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).
The HDA patients presented significantly lower scores, as evident from statistical tests, revealing a significant group difference for global score of the cognitive assessments such as the TMT-A, on memory, attention and executive function tests when compared with HDnA subjects. No significant group differences were observed for the language tasks and visuospatial abilities however. The performance of such cognitive tasks was also compared between patients with (50%) and without depression: no differences were observed between HDA group with and without depression on cognitive tasks.
The results demonstrated that interactions between apathy and motor disturbance have a significant effect on cognitive impairment in HD and lend support to the existence of a relationship between apathy and cognitive impairment in early HD patients (Levy et al., 1998), in agreement with what has been observed in patients with other diseases (Kuzis, Sabe, Tiberti, Dorrego, & Starkstein, 1999) (Starkstein et al., 1992). The presence of apathy was associated with more severe deficits of attention, executive function and episodic memory in early HD patients and thus the association seems to be focused on these cognitive elements. The findings also suggested that depression has little or no effect on cognitive deficits. It has been drawn that apathy increases in parallel with both motor and cognitive dysfunction. However it is unclear whether all patients with cognitive impairment will become apathetic later. The investigation of asymptomatic patients and the comparison with patients at different stages of the disease, relating apathy to cognitive and motor signs, should further enhance the insight into early disease processes. Some contradictory findings in the literature are possibly due to methodological issues such as the clinical characteristics of the HD patients involved in the different studies and the heterogeneity of the tools used to evaluate cognitive impairment and apathy (Baudic S, 2006).
Based on Gerfen (1989) and Goldman-Rakic et al, who established that patchy neurotransmitter changes in the striatum consist of differential cell loss in the striosome and matrix compartment , Tippett et al investigated HD clinical symptoms, both motor and mood, in 35 HD individuals. The researchers defined mood disorders to include symptoms of depression, anxiety, irritability, as well as types of compulsive and repetitive behaviour. It was hypothesised that patients whose damage was confined to largely the matrix would showcase severe sensorimotor activity as well as marked mood symptoms. Patients whose damage was mostly confined to striosomes were those in which deficits would affect processing of mood more adversely than motor. It resulted that despite the absence of a strong link between motor symptoms and matrix loss, there appeared a link between extent of mood changes and loss of striosomes. It also appeared that those patients with matrix losses only (n=11) had an earlier disease onset on average (30.6 years of age), died earlier (52.3 years of age), possessed a longer CAG repeat (46.6 units) and were graded much worse neuropathologically than their counterparts (2.73 matrix vs. 1.18 and 2.2 for striosome and mixed respectively). These anatomical findings were based on using the expression of immunohistochemically detectable GABAa receptors, and by testing the correlation between receptor and neuronal cell loss, it was established that GABAa receptor loss corresponded to patterns of neuronal cell loss. Analyses indicated that the level of mood impairment was related to striosome loss rather than to CAG repeat length. The findings suggest that mood dysfunction in HD is associated with pronounced abnormality of striosome-based pathways in the basal ganglia. The association between striosomal abnormality and mood dysfunction held both for early and late stage symptom assessments. It can be said therefore that patients with prominent mood disorder and striosome loss may represent a clinical subgroup within the spectrum of patients suffering from HD. The study provided the first demonstration of a relationship between the striosome compartment of the striatum and mood disturbance in patients (Tippett et al., 2007).
Post-mortem anatomical and neurochemical brain analysis has led to the establishment of HD pathology and its associated neural changes, of which there are three. First, atrophy and neuronal loss takes place, mainly in the striatum of the basal ganglia of HD patients. Secondly, there is a marked shift in neurotransmitter receptor changes, with GABA significantly being lost within the caudate nucleus and putamen regardless of associated neuronal cell loss or stage of disease progression. In patients who suffered an early death due to HD, it has been observed that neurotransmitter density was significantly disturbed without any particular cell death thus it has been hypothesised that the pattern of receptor loss may map onto the disease profile and how it develops, but this has been extensively researched (Folstein et al., 1986).
Previous thought assumed that atrophy in cortical regions (the third change), specifically within frontal and parietal cortices, occurred solely in late stages of the disease. The question of whether cortical changes were independent of basal ganglia deficit or due to secondary degeneration as a result of disease pathology was investigated by a number of researchers, who concluded that HD resulted in widespread atrophy (Jernigan, 1992; Backman, 1997), which affected almost all brain structures (Rosas, 2003).
Two recent papers have sought to research this still unclear link. Early cortical changes were investigated via voxel-based studies of cortical thinning, to elucidate cortical changes and their significance in HD. Rosas et al obtained cortical thickness measures of 11 living symptomatic HD patients with a range since onset of motor symptoms being 1-10 years. The absolute cortical thinning of 3 HD individuals with early, mid and late clinical stages of disease compared with normal age-matched controls portrayed interesting results: marked differences in cortex thickness within posterior areas, coupled with a progression of cortical thinning from posterior to anterior regions, was revealed. Statistical maps compared average thickness of all 11 HD subjects with the 13 controls to reveal significant thinning bilaterally, most pronounced in pre and post central regions, inferior temporal and dorsal occipital lobes. These studies have provided new insight into cortical atrophy, and contradicted the previous school of thought of it being exclusive solely to the basal ganglia (Rosas et al., 2002).
So far the attempts to provide a comprehensive description of the psychopathology of HD have been disappointing, possibly due to the limitations of the DSM classification system in this disease. Future research should not only focus on this, but also on neuropsychological functioning. Some hope for the future has been offered by a number of recent developments in Huntington's disease research, such as the use of positron emission tomography and applications of functional magnetic resonance imaging. These techniques may further clarify brain-behaviour relations when considered within models of basal ganglia circuitry (Steffan & Thompson, 2003). There is currently no effective treatment available to halt the progression of Huntington's disease. Pharmacotherapeutics have some utility in the reduction of movement disorders and psychiatric symptoms, but intervention has largely been restricted to genetic counselling and symptom management. Recent applications of cell transplantation technology to Huntington's disease may also provide some hope (Rosser & Dunnett, 2003). Further research into behavioural treatment strategies for patients with advanced Huntington’s disease as well as other dementias is needed (Frankish, 2006) .
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