Journal of Huntington's Disease

Neuropsychiatric symptoms are highly prevalent in Huntington’s disease (HD). However, little is known of the prevalence and course of obsessive-compulsive behaviors (OCBs) and perseverative behaviors (PBs) during the progression of the disease.

This review provides a summary of the literature on OCBs and PBs in HD gene expansion carriers (HDGECs).

Pubmed database was searched for articles on OCBs and PBs in HD up to 2017. We used search terms, all synonyms for HD, and various terms for OCBs and PBs.

We found 5 case series and 11 original articles that describe a prevalence range of 5 to 52% for OCBs and up to 75% for PBs depending on disease stage and measurement scale used. Premanifest HDGECs report more OCBs compared to controls, and manifest HDGECs report a higher rate of OCBs compared to premanifest HDGECs. OCBs and PBs are associated with a longer disease duration and disease severity in manifest HDGECs, but decrease in the most advanced stages. When HDGECs come closer to estimated motor onset, the companion ratings on OCBs appear to be higher than the self-ratings of HDGECs.

Both OCBs and PBs are characteristic neuropsychiatric features of HD. Perseveration is probably best distinguished from OCBs as it occurs without the individual’s full awareness or insight into their presence (and the behavior may not be distressing). Although these behaviors are seldom distinguished, we conclude that differentiating OCBs from PBs in HD is beneficial for the management and treatment of these symptoms in HDGECs.

To increase the reliability of translating preclinical findings to humans, large animal models, such as the transgenic (tg) Libechov minipig, were established. As minipigs possess high genetic homology with humans and have similarities in anatomy, physiology and metabolism to humans, they are considered for studying neurodegenerative diseases longitudinally. Recently, sleep abnormalities and changes in circadian rhythm in Huntington’s disease (HD) patients were acknowledged to present one of the early symptoms in HD.

The aim of the present study was to explore the activity behaviour of Libechov minipigs and to investigate whether tgHD and wildtype (wt) minipigs exhibit differences in activity behaviour. Furthermore, it was investigated whether activity assessments may serve as reliable endpoints for phenotyping minipigs transgenic for the Huntington gene.

Activity behaviour of minipigs was studied by video recording the stables twice a week over a total study period of five weeks for a cohort of five tgHD minipigs and five wt minipigs. Statistical analysis was performed using the linear mixed model. Once a week, the distances covered by two minipigs in focus (tgHD, wt) were measured using the VideoMotionTracker^® software.

Libechov minipigs showed a biphasic pattern of activity, spending most of the time inactive or grubbing in litter. Differences in activity behaviour (rooting, resting and standing) were detected between wt and tgHD minipigs. The influence of the genotype on behavioural patterns was observed during circadian monitoring. TgHD minipigs covered longer distances on average and during every 24 h observation period than wt minipigs.

Activity behaviour may be a viable marker for phenotyping minipigs transgenic for the Huntington gene. Video recordings of behavioural patterns provide a non-invasive opportunity to capture potential disease signs. Phenotypic progression including the age of disease manifestation may be explored by documentation of circadian characteristics.

Although the highest expression of mutant huntingtin (mtHtt) was observed in the brain, its negative effects were also apparent in other tissues. Specifically, mtHtt impairs metabolic homeostasis and causes transcriptional dysregulation in adipose tissue. Adipogenic differentiation can be induced by the activation of two transcription factors: CCAAT/enhancer-binding protein alpha (CEBPα) and peroxisome proliferator-activated receptor gamma (PPARγ). These same transcription factors were found to be compromised in some tissues of Huntington’s disease (HD) mouse models and in lymphocytes of HD patients.

This study investigated the adipogenic potential of mesenchymal stem cells (MSCs) derived from transgenic Huntington’s disease (TgHD) minipigs expressing human mtHtt (1–548aa) containing 124 glutamines. Two differentiation conditions were used, employing PPARγ agonist rosiglitazone or indomethacin.

Bone marrow MSCs were isolated from TgHD and WT minipig siblings and compared by their cluster of differentiation using flow cytometry. Their adipogenic potential in vitro was analyzed using quantitative immunofluorescence and western blot analysis of transcription factors and adipogenic markers.

Flow cytometry analysis did not reveal any significant difference between WT and TgHD MSCs. Nevertheless, following differentiation into adipocytes, the expression of CEBPα nuclear, PPARγ and adipogenic marker FABP4/AP2 were significantly lower in TgHD cells compared to WT cells. In addition, we proved both rosiglitazone and indomethacin to be efficient for adipogenic differentiation of porcine MSCs, with rosiglitazone showing a better adipogenic profile.

We demonstrated a negative influence of mtHtt on adipogenic differentiation of porcine MSCs in vitro associated with compromised expression of adipogenic transcription factors.

Previous studies suggest that Huntingtin, the protein mutated in Huntington’s disease (HD), is required for actin based changes in cell morphology, and undergoes stimulus induced targeting to plasma membranes where it interacts with phospholipids involved in cell signaling. The small GTPase Rac1 is a downstream target of growth factor stimulation and PI 3-kinase activity and is critical for actin dependent membrane remodeling.

To determine if Rac1 activity is impaired in HD or regulated by normal Huntingtin.

Analyses were performed in differentiated control and HD human stem cells and HD Q140/Q140 knock-in mice. Biochemical methods included SDS-PAGE, western blot, immunoprecipitation, affinity chromatography, and ELISA based Rac activity assays.

Basal Rac1 activity increased following depletion of Huntingtin with Huntingtin specific siRNA in human primary fibroblasts and in human control neuron cultures. Human cells (fibroblasts, neural stem cells, and neurons) with the HD mutation failed to increase Rac1 activity in response to growth factors. Rac1 activity levels were elevated in striatum of 1.5-month-old HD Q140/Q140 mice and in primary embryonic cortical neurons from HD mice. Affinity chromatography analysis of striatal lysates showed that Huntingtin is in a complex with Rac1, p85α subunit of PI 3-kinase, and the actin bundling protein α-actinin and interacts preferentially with the GTP bound form of Rac1. The HD mutation reduced Huntingtin interaction with p85α.

These findings suggest that Huntingtin regulates Rac1 activity as part of a coordinated response to growth factor signaling and this function is impaired early in HD.

Advances in molecular therapeutic approaches in the last decade are translating into the design of non-traditional clinical trials. In order to improve their feasibility, it is important to understand the attitudes of potential participants towards these trials, their motivations to get involved and acceptance of risks.

We aimed to better understand the willingness of potential participants to participate in different molecular therapy trials for Huntington’s disease (HD) based on their clinical and genetic status, trial design and goals of the treatment.

An anonymous survey was distributed through the Huntington’s Disease Society of America (HDSA) on-line portal/website. Various hypothetical scenarios were presented followed by a survey consistent of Likert scale responses ascertaining willingness to participate, collecting demographic, clinical and genetic information.

There were a total of 87 responses, including patients diagnosed with HD, pre-manifesting mutation carriers and asymptomatic participants at risk. The majority of participants indicated they were very likely or likely to participate in clinical trials independent of study design or goals of the therapy, with a more favorable view in premanifesting mutation carriers. However, more invasive procedures and trials including placebo were less favorably viewed across all diagnostic groups.

In summary, most individuals in the HD community would consider participation in novel molecular therapy trials, but study design and goals could impact patient recruitment. This data can be used to inform the recruitment and consent process into clinical trials and to address common concerns by potential participants.

DriveSafe DriveAware (DSDA) has been validated as an off-road screening tool for predicting on-road driving performance in clinical populations, but its utility in people with Huntington’s disease (HD) is unknown.

Our aim was to evaluate the utility of DSDA in people with HD by demonstrating sensitivity of DSDA scores to HD progression and exploring associations between DSDA performance and cognitive functions that are essential to driving and impaired in people with HD.

We administered the iPad application version of DSDA to 26 pre-symptomatic and symptomatic participants with HD. Disease progression was assessed via measures of motor impairment, disease burden and functional capacity. Standardised neuropsychological tests were used to assess cognitive function across several domains including attention, processing speed, planning, and visuoperception.

Results underscore the sensitivity of DSDA to HD progression and cognitive impairment; that is, poorer DSDA performance was associated with greater HD severity and poorer cognitive ability across the domains of attention, processing speed, and planning. Nevertheless, we identified a proportion of participants with HD who were predicted to pass on-road testing based on DSDA, but scored in the impaired range on multiple cognitive tests. These participants tended to score closer to the cut-off score used by DSDA to categorise pass/fail outcomes.

Our findings demonstrate potential for use of DSDA in the HD population, however, significant variability in cognitive performance among those predicted to ‘pass’ on-road driving assessment suggests the screening tool requires further development for use with HD drivers.

Physical exercise improves neurological conditions, but adherence is hard to establish. Dance might be a promising alternative; however, since patients with Huntington’s disease (HD) suffer from rhythmic movement execution deficits, any metric dance practice must be avoided.

Here we asked, if contemporary dance, a lyrical dance form, practiced for two hours per week over five months, might improve motor function, neuropsychiatric variables, cognition and brain volume of HD patients.

Nineteen patients aged between 43 and 78 years with mild to moderate HD (TFC range 7–13, UHDRS motor score range 3–58) participated in this randomized, controlled pilot study (NCT 01842919). The primary outcome measure was total motor score. Secondary outcome measures were differences in brain structure, cognitive function, neuropsychiatric variables, apathy and quality of life. A semi-structured interview assessed participants’ experiences.

Adherence to dance classes was very good. All participants completed 5 months of dance practice. Motor impairment (median [IQR] decreased from 28[6–51] to 27[7–33] for the dance group compared to an increase of 19[13–35] - 25[14–42] for usual care, Z = –2.44, p = 0.015). No other behavioral measures showed any changes.

Brain volume increased in the medial superior parietal and paracentral lobule, in line with compensatory structural brain changes in areas supporting spatial and somatosensory processing. These changes were also reflected in patients’ reports that contemporary dance altered the way they “felt and lived in their bodies”.

Contemporary dance practice, through work on spatial and bodily representations, helps improve motor function in HD patients.