Future directions in research with presymptomatic individuals carrying the gene for Huntington’s disease

Brain Research Bulletin, Vol. 59, No. 5, pp. 331–338, 2003 Copyright © 2002 Elsevier Science Inc. All rights reserved. 0361-9230/02/$–see front matter

PII: S0361-9230(02)00877-8

REVIEW

Future directions in research with presymptomatic individuals carrying the gene for Huntington’s disease Nellie Georgiou-Karistianis,1∗ Eleanor Smith,1 John L. Bradshaw,1 Phyllis Chua,2 John Lloyd,2 Andrew Churchyard3 and Edmond Chiu4 1 Experimental Neuropsychology Research Unit, Department of Psychology, Monash University, Clayton, Vic., Australia; 2 Department of Neuropsychiatry, Royal Melbourne Hospital, Parkville, Vic., Australia; 3 Department of Neurology, Monash Medical Centre, Clayton, Vic., Australia; and 4 Huntington’s Disease Clinic, St. George’s Hospital, Kew, Vic., Australia

[Received 2 January 2002; Revised 12 August 2002; Accepted 12 August 2002] the greatest burden on HD families. Its overall prevalence is 5 to 10 per 100,000 but this varies greatly between geographical regions [2]. The most striking example of its increased presence is in Lake Maracaibo, Venezuela, where the prevalence of HD is as high as 700 per 100,000 [3]. The disease affects the central nervous system and is characterised by progressive neurodegeneration leading to dementia and death around 15 years after initial diagnosis [4]. This review will discuss a range of factors that may be influential in the diagnosis of HD, and especially in those presymptomatic individuals with a gene-positive status. We will attempt to demonstrate that the research over the last 8 years, since the isolation of the gene, remains in the most part compromised by various confounds. Finally, we will discuss ethical considerations, as well as put forward the suggestion that a more comprehensive tool for clinical diagnosis should incorporate both cognitive and motor functions.

ABSTRACT: Presymptomatic individuals carrying the gene for Huntington’s disease (HD) provide researchers with a unique opportunity of learning more about the neuropathophysiology, symptom onset, behavioural functioning, and mediating factors of this fatal disease. In this review, we attempt to demonstrate that research over the last 8 years, since the isolation of the gene, has remained at large controversial. Although we are aware of some of the factors that can influence age at onset and disease progression, we are still unable to determine exactly when an individual will develop HD symptoms, and how fast these symptoms will progress. In an era rapidly advancing with respect to therapeutic intervention that could forestall the onset and progression of HD, systematic research with improved inclusion criteria is paramount. A greater understanding of the time course of the disease would be beneficial not only in monitoring the effectiveness of future treatments, but also in determining the most appropriate time to administer them. Finally, we present various ethical considerations, as well as put forward various recommendations that could assist in better diagnosing preclinical deficits in presymptomatic individuals. © 2002 Elsevier Science Inc. All rights reserved.

GENETICS OF HD Extensive genealogical evidence had earlier established the action of an autosomal dominant gene with complete penetrance. The first polymorphic DNA marker linked to the HD gene locus was discovered in 1983 [5]. The HD gene (IT15) was cloned in 1993 and is located on the short arm of chromosome 4 (4p16.3). Although the exact function of the encoded protein, “huntingtin”, remains unknown, its interaction with other proteins suggests that it may play a role in cytoskeletal transport [6,7]. The IT15 gene contains an expanded trinucleotide repeat (CAG) that ranges from 9 to 35 in healthy individuals, and anywhere from 36 to 180 in HD [8]. Alleles containing between 36 and 39 repeats show “reduced penetrance”, so that only some individuals within this range will go on to develop clinical symptoms within their

KEY WORDS: Huntington’s disease, Presymptomatic gene carriers, Disease onset, Therapeutic intervention, Ethical issues.

OVERVIEW Huntington’s disease (HD) is a hereditary neurodegenerative disorder characterised by a triad of progressive cognitive, motor and psychiatric symptoms [1]. Although the involuntary choreiform movements are the hallmark of HD, it is the mental alterations that often represent the most debilitating aspect of this disease and place ∗

Address for correspondence: Dr. Nellie Georgiou-Karistianis, Department of Psychology, Monash University, Vic., 3800, Australia.

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expected lifespans [9,10]. Individuals with juvenile onset HD (also known as the ‘Westphal variant’) usually have expansions above 55 CAG repeats, and develop HD before 20 years of age [11]. While the mechanism of expansion is beginning to be understood, it is still unknown why the original mutation occurs in some individuals and not in others. Studies using transgenic mouse models reveal the presence of neuronal inclusion bodies, that occur only when the expansion is in the pathogenic range, and are similar to the nuclear abnormalities observed in biopsy material of HD patients [12]. Another phenomenon is the tendency of the mutation to expand in the male germline in affected pedigrees, leading to an earlier onset of the disease in subsequent generations [13]. With the discovery of the IT15 gene, genetic testing has become available. A simple blood test provides a highly sensitive and specific method of detecting the presence of the HD gene. It has, therefore, become possible to study individuals who are carrying the HD gene but who are still free of symptoms [14]. This group, known as ‘presymptomatic gene carriers’ (PSGCs), provides researchers with an opportunity of learning more about the neuropathophysiology, symptom onset, behavioural functioning and mediating factors of the disease. While research with individuals “at risk” was conducted prior to 1993, it has been difficult to interpret findings given that 100% classification of gene-positive or gene-negative status was not then possible, unless symptoms later developed. Yet even now that gene status can be confirmed, conflicting findings continue to emerge. Prior research with PSGCs has focused primarily on determining whether preclinical behavioural anomalies or deficits exist, as well as investigating factors that may contribute to age at onset and rate of progression of the disease, although this latter aspect has received far less attention. MODIFIERS OF AGE AT ONSET Age at onset is highly variable in HD. While the average onset age is between 35 and 44 years, cases have been reported as young as 2 years and older than 80 years [15]. It is now known that much of the variation in onset age can be accounted for by CAG repeat length. There is a significant inverse correlation between the number of CAG repeats and the age at onset, although this relationship is not strictly linear [16,17]. Researchers have found CAG repeat size to account for between 50 and 69% of the variance in age at onset [18–21]; however, the size of the CAG repeat alone is not strong enough to predict exact onset age [10], with much of the effect being driven by larger repeats (>55) in individuals with juvenile onset HD. When this small group is removed from consideration, the relationship is much weaker [18]. Age at onset can also be influenced by the mode of transmission of the HD gene (maternal or paternal) and the age at onset in the affected parent. Merritt et al. were the first to note that the majority of cases who developed HD before 21 years of age had inherited the HD gene from their father [22]. It was subsequently observed that the age of death was earlier for cases in which the gene had been paternally transmitted [23], and that children of males with HD had significantly younger onset ages than their fathers, while offspring of females with HD developed HD at a similar age to their mothers. More recently, Ranen et al. confirmed these findings, reporting that offspring from affected males have, on average, longer CAG repeats, earlier age at onset (anticipation), and more rapid disease progression than their affected fathers [18,20,24,25]. This pattern of anticipation has been shown to occur more commonly in paternal transmission of the HD gene, while maternal transmission rarely results in CAG repeat expansion [24]. This can be explained by the progressive expansion of the unstable region which is much more

marked in spermatogenesis than oogenesis; this accounts for the greater incidence of anticipation and juvenile-onset in paternally transmitted cases [26,27]. Several researchers have estimated the number of years to onset of PSGCs by devising an equation based on the CAG repeat length, sex and age of the affected parent [10,28–30]. Campodonico et al. entered these three variables into a stepwise multiple regression analysis to predict age at onset [29]. While the sex of the affected parent did not pass the tolerance test, the other variables were used to generate a predictive formula: estimated age at onset = (−0.81× repeat length) + (0.51 × parental onset age) + 54.87. Campodonico et al. reported that the formula accounted for 64% of the variance in age at onset [29]. However, there has not been sufficient follow up of these studies to determine the accuracy of the equation in predicting onset age. Several additional modifiers could also influence age at onset [10,31,32]. Rubinsztein et al. [10] investigated five factors, in addition to CAG repeat length, that may affect age at onset: the influence of the normal allele in the HD gene, the 2642 polymorphism in the HD gene, apolipoprotein E, mitochondrial metabolism and the GluR6 kainate receptor. Rubinsztein et al. reported that 69% of the variance in age at onset could be accounted for by CAG repeat length. Of the variance in age at onset that could not be attributed to CAG repeat length, 13% could be accounted for by variation in the GluR6 kainate receptor [10]. The influence of additional familial or even environmental factors remains unknown. RATE OF DISEASE PROGRESSION AND DURATION OF ILLNESS Studies of neuropathological changes in PSGCs have revealed a correlation between the rate of neuropathological progression and CAG repeat length. Higher numbers of repeats are associated with greater neuronal loss in both the caudate and putamen, indicating that longer CAG repeat length is related to a faster rate of deterioration and greater pathological severity [20,33–35]. Antonini et al. reported a significant correlation between CAG repeat length and the rate of percent loss in striatal D2 receptor binding in both preclinical and manifest HD patients [36]. However, it is unclear whether CAG repeat length also correlates with clinical progression. Illarioshkin et al. evaluated the rate of progression of neurological and psychiatric symptoms in HD and reported a more rapid decline with increasing repeat number [37]. Brandt et al. also reported a significant relationship between repeat length and rate of clinical progression; patients with longer repeat lengths displayed significantly greater decline in both neurological and cognitive functioning over a 2-year period [38]. However, other investigators report no such correlation and argue that other genetic loci must be involved in determining rate of decline in HD [31,39,40]. The relationship between rate of progression and age at onset is also unclear. While an early study has found evidence that the rate of progression is modified by age at onset [41], a more recent study, measuring progression with the Huntington’s Disease Functional Capacity Scale [42], reported no correlation between rate of decline and age at onset [43]. Another factor possibly related to rate of progression is the sex of the affected parent; offspring of affected fathers tend to have a more rapid progression than offspring of affected mothers [44,45]. Myers et al. reported that lower body mass index early in the disease is also related to more rapid disease progression [45]. However, Feigin et al. reported no correlation between rate of disease progression and paternal or maternal transmission, body weight or history of neuroleptic use [43]. Marder et al. also found no correlation between sex, weight and education, although depressive

FUTURE DIRECTIONS IN RESEARCH FOR HUNTINGTON’S DISEASE symptomatology at diagnosis was associated with a more rapid rate of clinical decline [46]. Conflicting reports in the literature have also arisen regarding the relationship between onset age and duration of disease. Foroud et al. reported significant differences in illness duration based on age at onset, with juvenile and late-onset patients having shorter durations of illness compared with patients whose onset was between 20 and 49 years [11]. Others have reported late-onset patients have a shorter disease duration than early-onset patients [47,48]. Roos et al. argues disease duration is independent of age at onset, reporting similar disease duration in juvenile and later onset HD cases [49]. Discrepancies in findings may well be due to differences in clinically defining the age at onset. While other researchers have defined signs of chorea as the first sign of onset [49], Foroud et al. noted that only 28% of HD patients reported chorea as one of their first symptoms of disease. Conversely many patients reported nonspecific physical, emotional or cognitive difficulties as early symptoms of HD [11]. In fact, the order of symptom presentation in HD remains unknown. While HD continues to be diagnosed primarily on the basis of motor signs, many studies report that cognitive deficits or emotional changes actually precede motor disturbance [30,50,51]. Hahn-Barma et al. reported significant cognitive disturbance in PSGCs who were otherwise free of motor and psychiatric symptoms, and assert that cognitive changes represent the first signs of disease onset [50]. Other findings suggest motor deficits may be present before cognitive changes [1]. A longitudinal investigation of cognitive and motor changes conducted by Kirkwood et al. revealed that PSGCs displayed deficits in motor control only [46], a finding also confirmed by De Boo et al. [1]. Given that diagnosis is currently based on early motor soft signs (via the Unified Huntington’s Disease Rating Scale (UHDRS) [53], neurological examination and clinical judgement), the order of symptom presentation needs to be clarified. The development of a more sensitive scale incorporating cognitive and behavioural abilities could be beneficial in diagnosing HD.

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increased oligodendroglia in PSGCs who were far from expected age at onset, suggesting that the pathological process in HD commences earlier in life [4]. Campodonico et al. correlated the neuropsychological performance of PSGCs and nongene carriers (NGCs) with putamen and caudate volumes as measured by MRI. The authors found that the size of caudate nuclei and putamen were significantly smaller in the PSGCs, and that reductions in BG size in PSGCs correlated with greater neurological irregularity, slower mental processing speeds, and poorer verbal learning. According to Campodonico et al., neuropathological and cognitive changes can occur well before the onset of clinically measurable symptoms [59]. Antonini et al. [60] and Andrews et al. [58] suggest that neurodegeneration begins within the decade before symptom onset, and is preceded by relatively preserved neuronal function early in life. Antonini et al. reported no significant differences between striatal glucose metabolism and dopamine D2 receptor binding values of PSGCs and healthy controls [60]. Andrews et al. measured the rate of loss of striatal dopamine D1 and D2 receptor binding over a 3-year period in a sample of PSGCs. The authors reported that while some PSGCs showed active loss of striatal dopamine binding, over the period of the study, other PSGCs subjects showed little change in striatal dopamine binding over the 3 years [58]. Grafton et al. found a 3.1% per year decline in caudate glucose metabolism [61] while follow-up striatal D1 and D2 binding studies in PSGCs have reported disease progression rates of 3.7–6.3% per year [62]. Kirkwood et al. recommend a compromise. In a study measuring motor function and reaction time of PSGCs, the authors noted a tendency toward greater physiological abnormality as neurologic symptoms increased. They suggest that some essentially static abnormalities may be present from birth, with the degree of abnormality increasing around the time of clinical onset [63]. Taken together, the majority of data support greater involvement of the associative striatum (which is comprised mainly of caudate) than of the motor striatum (which is comprised mainly of putamen), and virtually no involvement of the limbic (ventral) striatum in the early stages of HD [58].

NEUROIMAGING STUDIES Post mortem and in vivo neuroimaging techniques have revealed that in the early stages of HD the striatum is most severely affected and that other brain regions, such as the cortex, may also show some pathological change [12,54]. Post mortem studies further reveal that striatal degeneration progresses along mediolateral and dorsoventral gradients, firstly affecting the dorsomedial caudate and dorsal putamen while sparing the more lateral and ventral aspects of the striatum, including the nucleus accumbens [54–56]. Recent neuroimaging studies with PSGCs have been less conclusive and have raised a number of important questions regarding the nature of disease progression [57]. Currently it is not known whether HD progresses slowly from birth [34], with age at onset determined by the rate of neuronal degeneration and the functional reserve of the striatum, or whether neurodegeneration begins later in life with progression to manifest HD over just a few years [58]. A somewhat similar situation of cause may even pertain with Alzheimer’s or Parkinson’s diseases. Researchers have shown that PSGCs have reduced BG volumes years prior to the expected age at onset [22,59]. In addition, Aylward et al. demonstrated that PSGCs close to onset had smaller BG volumes than subjects far from onset, suggesting that the striatum continues to shrink as the person approaches the likely time of symptom onset [28]. Recently, Gomez-Tortosa et al. conducted morphometric studies of the tail of the caudate nucleus of brain specimens from PSGCs who had died from causes other than HD. The authors reported the presence of intranuclear inclusion and

PRECLINICAL COGNITIVE FUNCTIONING In manifest HD, the most striking cognitive deficit is executive dysfunction (e.g. strategies in planning and problem solving, self-monitoring, attentional and cognitive flexibility). As one would expect, cognitive deficits reported in PSGCs are also executive in nature, with reported impairments in attentional set shifting [24]; learning and problem solving [63,64]; visual memory [63,65,66]; verbal learning, and verbal memory [64,65]. Rosenberg et al. assessed the neuropsychological performance of PSGCs and NGCs. They reported that PSGCs showed a specific deficit in psychomotor speed, attention, concentration and abilities to utilise learning strategies [64]. Lawrence et al. reported that PSGCs performed significantly less well than noncarriers on tests of attentional set shifting and semantic verbal fluency; the authors suggested an underlying deficit in inhibitory control [30]. Foroud et al. reported that PSGCs obtained lower mean scores on subtests from the Wechsler Adult Intelligence Scale-Revised (WAIS-R) [67], with significantly poorer performance on tests involving visual motor coordination, speed, concentration and planning [52]. In a study by McCusker et al. individuals underwent neurological assessment prior to gene testing. McCusker et al. found that while neurological symptoms did not distinguish gene status, behavioural and cognitive symptoms were reported more frequently by the gene-positive group [14]. In contrast, De Boo et al. reported no group differences between the performance of PSGCs and NGCs on verbal and visual

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aspects of memory, word fluency and procedural learning tasks. They concluded that memory dysfunction is not a distinctive characteristic of PSGCs [68]. A longitudinal study by Giordani et al. also revealed that while both PSGCs and NGCs demonstrated variability over a 4-year period, no significant differences were observed between their performance on tests of intelligence, memory, problem solving or motor ability [69]. Kirkwood et al. reported that PSGCs displayed deficits in motor control only, with no significant differences between PSGCs and NGCs on measures of cognitive function [52]. More recently Paulsen et al. showed cognitive impairment in a group of PSGCs and that the difference was most pronounced as motor symptoms increased [70]. Moreover, performance decline over a 2-year period on the cognitive section of the UHDRS was significantly greater in those individuals who were closer to demonstrating HD symptoms than those who were not imminent of disease onset. A few limitations, also noted by the authors, were that the cognitive component of the UHDRS is very brief and designed as a screening tool; also, the follow up and sample size was relatively small. It is clear that more research is warranted to address whether neuropsychological cognitive changes occur well before manifest disease. PRECLINICAL MOTOR FUNCTIONING Studies of motor control in PSGCs have also produced conflicting findings. Research examining the motor performance of PSGCs has typically included neurological examination and kinematic measures of reaction time under various conditions. In a reach-to-grasp study, Smith et al. reported that a large percentage of PSGCs displayed movement irregularities, including jerkiness and abruptness, even when as much as 7 years remained before their predicted age at onset [71]. Siemers et al. demonstrated significant differences in performance between PSGCs and NGCs on physiological measures of movement time with decision, and visual reaction time with decision [72]. Significant differences between PSGCs and NGCs on measures of psychomotor speed, optokinetic nystagmus, and rapid alternating movements have also been reported [52,63,72]. Conversely, other researchers have found no evidence of motor disturbance in PSGCs [29,69,72,73]. Giordani et al. found no significant differences between the performance of PSGCs and NGCs on tapping speed or simple and choice reaction time tasks [69]. Gomez-Tortosa et al. reported that PSGCs showed no deficits in visual processing when compared to NGCs, and suggested visual processing deficits develop later, with other manifestations of the disease [74]. PRECLINICAL BEHAVIOURAL CHARACTERISTICS Most research examining affective disturbances in PSGCs has been in the form of psychiatric symptom checklists included as part of a battery of neuropsychological tests. These studies report no differences between scores of PSGCs and NGCs on psychiatric measures [29,50,63,65,69]. Hahn-Barma et al. assessed the mood state of all subjects using the Montgomery and Asberg depression rating scale [75] and the gravity of anxiety scale of Covi and Lipman [76]. Both PSGCs and controls obtained comparable scores on both tests, indicating similar depression and anxiety levels in both groups [50]. Jason et al. reported only 1 of 86 PSGCs demonstrated significant mood disturbance on the Profile of Mood States (POMS) [66,77]. Shiwach and Norbury investigated the incidence of diagnosable psychiatric disorders in PSGCs and NGCs and found no difference between the two groups in incidence of psychiatric disorders [78]. Such reports clash with previous research findings suggesting that affective signs are the first clinical signs of the disorder [79].

A possible explanation for the lack of research into affective changes in PSGCs is the difficulty researchers face in determining whether any observed psychiatric disturbance should be attributable to HD, or whether they are an emotional response to the knowledge that they carry the HD gene. Ideally, psychiatric status should be determined both before and after PSGCs become aware of their genetic status. ETHICAL ISSUES ASSOCIATED WITH TESTING FOR HD With the development of an accurate predictive test for HD that is both relatively inexpensive and readily available, it is vital that both clinicians and researchers are aware of the ethical considerations. There are a number of possible reasons as to why individuals with a family history of HD request testing. Such reasons include the desirability of informing children, making reproductive decisions, relieving uncertainties, making financial/employment decisions, estimating timespan of health, and so on [80,81]. Since the introduction of the test the number of persons taking the test has been in the order of 2–16% [82] considerably lower than that originally anticipated (in the order of 60% or greater) [83]. This relatively small number of individuals seeking genetic testing is potentially making recruitment for large clinical trials somewhat difficult. The reasons for the reduced uptake of predictive testing may include factors such as inability to cope with a positive result, concern for the possible increased risk of children, absence to date of any clinically effective treatment, potential loss of health insurance, implications for a parent who might not wish to know their own genetic status, increased availability of contraception, new uncertainties for carriers of intermediate and reduced penetrance alleles and for their offspring and relatives, and so on. Even with new choices regarding control of reproduction the uptake of prenatal testing has remained quite low [84]. Indeed with the recent availability of the direct mutation test of the foetus as a simple and fast procedure, we encounter the dilemma of inevitable disclosure of the parental genetic status simultaneously with that of the foetus. The most obvious concern in relation to testing for HD would be an incorrect test result. Although incorrect genotypings resulting from the procedure are unlikely, mix-up of samples or errors of other sorts could be very traumatic for the individual concerned. The stressors associated with receiving a positive result, correct or incorrect, must also be considered. Factors of concern include onset of depressive symptoms, loss of motivation and possibly, in extreme cases, suicide [85]. Testing must be performed with the patient’s consent and there should be no coercion from a third party. Genetic testing centres have on occasion refused to perform tests when it is suspected that a doctor has requested a test for a patient without their full, informed consent [86]. Care should also be taken to ensure confidentiality at all times, and to avoid exposing the patient to discrimination for employment or insurance. In many countries minors are not tested as it is considered that they may not be fully informed or there could be parental pressure for them to take the test [87]. Of course, we should not ignore the psychological and emotional effects associated with genetic testing. Pre- and postgenetic counselling should always be part of the testing process. Not only the patient but also other family members may need psychological, emotional or social support to help them deal with the results. This may be true for either positive or negative results. Also, one should avoid the tendency to blame all of the patient’s complaints on HD and be certain to evaluate and treat any coexisting medical conditions [88]. The issue of whether at-risk individuals should be required to undergo genetic testing before participating in a clinical trial, or a longitudinal progression study, is open to debate. Of course, this

FUTURE DIRECTIONS IN RESEARCH FOR HUNTINGTON’S DISEASE issue is very difficult to answer and raises other questions, such as should at-risk individuals be allowed to participate without being told the results of their genetic test? If so, would it be ethical for gene negative individuals to receive experimental medication as part of a clinical trial? Is it ethical to entice at-risk individuals into genetic testing so that they can participate in a trial with an unproven experimental medication? Some of these issues are very difficult to answer; however in order to overcome potential ethical problems raised by these questions, perhaps only individuals who have willingly undertaken a genetic test of their own free will should be invited to take part in clinical trials or longitudinal studies. We have no right to expect that an individual should undergo a genetic test for the purpose of being included in a research study. In addition, we further recommend that an individual who is blinded to the genetic status of those participating in the study should collect clinical/experimental data so as to overcome potential biases of analysis or interpretation. The existence of such a reliable and quick method of presymptomatic detection of the HD gene raises some other important ethical questions, including the use to which this information may be put, the right of privacy, the right of people to know genetic information, and their right not to know. Wexler referred to the dilemma of presymptomatic testing as the “Tiresias complex”. In Sophocles’ Oedipus Tyrammus, the blind seer Tiresias warned Oedipus, “It is but sorrow to be wise when wisdom profits not.” Wexler extends this thought by asking: “Do you want to know how and when you will die, especially if you have no power to change the outcome? Should such knowledge be made freely available? How does one cope with the answer?” It is the experience of some clinicians that many presymptomatic individuals “would benefit from intensive counselling, sometimes in lieu of the test itself” [89]. CONCLUSIONS AND RECOMMENDATIONS (FUTURE DIRECTIONS) There are now a number of studies reporting the neuropsychological characteristics of PSGCs; however, it is still unclear whether this group display preclinical deficits. Although we are aware of some of the factors that influence age at onset and disease progression, we are still unable to determine exactly when an individual will develop HD symptoms, and how fast these symptoms will progress. Relatively small group samples, and the resulting limits on statistical power, may explain some of the inconsistent findings. Future research should take into consideration mode of transmission, CAG repeat length and where possible, attempt to estimate the likelihood of disease onset for each individual in the study using perhaps the Rubinsztein et al. equation [10]. In this way, researchers could then select for inclusion in a research study individuals on the basis of a specific set of criteria, perhaps 4 years before each individual’s calculated age at onset. Moreover, previous studies treated all PSGCs as a homogeneous group, when it may not always have been appropriate to do so. Individuals with longer CAG repeats may be closer to disease onset, resulting in possibly poorer performances on tasks than those further from disease onset [16]. There appears to be little agreement among investigators as to what defines PSGC status; this has resulted in variable inclusion criteria. For example, some studies excluded PSGCs who exhibited soft signs on neurological examination [1], while others did not [30]. In one study, inclusion was based on whether subjects reported themselves to be free of symptoms [1]. The authors made the assumption that if the “at-risk” individual did not report motor symptoms, detailed neurological examination need not be undertaken. However, given that previous research has demonstrated that PSGCs can lack insight, self-report should not be considered

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as a reliable guide to clinical onset and presentation of symptoms [14,72]. In both research and clinical practice, the presence or absence of HD signs is judged by the clinician. Some of the differences in findings in the literature might well be due to differences in clinicians’ judgements and criteria. De Boo et al. stated that HD signs may be missed on routine neurological examination. They also reported poor inter-rater agreement among three neurologists about manifestations of early disease onset [1]. The UHDRS was designed as a tool for clinicians to quantify the degree of impairment seen in patients already diagnosed with HD; it was not designed to be used as a diagnostic tool [53], yet the motor component of this scale is often used as a means of clinical diagnosis. Given the current controversy surrounding what type of symptoms constitute early signs of clinical onset (i.e., cognitive or emotional preceding motor, or vice versa) a more comprehensive scale is warranted. Ratings of PSGCs are based on the judgement of the attending clinician, and are therefore subjective. Given the apparent controversy in the PSCG literature, pertaining to type of symptom onset, a scale should be developed which includes aspects of cognitive, motor and affective signs; this could be useful not only in clinical practice, but also in research. Such a scale could reduce the subjectiveness of neurological examinations, and make inclusion criteria more consistent across studies. Additional longitudinal research is needed to further our understanding of the timing and extent of changes in neuropsychological functioning in PSGCs. With a better understanding of the pathogenesis and time course of HD, future therapeutic interventions may successfully delay or prevent the onset of the neurodegenerative process. At present there are many experimental treatments, including neuroprotective agents and striatal implants, which aim to slow the progression of the disease and restore BG function [57,90]. Currently, drugs such as lamotrigine, gabapentin, and riluzole, which indirectly inhibit the release or synthesis of the excitatory amino acid glutamate, and minocycline, which inhibits caspase-1 and inducible nitric oxide synthetase upregulation, are under investigation as potential agents to delay disease progression [91–93]. Antioxidants, such as α-tocopherol (Vitamin E) [94], idebenone [95], thioctic acid [96], or α-phenyl-t-butyl nitrone [97] are also under investigation. Moreover, drugs that improve intracellular metabolism, such as coenzyme Q10 [98], nicotinamide, ascorbic acid, riboflavin or carmitine theoretically operate by mechanisms that provide neuroprotection and thus may be efficacious in forestalling disease progression. Calcium channel blockers may also be beneficial via their ability to inhibit the increase of intracellular calcium and subsequent activation of nitric oxide synthetase associated with excitotoxicity [96]. A greater understanding of the time course of the disease would be beneficial not only in monitoring the effectiveness of future treatments, but also in determining the most appropriate time to administer them. A promising approach to therapeutics involves transplantation of either fetal striatal cells or of cell secreting growth factor. PET has been used to monitor the long-term survival of fetal midbrain implants in patients with Parkinson’s disease and is currently being used to monitor graft survival in HD patients [99]. These methods however have met with little success so far, though they may hold promise for the future. Stem cells, if they can be differentiated into striatal neurones in a controlled fashion, may also be of great potential [100]. Given that future therapeutic strategies are likely to be most beneficial to PSGCs, a more complete understanding of this group is urgently required, while still keeping in mind the various ethical issues. The investigation of preclinical deficits in PSGCs is a challenging new avenue of research, and while findings are still equivocal, improved inclusion criteria may lead to a clearer

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