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The Neuropsychology of Huntington’s Disease
Julie S Snowden
Greater Manchester Neuroscience Centre, Salford Royal NHS Trust, Salford, UK
Division of Neuroscience and Experimental Psychology, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
Address for correspondence:
Prof. Julie S. Snowden
Cerebral Function Unit,
Greater Manchester Neuroscience Centre
Salford Royal NHS Trust
Salford M6 8HD, UK
Running title: The Neuropsychology of HD
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 impact 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; neuropsychology
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 founders 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 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.
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 & Figlia.,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 understanding the role of the basal ganglia in cognition.
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 emphasized 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.
The salient changes in HD are in the domains of psychomotor and executive skills, memory, emotion processing and social cognition.
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, Brandt, Peyser, Folstein, & Folstein, 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).
Executive difficulties in HD include problems in planning (Lawrence et al.,1996; Unschuld et al., 2013; Watkins et al., 2000), organisation 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, 1995). It is worth highlighting, however, that dual task difficulty in HD