Neuropsychological and Behavioural Aspects of Huntington's Disease
George Huntington first described Huntington’s disease (HD) in 1872 as being a hereditary chorea, “an heirloom fortunately being confined to just a few families but known to exist as a horror” (Neylan, 2003). This disorder of the basal ganglia is prevalent in approximately 5-7 per 100, 000 people, with an average age of onset of symptoms being at 35-45 years of age. The duration between onset and severe disability or death spans an average of 17 years; most patients die of secondary reasons of the disease such as pneumonia (Folstein, Leigh, Parhad, & Folstein, 1986).
Huntington’s disease, one of several polyglutamine (PolyQ) diseases, is a genetic disorder attributable to a single autosomal, dominant gene. HD is well known for being one of the first inherited genetic diseases for which an accurate test can be performed and as a result its genetic characteristics are now well known (Albin & Tagle, 1995). The test was facilitated in 1993 by the work of Nancy Wexler and a conglomerate of researchers, who, under the US-Venezuela HD Collaborative Research Project deduced the genetic make up of the HD gene. From analysis of the world’s largest HD community Gusella et al (Gusella, MacDonald, Ambrose, & Duyao, 1993) delineated the characteristics of the IT15 gene, mapping it to the upper end of the short arm of human chromosome 4, and a decade thereafter the localisation of the gene was established. Molecular biology facilitated further analysis of the gene where it was found that its first exon contains repeats of a trinuleotide sequence (CAG) encoding the amino acid glutamine. The abnormal HD gene contains a CAG expansion (36+), the normal repeat being a length of 11-29 units in length, and codes for the huntingtin protein, a molecule comprised of 3000 amino acids and widely present in the body, particularly in the human brain where it is expressed in the cytoplasm of neurons (Gusella et al., 1993) (Albin & Tagle, 1995).
While the functions of the protein are still incompletely understood, it appears to play a role during embryogenesis, neurogenesis, neural gene expression and vesicle trafficking in cells. The HD IT15 gene facilitates abnormal folding of huntingtin which leads to formation of protein aggregates and neuronal inclusions. There still exists a poor understanding regarding the mechanism of change and damage that additional CAGs illicit to the HD brain (Albin & Tagle, 1995).
A classic triad of clinical impairments exist in HD patients. Firstly, difficulty sitting quietly (motor restlessness, the most common sign in early stages of the disease), chorea (the “Huntington’s dance”, a set of sudden and unintended movements) (Neylan, 2003), dystonia (awkward positioning of limb or body part), hyperkinesias (fast movement) and tremor represent the most documented and clinically diagnostic involuntary movement disorders. Abnormal voluntary movements also occur and involve clumsiness, slowness, impersistence or motor lag, and may affect swallowing, eye movements and speech (Folstein et al., 1986).
Secondly, cognitive deficits, occur, and involve short term and working memory, fluency of language, as well as attention and concentration (sub-cortical deficits); these often present well before motor disorders are evident. Cognitive changes in HD are not a global dementia, but are rather characterised as a sub-cortical dementia. There is impaired functioning of frontal regions, where executive functions such as planning and organisation, set-shifting (evident on the Stroop test and attention set-shifting tasks which are characterised by rigid behaviour, difficulty changing routines, inflexible in attitudes) and behavioural regulation (reduced self-generated activity called apathy and impulsive and socially inappropriate behaviour) take toll. Other deficits such as in the recognition of facial expressions of disgust also occur. However, semantic memory, several aspects of verbal skills unrelated to fluency, and insight (HD patients are not oblivious to the difficulties they have) are some cognitive elements which are retained in the HD brain (Paulsen, Ready, Hamilton, Mega, & Cummings, 2001) (Rosenblatt & Leroi, 2000).
Lastly, emotional mood changes also occur. Anxiety, characterised by a general feeling of tension and unrest, is often a prominent behavioural sign, while depression, the most common mood change, irritability, apathy, and intermittent outbursts of aggression are other behavioural symptoms (Paulsen et al., 2001; Rosenblatt & Leroi, 2000).
The remainder of the review focuses on the psychiatric aspects of HD, particularly depression and apathy, as well as some major cognitive changes that take place, their neural basis in light of current research in HD, and possible future directions for HD research.
Planning and organisation deficits which occur, consistent with frontal dysfunction, were investigated by Lawrence et al in 1998 in the “Tower of London” task (Lawrence et al., 1996). HD subjects were instructed to rearrange balls as seen in a display model, to mimic those in the experimental model, in an attempt to solve the problem in a minimum number of moves. Subjects were advised against making a move until confident that they could execute the entire sequence – this required them to figure out the sequence first. The task used computerised a touch screen, which provided a control for those patients who had slow motor responses. Results showed that the proportion of correct solutions decreased as problem difficulty increased (from 3 to 5 step problem). There was also an increase in the mean number of excess moves and an increment in initial thinking times with increasing problem difficulty levels. The task was also conducted in patients with other forms of fronto-striatal dysfunction. Early HD patients showed deficits in all of three end points: perfect solutions, initial thinking times, and subsequent thinking times. Lawrence at al suggested that the cause of the results was related to deficits in spatial working memory, which is crucial for planning. Clinically, HD patients show difficulty planning and organising day-to-day activities and have trouble assembling materials for the completion of multi-step tasks for example in cooking a meal (Peinemann et al., 2005). This sort of cognition has been shown to be linked to the dorsolateral prefrontal cortex and dorsal head of the caudate nucleus, and deficits in such elements confirm the neural changes and loss to these areas in the HD brain (Lawrence et al., 1996).
Another specific cognition thought to be affected, executive function (which is thought to include attention and inhibition, task management, planning, and coding) was investigated in early HD stages by Peinemann et al (Peinemann et al., 2005). Their aim was to clarify if cognitive dysfunction in early stages of HD was correlated with loco-regional structural changes in 3D-MRI. 25 HD patients in early clinical stages underwent neuropsychological testing (Stroop test, Tower of Hanoi etc). High resolution MRI scans were acquired and analysed by statistical mapping and voxel based morphometry (VBM) in comparison to an age matched control group. Group analysis of HD patients demonstrated regional decreases in grey matter volume in the caudate and putamen. Executive dysfunction was highly correlated with these areas on the scans. Sub-group analysis illustrated marked insular atrophy in HD patients who performed poorly in single executive tasks. The study concluded that striatal atrophy in HD patients in early stages plays an important role not only in impaired motor control but also in executive dysfunction. Furthermore, extra-striatal cortical areas (the insular lobe for example) seem to be involved in executive dysfunction as assessed in neuropsychological tests requiring planning and problem solving, as well as concept formation (Peinemann et al., 2005).
Hennenlotter et al combined this finding with the hypothesis that HD patients had difficulty in recognising disgust. The “expression continua” or emotion hexagon composed by Sprengelmeyer et al was used: each of the 6 primary facial expressions (happiness, surprise, anger, sadness, disgust, and fear) published by Ekman et al, were paired against each other, each face being a mix of a certain percentage of a facial expression. Subjects viewed blocks of faces showing disgust, surprise or neutral expressions, from which they were to gather the gender of the face. To investigate behavioural aspects, subjects were to deduce which emotion was illustrated. The results supported what other studies have found: the number of correct responses in identifying the emotion was significantly lower in HD patients for the recognition of disgust in relation to other expressions, compared to non-HD patients. fMRI imaging, lesion experiments, and intracerebral ERP studies on 9 HD presymptomatic (positive for the genetic defect) patients and 9 non-HD age, education and gender matched subjects, showed that only perception of disgusted faces relied on the activation of the insula and putamen.. The fMRI imaging results depicted a statistical parametric map illustrating differences in BOLD response between HD gene carriers and controls during perception of disgusted facial expression. HD patients showed significantly decreased activation (only during perception of disgusted facial expression) in the left dorsal anterior mid-insula, while controls only showed activation in putamen. The results were supported by a study that Hennenlotter et al conducted (Hennenlotter et al., 2004). They studied the neural correlates underlying impaired disgust processing in pre-symptomatic HD patients, and here evidence also pointed most consistently to neural dysfunction of the insular cortex. It was hypothesised that the absence of putamen activation in pre-clinical HD during processing of facial expressions of disgust may also contribute, but this remains unclear currently since cognitive deficits have proven challenging to asses, largely due to the variable motor disorders (Hennenlotter et al., 2004).
In the past 10 years, interest has grown in the domain of apathy in patients with neurodegenerative disease (Marin, 1991). According to Marin(Marin, 1991), apathy is defined as “disengagement, with passivity and loss of enthusiasm, interest, empathy and interpersonal involvement”. It has been established that apathy is already present in the early stage of HD and becomes more severe as the disease progresses (Levy et al., 1998) and that over 50% of patients with HD demonstrate it (Paulsen et al., 2001). Authors have found that apathy, in contrast to other psychiatric disorders, increases over time and hypothesise that it could be a marker of the evolution of the disease (Rosenblatt & Leroi, 2000).
Baudic et al sought to investigate the relationship between cognitive impairment and apathy in patients with early HD. The influence of depression on the outcome of cognitive changes associated with apathy was also explored. A cohort of 20 apathetic HD (HDA) and 16 non-apathetic non-HD subjects (HDnA), matched for age, education and disease severity, was tested. Cognitive functions were evaluated by a comprehensive battery of tests (selective attention measured by the Trail Making Test, TMT-A; attentional set shifting evaluated by a digit cancellation task known as Trail Making Test; inhibition of interference was evaluated by the Stroop Color Interference Test, SCIT), which correlated attention, executive function, episodic memory, language and visuospatial skills. Disease severity was staged according to the Total Functional Capacity (TFC) scale, a standard measure of functional capacity often employed in HD research (Paulsen et al., 2001). The patient and a close relative rated apathy using a scale validated in the HD population which evaluates five types of behaviour indicative of apathy, namely ‘loss of interest’, ‘lies around’, ‘not as active’, ‘keeps busy’ and ‘withdrawn’, after which the status of apathy was determined after an interview, which assessed daily activities and personality changes relative to the patient’s previous history (Baudic S, 2006).Continued on Next Page »