Huntington’s like conditions in China, A review of published Chinese cases

·

Background: Knowledge about HD in China is lacking in the international literature. We have therefore analyzed the Chinese literature to thoroughly explore the clinical characteristics of Huntington disease in China.

Methods: A computer-based online search of China National Knowledge Infrastructure was performed to review case reports concerning HD published between January 1980 and April of 2011, and the clinical characteristics were extracted.

Results: A total of 92 studies involving 279 patients (157 males and 122 females) were collected, 82.0% of which were from provinces of North China. Most of the cases (97.8%) had a family history of HD, and paternal inheritance (65.5%) was higher than maternal inheritance (34.5%). Onset age was 35.8 (± 11.8) years, death occurred with 45.6 (± 13.5) years after a course of 11.6 (± 5.6) years. Involuntary movements were the most frequent reported presentation (found in 52.3%, including 64.4% in the entire body, 19.8% in the upper limbs, and 13.7% in the head and face). Psychiatric symptoms at onset were reported in 16.1%, and cognitive impairment in 1.8%. With disease progression, 99.6% of patients had abnormal movements, 67.9% cognitive impairment, and 35.0% suffered psychiatric symptoms. Of the reported patients, only 22 underwent IT15 gene testing with positive results.

Conclusion: HD is a well-reported entity in Chinese medical literature, however, only a small number of instances have been proven by molecular diagnosis. Most of the features resemble what is known in other countries. The highly predominant motor presentation, and the higher male prevalence as well as the apparent concentration in Northern China may be due to observational bias. There is therefore a need to prospectively examine cohorts of patients with appropriate comprehensive assessment tools including genetic testing.

Current Pharmacological Management in Juvenile Huntington’s Disease

·

Background: The clinical presentation of Juvenile Huntington’s Disease (JHD) can be very different from adult-onset HD with little evidence to guide symptomatic management.

Aim: To survey the current use of pharmacological treatments for JHD.

Methods: Patients were identified through the HD Association, Hospital Doctors and the European Huntington’s Disease Network REGISTRY study.

Results: The most commonly prescribed agents were anti-psychotics (24/45), anti-depressants (17/45) and anti-parkinsonian medications (15/45). 5 patients were taking more than 8 medications.

Conclusions: The most commonly prescribed group of medication was the anti-psychotic. Many patients were on multiple therapies, highlighting the need to rationalise medications.

Stability effects on results of diffusion tensor imaging analysis by reduction of the number of gradient directions due to motion artifacts: an application to presymptomatic Huntington’s disease

·

In diffusion tensor imaging (DTI), an improvement in the signal-to-noise ratio (SNR) of the fractional anisotropy (FA) maps can be obtained when the number of recorded gradient directions (GD) is increased. Vice versa, elimination of motion-corrupted or noisy GD leads to a more accurate characterization of the diffusion tensor. We previously suggest a slice-wise method for artifact detection in FA maps. This current study applies this approach to a cohort of 18 premanifest Huntington’s disease (pHD) subjects and 23 controls. By 2-D voxelwise statistical comparison of original FA-maps and FA-maps with a reduced number of GD, the effect of eliminating GD that were affected by motion was demonstrated.

We present an evaluation metric that allows to test if the computed FA-maps (with a reduced number of GD) still reflect a “true” FA-map, as defined by simulations in the control sample. Furthermore, we investigated if omitting data volumes affected by motion in the pHD cohort could lead to an increased SNR in the resulting FA-maps.

A high agreement between original FA maps (with all GD) and corrected FA maps (i.e. without GD corrupted by motion) were observed even for numbers of eliminated GD up to 13. Even in one data set in which 46 GD had to be eliminated, the results showed a moderate agreement.

Aspiration pneumonia and death in Huntington’s disease

·

Huntington’s disease (HD) is a progressive neurodegenerative autosomal dominant disease characterized by choreatic and hypokinetic movements, disturbed behaviour, and cognitive decline. Pneumonia is the most common cause of death, followed by cardiovasculair diseases. It has been suggested that choking is the causative underlying factor for pneumonia in HD. As a detailed specification of the type of pneumonia has never been performed, we analyzed the records of our Brain Bank containing 224 cases to determine the exact cause of death and type of pneumonia. The conclusion is that the majority (86.8%) of our HD patients where the cause of death could be identified died from aspiration pneumonia.

Seven-year clinical follow-up of premanifest carriers of Huntington’s disease

·

Detecting subtle clinical abnormalities in the ‘premanifest’ phase of Huntington’s disease (HD) is of importance in the development of instruments to monitor early therapeutic intervention trials. The current study examined changes in motor function, cognition and behaviour over a period of seven years in premanifest carriers of the HD gene mutation. Twenty-nine carriers without unequivocal motor signs of HD and 43 non-carrier controls were prospectively examined four times. The assessments consisted of the Unified Huntington’s Disease Rating Scale (UHDRS) and an extensive neuropsychological test battery addressing global cognitive function, memory, language and executive function. Rate of Change (RoC) analysis was performed to measure longitudinal differences between carriers and non-carriers. Carriers performed consistently worse on executive function (Symbol Digit Modalities Test (SDMT), Stroop, Trail Making Test (TMT) and WAIS-R arithmetic). Over the years, carriers showed a decline in memory and concentration function (Wechsler Memory Scale (WMS)) and in motor function (UHDRS motor scale). Changes over time could be particularly ascribed to carriers converting to manifest HD. These results demonstrate that standardized motor assessments and objective memory and concentration tasks are sensitive to change over a period of 7 years, specifically in carriers converting to manifest HD. Executive tasks also showed subtle cognitive abnormalities in premanifest HD, but a decline over time could not be demonstrated.

No evidence of impaired gastric emptying in early Huntington‘s Disease

·

Background: Several factors, such as dysphagia, an increased motor activity, increased metabolic rate and a hypermetabolic state have been discussed as contributing to weight loss even at the early stages of Huntington’s Disease (HD). Aim of this pilot study was to investigate gastric emptying as a possible reason for weight loss in HD.

Methods: 11 HD participants at early stages of the disease and matched controls were investigated by using the well-established and non-invasive 13C-octanoate breath test. The “Gastroparesis Cardinal Symptom Index” and the “Short-Form Leeds Dyspepsia Questionnaire” were used for clinical evaluation of gastroparesis or dyspepsia.

Results: When compared to standard values ​​given in literature and controls all HD patients had normal breath test results. There was no evidence of gastroparesis or dyspepsia. There was a correlation of breath test results with the cognitive and functional performance of HD participants.

Conclusion: According to our data, there is no evidence of impaired gastric emptying in early HD. We can not exclude that gastric emptying contributes to weight loss at more advanced stages of the disease.

Corresponding author: PD Dr. med. Carsten Saft, Department of Neurology, Huntington-Center NRW, St. Josef Hospital, Gudrunstrasse 56, 44791 Bochum, Germany, E-mail: carsten.saft@ruhr-uni-bochum.de

§ Carsten Saft and Jürgen Andrich contributed equally to this work

Use of Tetrabenazine in Huntington Disease Patients on Antidepressants or with Advanced Disease: Results from the TETRA-HD Study

·

The safety and effectiveness of tetrabenazine in different sub-populations of Huntington disease (HD) is not known. In this study, we evaluated the safety of tetrabenazine in individuals on an antidepressant and its effectiveness in advanced HD. Tetrabenazine was not associated with an increased incidence of depressed mood among those taking antidepressants and was effective at reducing chorea in those with advanced HD.

Background: The safety and effectiveness of tetrabenazine in different sub-populations of Huntington disease (HD) is not known. We evaluated its safety in individuals on an antidepressant and its effectiveness in advanced HD.

Methods: The TETRA-HD study was a randomized, placebo-controlled, double-blind study of 84 individuals with HD who were randomized 2:1 to receive tetrabenazine (54 participants) or placebo (30 participants). We used data from the 12-week randomized controlled study of tetrabenazine to evaluate the incidence of depressed mood either as an adverse event or as a two points or greater worsening on the “depressed mood” item of the Unified Huntington Disease Rating Scale. We also evaluated the effectiveness of tetrabenazine in reducing chorea in advanced HD. Advanced HD was defined as a baseline maximum total chorea score of 19 or greater or as a total functional capacity score of seven or less. Only individuals who were randomized to tetrabenazine (n=54) were included in these analyses.

Results: At baseline, 27 (56%) of the 48 participants randomized to tetrabenazine who completed the trial were taking an antidepressant. The incidence of depressed mood did not differ between those taking (15%) and not taking (5%) an antidepressant (p=0.37), and the proportion of individuals experiencing a substantial worsening in their mood scores also did not differ (7% v. 10%; p=1.00). Based on chorea, 14 of the 54 (26%) tetrabenazine participants enrolled had advanced HD, and based on function, 22 (41%) had advanced HD. Chorea declined by 8.1 units among those with baseline scores 19 or greater compared to 4.3 units for those with scores under 19 (p<0.01), but the relative rates of decline did not differ (p=0.62). The decline in chorea did not differ by HD severity as measured by function (p=0.20).

Conclusion: In this post hoc analysis, tetrabenazine was not associated with an increased incidence of depressed mood among those taking antidepressants and was effective at reducing chorea in those with advanced HD. Larger, prospective studies are needed to confirm these findings.

HD mouse models reveal clear deficits in learning to perform a simple instrumental response

·

Mouse models of Huntington’s disease (HD) were trained to acquire one of two simple instrumental responses (a lever press or a nosepoke) to obtain food reinforcement. Animals from several HD strains revealed apparently progressive deficits in this task, being significantly less able than littermate controls to perform the required responses, at ages where motor function is only mildly affected. These data could provide a simple way to measure learning deficits in these mouse models, likely related to the characteristic pattern of neural damage observed in HD mouse models.

Effect of enhanced voluntary physical exercise on brain levels of monoamines in Huntington disease mice

·

Using the R6/1 mouse model of Huntington disease (HD), we have recently shown that voluntary physical activity was able to correct the depressive-like behaviours exhibited by the HD animals at a pre-motor symptomatic stage of the disease. Using the high performance liquid chromatography system, we have now evaluated the effect of exercise on monoamine metabolism in HD mice. We found that serotonin and its metabolite as well as dopamine and noradrenaline were reduced across several brain regions in female R6/1 animals. Our data also suggest that some of these neurochemical deficits were modulated by physical activity, in a genotype-region dependent manner. These newly identified changes could account for some of the behavioural effects of exercise previously reported in HD mice.

Longitudinal Change in Gait and Motor Function in Pre-manifest Huntington’s Disease

·

The purpose of this study was to examine longitudinal change in gait and motor function in pre-manifest Huntington’s disease (HD).

We examined ten pre-manifest subjects at baseline, one and five years. Quantitative gait data were collected with an electronic mat (GAITRite®). We analyzed measures related to speed (velocity, step length, cadence), asymmetry (step length difference), dynamic balance (percent time in double support, support base) and variability in stride length and swing time. Motor function was assessed with the motor component of the Unified Huntington’s Disease Rating Scale.

Gait velocity decreased (p=0.001), whereas step length difference (p=0.006), stride length variability (p=0.0001) and swing time variability increased (p=0.0001) from baseline to year five. Step length difference (p<0.05) and swing time variability (p<0.05) increased marginally in one year from baseline. UHDRS Total motor score increased over five years (p=0.003), though the increase in one year was not significant (p=0.053). Of the individual motor domain scores (eye, hand movements, gait and balance, chorea) only dystonia worsened over five years (p=0.02). Total motor score (r2= 0.49, p<0.001) and swing time variability (r2= 0.22, p<0.009) were correlated with estimated years to diagnosis.

Our results present the longest longitudinal follow up of gait in pre-manifest HD thus far. Despite the small sample size, quantitative gait analysis was able to detect changes in gait speed, symmetry and variability. Swing time variability was particularly important because it increased in one year from baseline and was correlated with estimated time to diagnosis. Our results highlight the importance of predictive outcomes such as gait variability using quantitative analysis.