Apathy predicts rate of cognitive decline over 24 months in premanifest Huntington's disease.

BACKGROUND: Cognitive impairment is a core feature of Huntington's disease (HD), however, the onset and rate of cognitive decline is highly variable. Apathy is the most common neuropsychiatric symptom of HD, and is associated with cognitive impairment. The aim of this study was to investigate apathy as a predictor of subsequent cognitive decline over 2 years in premanifest and early HD, using a prospective, longitudinal design. METHODS: A total of 118 premanifest HD gene carriers, 111 early HD and 118 healthy control participants from the multi-centre TRACK-HD study were included. Apathy symptoms were assessed at baseline using the apathy severity rating from the Short Problem Behaviours Assessment. A composite of 12 outcome measures from nine cognitive tasks was used to assess cognitive function at baseline and after 24 months. RESULTS: In the premanifest group, after controlling for age, depression and motor signs, more apathy symptoms predicted faster cognitive decline over 2 years. In contrast, in the early HD group, more motor signs, but not apathy, predicted faster subsequent cognitive decline. In the control group, only older age predicted cognitive decline. CONCLUSIONS: Our findings indicate that in premanifest HD, apathy is a harbinger for cognitive decline. In contrast, after motor onset, in early diagnosed HD, motor symptom severity more strongly predicts the rate of cognitive decline.

"It's being part of the big picture, even though you're a tiny jigsaw piece"-motivations and expectations of individuals participating in the Enroll-HD observational study.

Predictive test guidelines for Huntington's disease (HD) recommend individuals are offered opportunities to participate in research regardless of test outcome. Consistent with most HD centres of excellence, the Manchester Centre for Genomic Medicine (MCGM) invites eligible individuals to participate in the observational study, Enroll-HD. Limited research has been conducted to date on the views of research participants and the possible impact of participation. The aim of this qualitative study was to explore the experiences of ten individuals taking part in the Enroll-HD study following pre-symptomatic testing for HD. Half of the individuals had tested positive for the HD mutation and the other half had tested negative. Participants were generally motivated to take part in the study by both personal and altruistic reasons. Overall, they were very positive about participation in Enroll-HD. Valuable aspects included good relationships with the research/clinical team, increased understanding of the condition, an enhanced self-image and a shared experience with affected parents. Issues for improvement to encourage participation included access to study site and more regular communication about study progress. Participants, while generally optimistic about research progress, were realistic about challenges.

Comparison of proactive and usual approaches to offering predictive testing for BRCA1/2 mutations in unaffected relatives.

There have been few studies addressing uptake of predictive testing for BRCA1/2, only one comparing a proactive with usual family networking approach to dissemination. We report uptake of predictive genetic testing after directly offering BRCA1 presymptomatic genetic testing to 100 individuals in two generations of 5 large BRCA1 families compared with service testing of 196 families since that time. Uptake was significantly higher in the first generation (group 1), who were directly offered testing, and much higher in females. Seventy-four percent of unaffected women in the first generation proceeded to testing, 42% of men. This decreased to 44% of women in the second generation (group 2) and 9% males (p = 0.0003). Uptake in unaffected individuals in the final group (group 3) with no proactive approach was significantly lower than that in the first group. Overall uptake after 10 years was 56% (95% confidence interval, CI, 50-62%) for group 1 and 36% (95% CI 34.3-37.7%) for 1084 group 3 individuals (p = 0.0003). Among women, uptake was 74% (95% CI 67-81%) in group 1 at 10 years compared with 51.5% (95% CI 49-54%) in 552 group 3 women (p = 0.023). In men, uptake was 42% (95% CI 33-52%) in group 1 and 21.1% (95% CI 18.1-23.1%) among 532 men in group 3 (p = 0.0098). Although these results are not from a randomized trial, they show particularly among men a substantially higher uptake of genetic services with a direct approach. Importance should be given to more proactive approaches to ensure that men in BRCA1/2-positive families receive the appropriate information.

Emotion recognition in Huntington's disease and frontotemporal dementia.

A well-documented feature of Huntington's disease (HD) is disproportionate impairment in the ability to recognise the emotional expression of disgust. However, this finding has been challenged by studies that report no differential disgust impairment and attribute apparent differences across emotions to task difficulty. The present study sought to shed light on disparities in findings through a comparative study of emotion recognition in HD and frontotemporal dementia (FTD). Ten HD, 12 FTD patients and 12 healthy controls were administered 10 tasks assessing facial and vocal recognition of emotions and comprehension of emotion terms. The findings were not consistent with either the 'selective disgust impairment' or 'task difficulty' view. Both HD and FTD groups were impaired compared to controls, deficits in HD being less severe. Impairments in FTD were elicited for all emotions whereas in HD they were demonstrated predominantly for negative emotions of fear, disgust and anger. Consistency in performance, despite varying task demands, excluded an explanation in terms of item difficulty, and was in keeping with the notion of distinct neural substrates for processing of negative emotions. Contrary to the notion of disproportionate disgust impairment, the most severe deficits in HD were elicited for anger, a finding that may have relevance for the poor anger control that is the hallmark of HD. The data raise the possibility that linguistic influences and conceptual complexities of the emotion of disgust may contribute to the variable finding of selective disgust impairment in HD.

Progression of motor subtypes in Huntington's disease: a 6-year follow-up study.

The objective of this study is to investigate the progression of predominantly choreatic and hypokinetic-rigid signs in Huntington's disease (HD) and their relationship with cognitive and general functioning over time. The motor signs in HD can be divided into predominantly choreatic and hypokinetic-rigid subtypes. It has been reported in cross-sectional studies that predominantly choreatic HD patients perform better on functional and cognitive assessments compared to predominantly hypokinetic-rigid HD patients. The course of these motor subtypes and their clinical profiles has not been investigated longitudinally. A total of 4135 subjects who participated in the European HD Network REGISTRY study were included and classified at baseline as either predominantly choreatic (n = 891), hypokinetic-rigid (n = 916), or mixed-motor (n = 2328), based on a previously used method. The maximum follow-up period was 6 years. The mixed-motor group was not included in the analyses. Linear mixed models were constructed to investigate changes in motor subtypes over time and their relationship with cognitive and functional decline. Over the 6-year follow-up period, the predominantly choreatic group showed a significant decrease in chorea, while hypokinetic-rigid symptoms slightly increased in the hypokinetic-rigid group. On the Total Functional Capacity, Stroop test, and Verbal fluency task the rate of change over time was significantly faster in the predominantly choreatic group, while on all other clinical assessments the decline was comparable for both groups. Our results suggest that choreatic symptoms decrease over time, whereas hypokinetic-rigid symptoms slightly increase in a large cohort of HD patients. Moreover, different motor subtypes can be related to different clinical profiles.

Ten years of presymptomatic testing for Huntington's disease: the experience of the UK Huntington's Disease Prediction Consortium.

Data on all presymptomatic genetic tests for Huntington's disease (HD) in the UK have been collected over the 10 year period since testing became available as a service. A total of 2937 completed tests have been performed up to the end of 1997, 2502 based on specific mutation testing, feasible since late 1993.A total of 93.1% of these were at 50% prior risk, with a significant excess of females (58.3%); 41.4% of results were abnormal or high risk, including 29.4% in subjects aged 60 or over. The trend in test numbers has currently levelled out at around 500 per year. Almost all presymptomatic tests are carried out in National Health Service genetics centres, with a defined genetic counselling protocol and with availability now in all regions of the UK. The introduction and establishment of HD presymptomatic testing shows that this form of predictive medicine for Mendelian disorders can be successfully incorporated into National Health Service structures. The comprehensive collection of simple data allows trends in demand and outcomes to be monitored and has also been the foundation for more detailed specific studies. A comparable approach to data collection in other genetic disorders will be important as presymptomatic testing becomes more generally feasible.

Comparison of genetic services with and without genetic registers: knowledge, adjustment, and attitudes about genetic counselling among probands referred to three genetic clinics.

Genetic register services incorporating long term follow up and a proactive approach to at risk subjects have been recommended as a way of improving access to genetic counselling for families with dominant or X linked genetic disorders and chromosome translocations. The aims of the present study were to evaluate the psychosocial benefits and drawbacks of long term family contact, and to evaluate the attitudes of probands and their general practitioners towards proactive genetic counselling. We interviewed 192 people referred to three regional genetic clinics because of a family history of Duchenne or Becker muscular dystrophy, myotonic dystrophy, or chromosome translocations, and 43 of the referring GPs. Probands attending the centre using a genetic register approach were compared with those from the two centres offering the standard clinical genetic service. A very high proportion of probands in both groups were well informed about the genetic risks to themselves and their children, were satisfied with the service they had received from their local genetic clinic, and felt adequately prepared to discuss the family illness with their children. The register probands expressed approval of the ongoing contact and open access provided by the register service. Asked whether previously unaware relatives should be informed of their at risk status, 98% (188/192) said it was acceptable for this information to be disclosed by a family member, while three quarters of the probands (149/192) and just over half the GPs (27/43) thought it acceptable for the genetic service to approach them; a similar proportion of both GPs and probands also found it acceptable for GPs to do so. More than half the probands (107/190) thought it was the family's responsibility to pass on genetic risk information, but 43% said that either the genetic service or the GP should be responsible for this. The findings show that the genetic register approach incorporating long term follow up and a proactive approach to genetic counselling is highly acceptable to the families concerned, and although the register and non-register probands did not differ significantly on any of the main outcome measures used in this relatively short term study, it may be that the continuing contact associated with the register approach offers long term benefits, especially for those genetic conditions where medical surveillance may have an impact on the prognosis.

Comparison of genetic services with and without genetic registers: access and attitudes to genetic counselling services among relatives of genetic clinic patients.

The pedigrees of 192 subjects at risk of Duchenne or Becker muscular dystrophy, myotonic dystrophy, or balanced chromosome translocations attending three regional genetic clinics were inspected to identify relatives who were themselves at high risk of these disorders. Of the 342 relatives eligible for inclusion, 43% (63/147) of the register relatives and 26% (50/195) of the non-register relatives had had contact with the clinical genetic services, a significant difference (p<0.02). Relatives from families with muscular dystrophy were significantly more likely to have been in contact with genetic services than those from BT families. Fifty-two relatives were interviewed about their experience and attitudes regarding genetic counselling. Almost all regarded knowledge about the family genetic disorder as helpful, and only one thought it unacceptable for relatives to be informed that they are at risk; 94% thought it was acceptable for this information to come from family members, 92% from general practitioners, and 90% from the clinical genetic service. A majority of relatives (53%) thought it was the family's responsibility to pass on genetic risk information, but 22% said the genetic service should be responsible and 18% thought it should be the GP. These data, together with the findings from the study of probands attending genetic clinics for these disorders, indicate that the genetic register approach incorporating long term follow up and a proactive approach to genetic counselling is acceptable to the families concerned and improves access to genetic services for at risk relatives.

Awareness of involuntary movements in Huntington disease.

OBJECTIVE: To determine why patients with Huntington disease are apparently unaware of their involuntary movements. DESIGN: Correlative study using a subjective report questionnaire of physical symptoms and objective measures of neurologic and cognitive dysfunction. PATIENTS: Forty patients with Huntington disease attending a regional Huntington disease clinic. RESULTS: Patients were poor at reporting experiential symptoms of involuntary movements. There was no relationship between self-report of these symptoms and objective indices of motor dysfunction or severity of cognitive impairment. Patients could, however, report secondary consequences of their movement disorder, which correlated highly with nonchoreic indices of motor dysfunction. CONCLUSIONS: Patients with Huntington disease have impaired subjective experience of chorea. Denial of symptoms is likely to have a physiological basis and is not a secondary consequence of patients' cognitive impairment or a psychological defense against a debilitating disease.

Homozygotes and heterozygotes for ciliary neurotrophic factor null alleles do not show earlier onset of Huntington's disease.

The CAG repeat number on Huntington's disease (HD) chromosomes accounts for about 60% of the variance in the age at onset of HD. However, distinct familial factors may also influence the age at onset. HD is associated with loss of medium-sized GABA-ergic striatal output neurons. Intracerebral administration of human ciliary neurotrophic factor (CNTF) protects striatal output neurons in excitotoxic rodent and primate models of HD induced by intrastriatal quinolinic acid injection. We have examined the effect of a common null mutation in the human CNTF gene on the age of onset of HD using a multiple regression approach that takes into account the CAG repeat number on HD chromosomes. We failed to detect an earlier onset of HD in nine homozygotes and 71 heterozygotes with this CNTF mutation compared with 203 homozygotes with wild-type alleles.

Social cognition in frontotemporal dementia and Huntington's disease.

Frontotemporal dementia (FTD) and Huntington's disease (HD) are degenerative disorders, with predominant involvement, respectively of frontal neocortex and striatum. Both conditions give rise to altered social conduct and breakdown in interpersonal relationships, although the factors underlying these changes remain poorly defined. The study used tests of theory of mind (interpretation of cartoons and stories and judgement of preference based on eye gaze) to explore the ability of patients with FTD and HD to interpret social situations and ascribe mental states to others. Performance in the FTD group was severely impaired on all tasks, regardless of whether the test condition required attribution of a mental state. The HD group showed a milder impairment in cartoon and story interpretation, and normal preference judgements. Qualitative differences in performance were demonstrated between groups. FTD patients made more concrete, literal interpretations, whereas HD patients were more likely to misconstrue situations. The findings are interpreted as demonstrating impaired theory of mind in FTD, as one component of widespread executive deficits. In HD the evidence does not suggest a fundamental loss of theory of mind, but rather a tendency to draw faulty inferences from social situations. It is concluded that social breakdown in FTD and HD may have a different underlying basis and that the frontal neocortex and striatum have distinct contributions to social behaviour.

Abnormalities of motor timing in Huntington's disease.

The ability of patients with Huntington's disease (HD) and control subjects to produce rhythmic finger tapping movements at target frequencies (1-5 Hz) signalled by auditory cues, and to sustain the tapping tempo following sudden withdrawal of cues, was investigated. HD performance, in both the presence and absence of cues, was characterised by, (i) marked irregularity of instantaneous tapping rates and (ii) a tendency to tap too slowly at higher (3-5 Hz) frequency targets and too rapidly at low target frequencies. Analysis of the variability of inter-tap intervals, during uncued tapping at a target rate of 1.8 Hz, using Wing and Kristofferson's model of motor timing (Wing AM, Kristofferson AB. Percept. Psychophys. 1973; 14: 5-12), indicated disturbances of both hypothetical 'clock' and 'motor implementation' systems in HD.

Pilot study of the acceptability of cystic fibrosis carrier testing during routine antenatal consultations in general practice.

BACKGROUND: In 1989, the gene for cystic fibrosis was cloned and it became possible to detect carriers of the gene among the general population, including pregnant women. AIM: The aim of the pilot study was to assess the acceptability of integrating cystic fibrosis carrier testing into antenatal care by general practitioners at the first booking appointment. METHOD: Between 1 September 1991 and 31 August 1992, inclusive, all patients receiving routine antenatal care in a two-partner training practice in south Manchester were offered carrier testing for cystic fibrosis using a computer protocol for antenatal care developed by the practice. A questionnaire including a Spielberger state-trait anxiety inventory was sent to patients 2 weeks after they received the results of their carrier test, and interviews with the patients in their home were carried out 4 weeks and one year after they received the result. RESULTS: All but one patient (75 out of 76) booking before 14 weeks of pregnancy accepted the offer of cystic fibrosis carrier testing, and 96% (72 out of 75) felt that they had made the right decision and that they had enough time for discussion with their general practitioner before testing. CONCLUSIONS: Cystic fibrosis carrier testing can be successfully integrated into the antenatal booking appointment in general practice and is acceptable to patients. This is a model for other genetic screening opportunities resulting from advances in medical genetics.

Life events and psychological disturbance in patients with low-back pain.

To elucidate the possible contribution of psychologic factors in the pathogenesis of back pain, an assessment of life events and psychiatric symptoms was undertaken in 80 new referrals. In 57, the back pain had a definite onset recent enough to allow this to be dated accurately; these definite onset cases were divided into 26 in whom a specific organic diagnosis could be made and 31 in whom the cause of the pain was uncertain. An additional 23 patients had chronic pain, or could not date the onset of their symptoms. Unlike previous studies, events that occurred after the onset of back pain and thus could have been a consequence of the back pain were excluded. Before onset of back pain there was a significant excess of adverse life events in those with definite onset back pain of uncertain cause, compared with those with a specific diagnosis: there was no such excess in the periods before referral and attendance at the clinic. Diagnosable psychiatric illness was virtually confined to those with chronic pain. These findings indicate that stress, but not psychiatric illness, is involved in the onset of back pain. Further research is now required to ascertain whether those patients who have many psychiatric symptoms at the time of onset are those who develop chronic pain.

Presymptomatic testing for Huntington's disease in the United Kingdom. The United Kingdom Huntington's Disease Prediction Consortium.

OBJECTIVE: To evaluate the United Kingdom Huntington's disease presymptomatic testing programme. DESIGN: Postal questionnaire survey to collect data on all tests performed by clinical genetics centres between 1987 and 1990. SETTING: Genetic centres providing presymptomatic testing in the United Kingdom. SUBJECTS: 248 subjects at risk of Huntington's disease who had presymptomatic testing at their request. MAIN OUTCOME MEASURES: Sex, age, prior risk, and risk after testing. RESULTS: The risk of carrying the Huntington disease gene was reduced for 151 (61%) of the applicants and raised for 97 (39%). 158 (64%) of the subjects were female and 90 (36%) male. The median age at which the results were given was 32.5 years. CONCLUSIONS: The demand for testing was lower than expected and may have reached its peak in 1990. The excess of low risk results was not fully explained by the age effect. All the genetics centres concerned have agreed a common service protocol which requires extensive pre-test counselling and post-test follow up. The worth of the procedure remains to be decided. The availability of a large body of pooled data from all the United Kingdom testing centres, which individually are likely to have only a few results, will form a valuable resource for monitoring the long term psychosocial impact of testing.

Cystic fibrosis carrier testing in early pregnancy by general practitioners.

OBJECTIVE: To assess the feasibility of genetic counselling in general practice by using cystic fibrosis carrier screening at the booking appointment as an integral part of routine antenatal care and as a paradigm for the wider participation of general practitioners in medical genetics. DESIGN: Maternal testing (male partner tested only if woman screens positive) and couple testing for cystic fibrosis carrier status in the antenatal population attending one general practice and, later, in a further six (outreach) practices also. SETTING: Two partner urban training practice (pilot practice) in south Manchester, and six north west practices (two inner city, three urban, one rural dispensing). SUBJECTS: Total practice population of 50,000 (pilot practice plus six outreach practices) with an estimated 500-800 pregnancies per year. MAIN OUTCOME MEASURES: (a) Proportion of carriers of cystic fibrosis identified, counselled, and appropriately managed within the first trimester of pregnancy; (b) questionnaire and interview measures of patient satisfaction and stress. RESULTS: Eleven carriers of cystic fibrosis were detected including one carrier couple. This carrier couple, after extensive counselling, elected to have prenatal diagnosis by chorionic villus biopsy. The fetus was homozygous normal. CONCLUSIONS: General practitioners can successfully integrate genetic counselling and cystic fibrosis carrier screening into the first antenatal booking appointment. When a carrier couple is identified clinical geneticists can help with the discussion of reproductive options, and prenatal diagnosis by chorionic villus biopsy can be completed within the first trimester. The results suggest that general practitioners will have an increasingly important role in medical genetics, subject to continuing evaluation of patient acceptability and stress.

Magnetization transfer imaging in premanifest and manifest huntington disease: a 2-year follow-up.

BACKGROUND AND PURPOSE: MTI is a quantitative MR imaging technique that has recently demonstrated structural integrity differences between controls and patients with HD. Potentially, MTI can be used as a biomarker for monitoring disease progression. To establish the value of MTI as a biomarker, we aimed to examine the change in these measures during the course of HD. MATERIALS AND METHODS: From the Leiden TRACK-HD study, 25 controls, 21 premanifest gene carriers, and 21 patients with manifest HD participated at baseline and during a 2-year follow-up visit. Brain segmentation of the cortical gray matter, white matter, caudate nucleus, putamen, pallidum, thalamus, amygdala, and hippocampus was performed by using the automated tools FAST and FIRST in FSL. Individual MTR values were calculated from these regions, and MTR histograms were constructed. RESULTS: In the premanifest HD group stage "far from disease onset," a significant increase in MTR peak height of the putamen was observed with time. During the manifest HD stage, neither the mean MTR nor the MTR peak height showed a significant change during a 2-year follow-up. CONCLUSIONS: MTI-derived measures are not suitable for monitoring in Huntington disease during a 2-year period because there was no decrease in structural integrity detected in any of the manifest HD groups longitudinally. The finding of increased putaminal MTR peak height in the premanifest far from disease onset group could relate to a predegenerative process, compensatory mechanisms, or aberrant development but should be interpreted with caution until future studies confirm this finding.

Magnetization transfer imaging in premanifest and manifest Huntington disease.

BACKGROUND AND PURPOSE: MTI has the potential to detect abnormalities in normal-appearing white and gray matter on conventional MR imaging. Early detection methods and disease progression markers are needed in HD research. Therefore, we investigated MTI parameters and their clinical correlates in premanifest and manifest HD. MATERIALS AND METHODS: From the Leiden TRACK-HD study, 78 participants (28 controls, 25 PMGC, 25 MHD) were included. Brain segmentation of cortical gray matter, white matter, caudate nucleus, putamen, pallidum, thalamus, amygdala, and hippocampus was performed using FSL's automated tools FAST and FIRST. Individual MTR values were calculated from these regions and MTR histograms constructed. Regression analysis of MTR measures from all gene carriers with clinical measures was performed. RESULTS: MTR peak height was reduced in both cortical gray (P = .01) and white matter (P = .006) in manifest HD compared with controls. Mean MTR was also reduced in cortical gray matter (P = .01) and showed a trend in white matter (P = .052). Deep gray matter structures showed a uniform pattern of reduced MTR values (P < .05). No differences between premanifest gene carriers and controls were found. MTR values correlated with disease burden and motor and cognitive impairment. CONCLUSIONS: Throughout the brain, disturbances in MTI parameters are apparent in early HD and are homogeneous across white and gray matter. The correlation of MTI with clinical measures indicates the potential to act as a disease monitor in clinical trials. However, our study does not provide evidence for MTI as a marker in premanifest HD.