features of HD. Social breakdown in daily life encompasses difficulties with interpersonal relationships and reduced flexibility in adapting to the needs of others as well as impaired regulation of behavior in accordance with social conventions. Other aspects of social cognition may also be compromised. People with HD perform poorly on tests of “Theory of mind” that require attribution of intentions, beliefs, and mental states (Allain et al., 2011; Brune, Blank, Witthaus, & Saft, 2011; Eddy, Sira, & Rickards, 2012, 2014; Snowden et al., 2003), recognition of socially inappropriate behavior (Eddy et al., 2012) and sarcasm (Philpott, Andrews, Staios, & Churchyard, 2016). The precise interpretation of these findings and relationship between social cognitive and executive impairments is a subject of debate (Allain et al., 2011; Eddy et al., 2012; Philpott J.S. Snowden / Archives of Clinical Neuropsychology 32 (2017); 876–887 879 et al., 2016; Snowden et al., 2003). Nevertheless, the presence of such difficulties is likely to contribute to the social breakdown in HD. The practical social implications are well illustrated by a study by Sprengelmeyer et al. (2016), which showed that people with HD have difficulty perceiving character traits such as trustworthiness and dominance. Some authors have demonstrated problems in social cognition in the “pre-manifest” stages of HD, before the development of motor symptoms (Adjeroud et al., 2016; Eddy & Rickards, 2015b).

Other Cognitive Domains

The domains outlined above are the most important from the perspective of characterizing the neuropsychological profile in HD. People with HD do not show frank aphasia, agnosia, or apraxia. Nevertheless, speech production becomes progres- fi sively less intelligible due to the motor disorder, they may have dif culty coping with complex syntax and impairments on Downloaded from https://academic.oup.com/acn/article/32/7/876/4161107 by guest on 27 September 2021 language tasks may arise secondary to other cognitive difficulties (Podoll, Caspary, Lange, & Noth, 1988). In the visuospatial domain, people with HD have difficulty on high-level perceptual discrimination (Brouwers, Cox, Martin, Chase, & Fedio, 1984; Lawrence et al., 1996), perceptual integration (Bamford, Caine, Kido, Plassche, & Shoulson, 1989; Gomez Tortosa, del Barrio, Barroso, & Garcia Ruiz, 1996) and constructional (Bamford et al., 1989) tasks, which make executive demands. Spatially, people with HD show problems on tasks involving mental rotation or manipulation of information (Brouwers et al., 1984; Bylsma, Brandt, & Strauss, 1992; Mohr et al., 1991) and timed visual search (Labuschagne et al., 2016). Slowed visual search has been shown in the pre-manifest stages of disease and impaired mental rotation in people close to clinical onset (Labuschagne et al., 2016). From a practical perspective, perceptual and spatial problems in HD have not been identified as specific predictors of difficulties in activities such as driving, whereas psychomotor slowing is a strong predictor of driving cessation (Beglinger et al., 2012). Problems in executive function and cognitive decline have a detrimental effect on everyday functioning and level of independence of people with HD (Mayeux et al., 1986; Rothlind et al., 1993) and quality of life (Ready et al., 2008) and these problems have been described by caregivers as having the greatest impact (Simpson et al., 2016).

Neuropsychiatric Features

Apathy, irritability and depression are the most common and problematic neuropsychiatric symptoms in HD (Craufurd & Snowden, 2014). These symptoms are distinct and dissociable (Craufurd, Thompson, & Snowden, 2001; Kingma, van Duijn, Timman, van der Mast, & Roos, 2008; Naarding, Janzing, Eling, van der Werf, & Kremer, 2009; Rickards et al., 2011), and they follow different trajectories over the disease course (Thompson et al., 2012). Broadly, loss of motivation and drive is an early symptom, which becomes increasingly pervasive over the disease course. Irritability and loss of temper control worsen initially but subside in late stage disease, likely subsumed by apathy. Depressive symptoms may emerge at any time in the course of disease. The presence of apathy correlates with motor, cognitive and functional markers of disease progression (Baudic et al., 2006; Naarding et al., 2009; Thompson, Snowden, Craufurd, & Neary, 2002) and therefore it provides a marker of disease progression, even if not independent, whereas depression and irritability do not. People with HD rarely complain of apathy. Nevertheless, this symptom has a signiﬁcant effect on functional disability and quality of life (Banaszkiewicz et al., 2012; Hamilton et al., 2003; Read et al., 2013). Importantly, from the perspective of pos- sible intervention, loss of motivation, initiative and spontaneity in HD has been noted to be situation-dependent, and may be reduced in the presence of stimulating input and structure (Caine & Shoulson, 1983; Caine, Hunt, Weingartner, & Ebert, 1978). Irritability and poor temper control are amongst the most troublesome behavioral features of HD and are typically assessed using standardized self-report or informant-based irritability scales (Craufurd et al., 2001; Reedeker et al., 2012). In one study cohort (Craufurd et al., 2001), clinically signiﬁcant irritability was reported in more than 50%, verbal outbursts of temper in 40% and threatening behavior or violence in 22%. Studies have also shown higher levels of irritability in asymptomatic carriers of the HD gene compared to non-carriers (Berrios et al., 2002; Julien et al., 2007). In these latter studies interviews were carried out prior to genetic testing so that differences could not be attributed to gene carriers’ knowledge of their genetic status. An increased frequency of irritability was seen up to 10 years before the onset of motor abnormalities. Irritability and poor temper control inevitably has a damaging effect on personal relationships, and so requires recognition and management. Treatment commonly involves the use of selective serotonin reuptake inhibitors, although the potential value of behavioral ap- proaches to management is recognized (van Duijn, 2010). Depressive symptoms, which may occur even in the prodromal phases of disease (Epping et al., 2016; Julien et al., 2007; van Duijn et al., 2008), may exacerbate apathy and social withdrawal, worsen cognitive performance (Smith, Mills, Epping, 880 J.S. Snowden / Archives of Clinical Neuropsychology 32 (2017); 876–887

Westervelt, & Paulsen, 2012), contribute to functional decline (Beglinger et al., 2010; Marder et al., 2000; Mayeux et al., 1986) and further impair quality of life (Read et al., 2013), exemplifying the need for recognition and treatment. Moreover, depressive symptoms may be associated with suicidal ideation (Hubers et al., 2013). An increased risk of suicide has been recognized since Huntington’s seminal description of the condition (Huntington, 1872). A recent study of more than two thousand HD mutation carriers, 98% with physical symptoms of HD, reported suicidal ideation in 8% (Hubers et al., 2013). Paulsen, Hoth, Nehl, Stierman and the Huntington Study Group (2005a) identified two particularly critical periods of vulnera- bility: the prodromal phase of disease, defined by the presence of mild neurological signs insufficient to make a firm diagnosis of HD, and when functional independence begins to diminish.

Neuropsychological Assessment Strategy Downloaded from https://academic.oup.com/acn/article/32/7/876/4161107 by guest on 27 September 2021 With the advent of the genetic test, neuropsychological assessment now plays a relatively minor role in differential diagnosis. A clinical diagnosis of HD is typically made on the basis of family history of HD, presence of the characteristic movement disorder and confirmed mutation on genetic testing. Nevertheless, neuropsychology has a crucial role in the identification of cognitive changes in the early phases of disease, in monitoring progression and in the evaluation of outcome of therapeutic interventions. Ideally, an assessment protocol should include each of those key components that have been found most sensitive to HD: psychomotor speed, memory, executive skills, and emotion recognition. However, consideration needs to be given to the purpose of the assessment and stage of illness. People in preclinical phases of disease may show only very subtle changes whereas people in the later stages of disease may be unable to tolerate lengthy assessments. Timed tasks are particularly valuable because they elicit the earliest detectable changes in pre-manifest HD and are also most sensitive to change over the course of the disease (Snowden et al., 2001, 2002; Stout et al., 2011, 2012; Tabrizi et al., 2012). In keeping with such findings, the Huntington’s Disease Rating Scale (Huntington Study Group, 1996), a widely used screening instrument for HD, in- corporates a brief cognitive screen consisting of three tests, all of which are timed: verbal fluency, symbol digit modality, and Stroop. Similarly, the European Huntington’s disease network (Euro-HD), a European-wide network for research into Huntington’s disease, has adopted letter and category fluency, symbol-digit modality, and Stroop tests as “core” components of their recommended neuropsychological test battery, with additional elements where more extensive assessment is feasible. Some memory and executive measures are of value for cross-sectional assessment but show poorer sensitivity to change over time (Bachoud-Lévi et al., 2001; Snowden et al., 2001). One contributory factor is the effect of practice. It has been found (Bachoud-Lévi et al., 2001) that the practice effect is greatest between first and second assessment. In intervention studies, the confounding effect can be mitigated if dual baseline assessments are introduced preceding the intervention. An additional consideration in evaluating cognition in HD is the contribution to performance of motor and neuropsychiatric/behavioral changes. Timed tasks that control for motor slowing are valuable because they provide information about cognitive speed that is independent of general slowing of motor responses. Apathy is a core behavioral change in HD that correlates with executive impairment (Thompson et al., 2002). The inclusion of informant-based behavioral measures, such as the Problems Behavior Assessment (Craufurd et al., 2001) can assist interpretation of cognitive test performance.

Laboratory and Radiographic Investigations

The genetic mutation responsible for HD was identified in 1993 (Huntington’s Disease Collaborative Research Group, 1993). Since then a clinical genetic test has become available to test for the CAG repeat expansion and is used routinely to confirm the clinical diagnosis of people who show symptoms of HD. The test, along with genetic counseling, is also available for “at risk” family members (i.e., offspring of an affected parent) who wish to know whether or not they have inherited the gene mutation. Some people prefer the certainty of knowing their gene status because this affords control of life choices, such as whether to have a family or to take promotion at work. On the other hand, the knowledge can lead to a variety of practical and emotional difficulties, ranging from difficulty in obtaining insurance cover to breakdown in interpersonal relationships with siblings who have a different genetic result from one’s own. The experience of predictive testing may be stressful and adjustment to test results can be difficult (Crozier, Robertson, & Dale, 2015; Meiser & Dunn, 2001). Around 80% of “at risk” people opt not to know (Meiser & Dunn, 2001). There has not, thus far, been a notable increase in uptake of the genetic test over the years that it has been available, and the reverse has even been reported (Bernhardt, Schwan, Kraus, Epplen, & Kunstmann, 2009). Nevertheless, the situation may change in the future as clinical therapeutic trials become available, for which confirmation of gene status may be a criterion for eligibility (Nance, 2017). J.S. Snowden / Archives of Clinical Neuropsychology 32 (2017); 876–887 881

The genetic test confirms whether an asymptomatic person will develop symptoms of HD but not when those symptoms will first appear. There is an inverse correlation between age at which disease becomes manifest and length of the CAG repeat expansion and formulae have been produced to predict age of clinical onset, i.e., when overt symptoms will begin (Langbehn, Brinkman, Falush, Paulsen, & Hayden, 2004; Zhang et al., 2011). Such prediction is insufficiently accurate to be helpful at an individual level for an asymptomatic person taking the genetic test. Nevertheless, it provides a valuable proxy of clinical onset for research studies. Major large-scale international research studies have been undertaken: the PREDICT-HD study in the USA (Paulsen et al., 2008) and TRACK-HD in Europe (Tabrizi et al., 2009, 2012, 2013) that have tracked people who have the HD gene mutation to establish the natural history of the disease. Brain imaging in HD shows atrophy, with structural and functional changes most prominent in the striatum (caudate nucleus and putamen). Striatal changes are present even in pre-manifest HD, i.e., before the emergence of overt clinical symptoms and signs, (Andrews et al., 1999; Antonini et al., 1996; Aylward et al., 2004; Tabrizi et al., 2013), reinforcing the view that this is the earliest site of pathology. The availability of the genetic test means that neuroimaging is not essential for clini- Downloaded from https://academic.oup.com/acn/article/32/7/876/4161107 by guest on 27 September 2021 cal diagnosis of HD. Nevertheless, it has been important in helping to understand the basis for the symptoms and signs in HD, and the natural history of the condition. Psychomotor speed in HD has been shown to correlate with measures of caudate atrophy (Bamford et al., 1989; Starkstein et al., 1992). There is evidence too of a relationship between executive test performance in HD and changes in the striatum, measured either by structural (Peinemann et al., 2005) or functional (Backman, Robins-Wahlin, Lundin, Ginovart, & Farde,1997; Lawrence et al., 1998) brain imaging. Interestingly, functional imaging studies in HD have demonstrated increased cortical recruitment in cognitive tasks (Georgiou-Karistianis et al., 2007), indicat- ing compensation for reduced striatal function.

Treatment

HD is a relentlessly progressive disorder that is currently incurable. Treatments have, until recently, largely comprised pharmacological symptomatic therapies for the alleviation of motor and mood-based symptoms. Tetrabenazine is a well- established treatment for involuntary movements, although it may increase the likelihood of depression in pre-disposed people (Kenney, Hunter, Meijia, & Jankovic, 2006) so needs to be used judiciously. SSRIs have been used for the treatment of irritability (Groves et al., 2011). Currently, the evidence-base for non-pharmacological interventions in HD is limited. Assistive technology for cognition (ATC) refers to external aids that serve to compensate for a person’s cognitive difficulties. Two studies have shown that Talking Mats improved communication in people with relatively advanced HD who had poorly intelligible speech (Ferm, Sahlin, Sundin, & Hartelius, 2010; Hallberg, Mellgren, Hartelius, & Ferm, 2013). Notwithstanding this encouraging finding, evidence for the benefit of assistive technology use in HD remains scarce. Van Walsem, Howe, Frich and Andelic (2016) carried out a review of assistive technology use in 158 people with HD. The authors distinguished between self-generated, informal use of mainstream products such as calendars, planners, cell phones and alarm clocks and formal use of computer software, specifically designed to support people with cognitive impairment. Around a third of participants used assistive technology, with informal use occurring mainly in early-stage disease and formal use in moderate-stage disease. Notably, however, a formal needs assessment for assistive technology had been carried out in only a third of participants and even fewer had received formal training for its use. No association was found between the use of assistive technology and improved quality of life. The study by van Walsem et al. (2016) was descriptive rather than efficacy study. The authors highlighted the need for systematic investigation of the value of assistive technology in HD and its association with health-related quality of life. There are a priori grounds for thinking that assistive technology may be helpful. Memory inefficiencies, which include problems in prospective memory (Nicoll et al., 2014), might potentially be alleviated by use of external prompts and memory aids. A potential rationale for cognitive intervention in HD comes from functional brain imaging findings, which suggest that neural compensation takes place in preclinical HD to preserve motor and cognitive performance. Cognitive interventions aim to support and enhance that neural compensation (Andrews, Dominguez, Mercieca, Georgiou-Kartistianis & Stout, 2015; Metzler-Baddeley et al., 2014; Papoutsi, Labuschagne, Tabrizi, & Stout, 2014). In a pilot study, Metzler-Baddeley et al. (2014) showed improved executive functions and white matter microstructure in ten people at varying stages of HD following a 2-month intervention involving rhythm exercises. Busse et al. (2013) too reported modest benefits from physical exercise training on cognition and mobility. Cruickshank et al. (2015) reported a multidisciplinary 9-month intervention study, involving a program of physical exercises combined with cognitive exercises of verbal planning, memory and problem solving. The study group of 15 HD participants showed increased gray matter volumes on brain imaging that correlated with improved verbal learning performance at the end of the 9-month period. These findings offer a degree of optimism that interventions have 882 J.S. Snowden / Archives of Clinical Neuropsychology 32 (2017); 876–887

Table 1. Key empirically supported recommendations Assessment value References Findings Recommendations domain Diagnostic Lawrence et al. (1996), Paulsen et al. (1995b), Psychomotor slowing, executive, Include in test battery timed tasks such as Stroop, assessment of Snowden et al. (2001), Watkins et al. (2000), memory and emotion Trail making, Symbol Digit modalities test and manifest HD Henley et al. (2012) recognition impairments are verbal fluency as well as a memory test such as prominent features list learning and test of emotion recognition such as Ekman faces Diagnostic Maroof et al. (2011), Snowden et al. (2002), Psychomotor deficits are the Include Symbol Digit Modalities and Stroop tests assessment in Stout et al. (2012), Tabrizi et al. (2009) earliest detectable change in in assessment of gene carriers pre-manifest gene carriers HD Longitudinal Snowden et al. (2001), Stout et al. (2012), Psychomotor tasks are the most Symbol digit Modalities and Stroop tests are Downloaded from https://academic.oup.com/acn/article/32/7/876/4161107 by guest on 27 September 2021 assessment – Tabrizi et al. (2012, 2013) sensitive markers of change useful outcome measures for clinical trials and sensitivity to over time intervention studies change over time Prediction of Sprengelmeyer et al. (1995), Georgiou et al. Difficulty with multi-tasking Encourage one thing at a time. Separate tasks into treatment (1995), Delval et al. (2008), Butters et al. including low level tasks manageable components. response (1985, 1994), Lundervold et al. (1994), Pillon Poorer free recall than cued Provide structure and external memory aids et al. (1993), Metzler-Baddeley et al. (2014), recall and recognition Multidisciplinary interventions can be helpful Andrews et al. (2015), Cruickshank et al. Adopts passive learning Use external stimulation to improve motivation (2015), Caine and Shoulson (1983), Caine strategies and engagement et al. (1978) Physical and cognitive exercises can improve cognitive function Apathy is reduced by stimulation Prediction of Eddy and Rickards (2015a), Mayeux et al. Cognitive slowing predicts Cognitive assessment is necessary as predictor of functional (1986), Rothlind et al. (1993), Simpson et al. reduced functional ability overall functional ability, quality of life and ability (2016), Tabrizi et al. (2012, 2013) Executive deficits impair care-giver impact functional ability Executive deficits have impact on caregivers Change in psychomotor scores predicts functional decline the potential for neural enhancement, which may delay clinical decline. Nevertheless, randomized controlled trials of cognitive intervention are required to establish the efficacy of this approach. Interventions in HD need to address behavioral/neuropsychiatric as well as cognitive problems. Apathy is a pervasive feature that affects the quality of life. The finding of improvement with stimulating input and structure (Caine & Shoulson, 1983; Caine et al.,1978) mirrors clinical experience and has obvious implications for management. People with HD can benefit from external prompts, encouragement to participate in pleasurable activities and the provision of a structured environment. Irritability is another troubling feature of HD. There may, however, be predisposing or precipitating factors, and if recognized, aggressive outbursts can be circumvented. Education of family members is an important aspect of management of people with HD. When embarking on interventions with people who have HD, an important consideration is their reduced awareness of motor (Sitek et al., 2011; Snowden et al., 1998), cognitive/behavioral (Ho, Robbins, & Barker, 2006; Hoth et al., 2007; Sitek, Thompson, Craufurd, & Snowden, 2014), emotional, and functional (Hoth et al., 2007) changes.

Recommendations

Recommendations for neuropsychological assessment and intervention are summarized in Table 1. Timed psychomotor tasks need to be considered a core and necessary component of the assessment, regardless of stage of disease or the purpose of assessment. Executive, memory, and emotion recognition tests are valuable, particularly in manifest disease. Aside from cognitive assessment, evaluation needs to take account of behavioral/affective symptoms. Rating scales for behavioral symptoms of HD have undergone a systematic critique by an International study group, commissioned by the Movement Disorder Society (Mestre et al., 2016). “Suggested” scales speciﬁcally designed for use in HD include the Problems Behaviors Assessment for Huntington’s disease (PBA) (Craufurd et al., 2001) and Uniﬁed Huntington’s Disease J.S. Snowden / Archives of Clinical Neuropsychology 32 (2017); 876–887 883

Rating Scale, behavioral section (Huntington’s Study Group, 1996). The Apathy sub-scale of the PBA has been recommended by Tabrizi et al. (2012) as a behavioral measure for use in clinical trials. Interventions in HD need to take account of a number of characteristics.

• People with HD require extra time to carry out everyday tasks. • People with HD are forgetful but do not have a classical amnesia. They have the potential to beneﬁt from memory aids. • Tasks, such as walking and talking, which under normal circumstances might be regarded as relatively “automatic”, require more conscious attention in people with HD. They are more demanding of attentional resources. It is important for people with HD to focus on one activity at a time. • People with HD may not initiate activities but with encouragement can engage successfully in them and experience enjoyment. Downloaded from https://academic.oup.com/acn/article/32/7/876/4161107 by guest on 27 September 2021

Conﬂict of interest

None declared.

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