HD Highlights

Highlights from the Journal of HD

By: Jennifer A. Simpson, LMSW and George J. Yohrling, PhD

Original Article: Simpson JA, Lovecky D, Kogan J, et al. Survey of the Huntington’s Disease Patient and Caregiver Community Reveals Most Impactful Symptoms and Treatment Needs. J Huntingtons Dis. 2016 Dec 15;5(4):395-403.

In 2012, the US Food and Drug Administration (FDA) launched a Patient-Focused Drug Development Initiative as required under the fifth authorization of the Prescription Drug User Fee Act. The goal of this initiative was to systematically gather patients’ perspectives on their conditions and the available therapies to treat them. As part of this initiative, the FDA scheduled approximately 20 public meetings, each focused on a specific disease area. HD was chosen as one of the diseases for public input. After announcing that the meeting would be held in 2015, the Huntington’s Disease Society of America (HDSA) distributed two surveys to solicit specific comments from HD patients and their caregivers regarding symptomatology, quality of life, and therapeutic needs. The HD community responded enthusiastically, with 2,591 people providing answers for questions in the symptom-focused survey, and 1,040 people providing answers to questions in the treatment-focused survey. The objectives of these surveys were to identify the specific symptoms that most impact the daily lives of individuals with HD or juvenile HD (JHD) and their caregivers, and to identify the types of treatments desired by HD-affected families.

Although HD has long been classified as a motor disease, analysis of the data revealed that individuals with HD/JHD perceived symptoms related to dysexecutive syndrome to be most impactful (22% of responses). Caregivers responded even more strongly regarding the impact of dysexecutive syndrome, with 54% of caregivers identifying a combination of behavioral and cognitive symptoms such as anger/rage, anxiety, cognitive decline, and depression/apathy as having the greatest impact on daily life.

Figure: HD patient and caregiver perspectives on frequency of HD symptom experience. HD patient (N=248), HD caregiver (N=731). Figure from Simpson JA, Lovecky D, Kogan J, Vet al. Survey of the Huntington’s Disease Patient and Caregiver Community Reveals Most Impactful Symptoms and Treatment Needs. J Huntingtons Dis. 2016 Dec 15;5(4):395-403.

Although caregivers and HD patients aligned on some responses, there were also major divergences between the two groups. Perceptions of symptom frequency differ vastly between HD patients and their caregivers (See Figure). Nearly 14% of the 248 individuals with HD/JHD reported that they never experience HD symptoms, while just 1% of caregivers reported that they never observe symptoms in their loved ones. Greater than 80% of caregivers said they constantly saw symptoms in their loved ones, while less than 35% of individuals with HD/JHD reported constant HD symptoms.

Caregivers also responded more frequently that their loved ones with HD had completely lost their ability to perform a task, with 60% responding that their loved ones had completely lost the ability to work, drive, manage finances, take care of family, multi-task, or engage in a sex life. More than 85% of caregivers responded that their loved ones had completely lost their employability, while only 47% of individuals with HD/JHD responded similarly. Less than 50% of HD/JHD respondents said that they had completely lost the ability to do any of the 19 daily tasks listed in the survey. Caregivers also reported cognitive symptoms at greater rates compared to individuals with HD/JHD. However, data for both caregivers and individuals with HD/JHD suggest that an inability to maintain employment was among the most frequently experienced effects of HD on their lives.

When discussing treatments, data showed that very few individuals were taking any prescribed or not prescribed medications for some of the most impactful symptoms of the disease, such as dysexecutive syndrome. More than 80% of respondents noted that they or their loved ones with HD were not taking any kind of medication for deterioration in memory and thinking. Similarly, more than 40% of respondents noted that they or their loved ones were not using any form of medication to manage perseveration or anxiety, which can also be associated with dysexecutive syndrome. The only FDA-approved drug to treat a symptom of HD is tetrabenazine (Xenazine), which is used to treat chorea associated with HD. Even with an FDA-approved treatment, nearly 40% of respondents reported being unaware of, or not using, any medication to treat chorea. Just 23% of respondents reported taking tetrabenazine to treat chorea.

The efforts of the FDA in the implementation of the patient-focused drug development meetings are already creating a positive impact on the lives of patients across the spectrum of diseases. Patient and caregiver perspectives on HD symptomatology and treatment efficacy will be critical components in shaping future HD clinical development efforts. With this information, we can tailor clinical development efforts to treat the symptoms that those impacted by HD believe are the most disruptive.

Highlights from the Journal of HD

Assistive technology for cognition in HD

By: Marleen R. van Walsem, MSc, Emilie I. Howe, MSc and Jan C. Frich, MD, PhD

Original Article: van Walsem MR, Howe EI, Frich JC, Andelic N. Assistive Technology for Cognition and Health-related Quality of Life in Huntington’s Disease. J Huntingtons Dis. 2016 Oct 1;5(3):261-270.

Assistive technology for cognition (ATC) can be defined as any external device aimed at improving or maintaining functional abilities of individuals with cognitive impairment.1 ATC can specifically address disabilities in memory, executive functions (planning, organization and attention), and reduced psychomotor speed. ATC comprises devices that are easily accessible and readily employed by anyone (i.e. smartphones, post-it notes), and also complex high-tech devices or programs specifically developed for supporting cognitive abilities. ATCs are used as a supportive service, and have shown themselves to be a promising strategy in conditions characterized by cognitive disabilities, for example traumatic brain injury and Alzheimer’s disease.2

Progressive development of cognitive disability is a hallmark of HD. Given the nature of cognitive impairment in HD, including reduced planning and organization skills, attention deficits and reduced psychomotor speed, there may be a benefit of ATCs for patients with HD, including devices that support structuring everyday life and memory. However, to date no research has investigated the use of ATC in HD patients.

The aim of our study was to describe aspects of ATC, including ATC use, information, needs assessment, and training, in HD patients, and to explore the association between using ATC and health-related quality of life (HRQoL). We used a cross-sectional population-based study design that included 84 HD patients who lived in south-eastern Norway, who had a clinical diagnosis of HD across the five disease stages. In addition to information regarding aspects of ATC, we collected socio-demographic and clinical data including disease-specific information. A general evaluation of cognitive impairment was also performed. We used the Unified Huntington’s Disease Rating Scale (UHDRS) Total Functional Capacity (TFC) scale as a standardized measure of functional ability. Overall HRQoL was assessed using the EQ-5D Visual Analogue Scale. In order to describe the aspects regarding ATC use and provision, we used descriptive statistical analyses, and we used multivariate regression analyses to explore the association between ATC use and HRQoL.

Results of the descriptive analyses on ATC are presented in Table 1. We found that approximately one-third (36.9%) of the patients with HD used ATC. We also found that patients who used an ATC device were predominantly in stages I−III, with mild to moderate cognitive impairment. Regarding other aspects of ATC, less than half (44%) of patients had received information about ATC, less than one-third (32.1%) had undergone a needs assessment, and only one-fifth had received ATC training. Most of these patients were in stage III. Furthermore, TFC was identified to be the only variable that bore significant impact on HRQoL (β-value = -0.564; β 95% CI 1.47− 5.34; r2 = 0.142; p = 0.001) in our multivariate regression model, which explained 30% of the variance.

Our findings indicate relatively infrequent ATC use, information provision, needs assessment and training, especially considering that the progressive development of cognitive disabilities for which specialized ATC devices exist is an inevitable symptom of HD. The lack of association between ATC use and HRQoL may reflect a lack of awareness and knowledge about ATC availability and provision among healthcare professionals. Further research into the potential benefits of ATCs in supporting cognitive disabilities and thereby positively affecting functional ability and HRQoL is warranted. Future studies should employ disease-specific measures of HRQoL that may be more sensitive to disease-specific aspects of HRQoL. ATC may prove to be a beneficial addition to the existing healthcare services for patients with HD.

  Complete sample (N = 84) Stage I

(n = 12)

Stage II

(n = 22)

Stage III

(n = 19)

Stage IV

(n = 14)

Stage V

(n = 17)

 
Variables   n (%) n (%) n (%) n (%) n (%) n (%) P-value (2-sided)
ATC formal/ informal Formal

Informal

None

12 (14.3)

19 (22.6)

53 (63.1)

0 (0)

9 (75)

3 (25)

4 (18.2)

10 (45.5)

8 (36.4)

7 (36.8)

0 (0)

12 (63.2)

1 (7.1)

0 (0)

13 (92.9)

0 (0)

0 (0)

17 (100)

P < 0.0001
ATC use Yes

No

Used previously

30 (35.7)

48 (57.1)

6 (7.1)

9 (25)

3 (75)

0 (0)

14 (63.6)

8 (36.4)

0 (0)

7 (36.8)

12 (63.2)

0 (0)

0 (0)

11 (78.6)

3 (21.4)

0 (0)

14 (82.3)

3 (17.7)

P < 0.0001
ATC information* Yes

No

37 (44)

46 (54.8)

4 (33.3)

8 (66.7)

10 (45.4)

12 (54.5)

14 (73.7)

5 (26.3)

4 (28.6))

10 (71.4)

5 (29.4)

11 (64.7)

P = 0.045
ATC evaluation** Yes

No

27 (32.1)

56 (66.7)

0 (0)

12 (100)

7 (31.8)

15 (68.2)

12 63.2)

7 (36.8)

4 (28.6)

9 (64.3)

4 (23.5)

13 (76.4)

P = 0.006
ATC training Yes

No

17 (20.2)

67 (79.8)

0 (0)

12 (100)

5 (22.7)

17 (77.3)

7 (36.8)

12 (63.2)

2 (14.3)

12 (85.7)

3 (17.6)

14 (82.4)

P = 0.150

ATC: Assistive Technologies for Cognition/cognitive disabilities. Chi-squares were used to calculate overall group differences; * 1 missing in Stage V; **1 missing in Stage IV.

Table from van Walsem MR, Howe EI, Frich JC, Andelic N. Assistive Technology for Cognition and Health-related Quality of Life in Huntington’s Disease. J Huntingtons Dis. 2016 Oct 1;5(3):261-270. Published under a Creative Commons Attribution Non-Commercial (CC BY-NC 4.0) License.


1Scherer MJ, Hart T, Kirsch N, Schulthesis M. Assistive Technologies for Cognitive Disabilities. Crit Rev Phys Rehabil Med. 2005;17(3):195-215.

2Gillespie A, Best C, O’Neill B. Cognitive function and assistive technology for cognition: a systematic review. J Int Neuropsychol Soc. 2012;18(1):1-19.

Highlights from the Journal of Huntington’s Disease

jhdInduced pluripotent stem cells in HD research
By: Kimberly Kegel-Gleason, PhD
Original article: Tousley A, Kegel-Gleason KB. Induced Pluripotent Stem Cells in Huntington’s Disease Research: Progress and Opportunity. J Huntingtons Dis. 2016 Jun 28;5(2):99-131. doi: 10.3233/JHD-160199.

Although many cell types are affected in HD, the impact of the disease on CNS neurons is remarkable. Neurons of the cortex and striatum degenerate and eventually die, causing the majority of HD symptoms. Until recently, it has been difficult to study human CNS neurons because of ethical considerations – it is not ethical to perform a biopsy on human patients to obtain brain cells for research. Embryonic stem cells (ESCs) are pluripotent, meaning that they have the ability to become neurons; however, the use of ESCs to obtain neurons is also fraught with ethical challenges, including the destruction of an embryo. Enter induced pluripotent stem cells (iPSCs). Skin or blood cells from controls and HD patients can be made into iPSCs by the introduction of just a few factors. iPSCs are very similar to ESCs and can be differentiated to resemble CNS neurons or other CNS cell types in order to study disease mechanisms, and to screen compounds that might be developed into new therapies.

A major advantage to iPSCs is that normal and mutant proteins are expressed at endogenous levels just as they are in the human patient; furthermore, the effects of varied genetic backgrounds on the behavior of the mutant protein can be assessed. Studies with iPSCs from patients with neurodegenerative diseases other than HD have provided new insights previously not found using animal models. For instance, using three-dimensional cultures of CNS neurons from iPSCs from human Alzheimer disease (AD) patients, intracellular tangles, which are major feature of AD, were observed.1 Intracellular tangles had never been recapitulated in mouse models of AD, and the results pointed to a particular protein only found in humans as a major target of pathology.

As with research in other neurodegenerative diseases, iPSCs from controls and HD patients have been in development to uncover previously unknown human-specific pathological mechanisms, to validate phenotypes identified in animal models, and for compound screening. In our review,2 we characterize the state of the HD iPSC field. We describe the current inventory of cells available to HD researchers, many of which cells are freely available. We also highlight changes that have been identified in HD cells compared to controls, in pathways, individual gene changes, functional phenotypes, and the role of stress and aging. Furthermore, we compare results obtained with various neuronal differentiation protocols.

Table: Summary of major progress and opportunities for expanded research using HD IPSCs

 

Progress Opportunities
Numerous HD iPSCs created Increase the number of HD and control lines used within each study
A few genetically corrected, isogenic iPSCs created Increase number of genetically corrected, isogenic iPSCs created and available (CRISPR/Cas9)
Several studies on neuronal cultures using diverse differentiation protocols Use of reproducible protocols for comparison of results across laboratories
Stress-induced phenotypes identified Expand the phenotypes identified in the absence of stress
SiRNAs and miRNAs targeting alleles with SNPs, Zinc Finger Proteins Develop additional allele-specific reagents and tools to target mHTT
Two studies with iPSC astrocytes Studies with iPSC glia (astrocytes, oligodendrocytes, microglia)
Co-culturing, 3-D cultures, and organoids
Artificial aging

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We also note the pervasive use of stress to unveil functional phenotypes in HD cells. Because stress exacerbates HD symptoms in patients, this may reflect important disease mechanisms. One argument in favor of this approach is that iPSC induced neurons are very immature compared to those in the brain of an adult with HD, so stress might mimic aging to enhance a phenotype. However, more time spent investigating what may be more subtle phenotypes in the absence of stress may lead to a better understanding of underlying pathology that leaves a cell vulnerable to stress and eventually triggers disease.

Although much progress has been made, culturing and differentiating iPSCs is still extremely expensive, time consuming and difficult, thus limiting the number of investigators who can take advantage of this valuable resource. We hope this review will enable those new to the iPSC field to consider and control the inherent problems with iPSC lines, and so enable reproducible research across the field.

One major limitation we found for interpreting data across the HD field is the relative paucity of cell lines used – many times, reports include data from just one cell line. In order to increase the reproducibility of research across the field, we suggest that results from at least three HD cell lines from three individual patients and three cell lines from three individual controls be used for robust phenotypes (six lines total). For more subtle phenotypes it may be necessary to use many more cell lines. For comparison, 10–12 control cell lines are currently being used by investigators in other fields.3 Alternatively, a combination of control cell lines (cell lines from unaffected individuals), and genetically corrected cell lines (using homologous recombination or CRISPR), and use of effective mHTT-lowering reagents such as siRNAs, miRNAs or zinc finger proteins in HD lines could be used. We note that data from genetically corrected cell lines should be interpreted with caution because the cell lines undergo several rounds of selective pressure during their generation that could alter a particular phenotype.

Our review of the field identifies areas of opportunity for which additional research would be of great value. For instance, very few studies used other brain cell types that can be differentiated from iPSCs such as astrocytes and oligodendrocytes, which may also impact HD pathology. The field should welcome more studies using iPSC-derived glial cells.

References
1. Choi SH, Kim YH, Hebisch M, et al. A three-dimensional human neural cell culture model of Alzheimer’s disease. Nature. 2014;515(7526):274-278.
2. Tousley A, Kegel-Gleason KB. Induced Pluripotent Stem Cells in Huntington’s Disease Research: Progress and Opportunity. J Huntington’s dis. 2016;5(2):99-131.
3. Boulting GL, Kiskinis E, Croft GF, et al. A functionally characterized test set of human induced pluripotent stem cells. Nat Biotechnol. 2011;29(3):279-286.

HD Highlights: 19th International Congress of Parkinson’s Disease and Movement Disorders

This year’s MDS International Congress took place in San Diego, California
By: Meredith A. Achey, BM
HD HighlightsThe 2015 International Congress of Parkinson’s Disease and Movement Disorders took place on June 14−18 in San Diego, California. Despite some less-than-sunny weather, the congress offered some bright glimpses into the next decade of HD research and therapeutic development.

This year marked the 25th anniversary of the MDS International Congress. In a therapeutic plenary session on the first day of the meeting, Dr. Ira Shoulson (see HD Insights, Vol. 9) discussed the great increase in attention paid to HD, demonstrated by the number of sessions and posters presented at this meeting compared with the first Congress 25 years ago. Highlights of these sessions included a video course titled “What if it’s not Huntington’s disease?”, a session on “What’s new in Huntington’s disease?”, and a guided poster tour focused on “HD and other choreiform disorders.”

In their video session “What if it’s not Huntington’s disease?” Drs. Anne-Catherine Bachoud-Lévi and Joaquim Ferreira guided attendees through an impressive series of video clips demonstrating common and uncommon presentations of HD, as well as other movement disorders often confused with HD. The presenters emphasized the importance of distinguishing generalized chorea from other movements, along with the necessity of recognizing less common presentations of HD. As a reminder that clinicians may see movement disorders where there are none, the presenters also threw in a video of a normal patient, asking the audience first to identify her diagnosis and the “abnormalities” observable in her facial movements. This fast-paced but enjoyable session reinforced the necessity of not jumping too quickly to a diagnosis for the practicing movement disorders clinician.

The “What’s new in Huntington’s disease?” session covered the most recent developments in HD biomarkers, basic science, and clinical research. Dr. Ralf Reilmann discussed the current array of biomarkers in pre-manifest and manifest HD and whether these are ready for use in clinical trials. Dr. Michael Levine followed with a discussion of the latest findings in laboratory and animal-model research and their influence on the development of novel therapies. The session concluded with an update from Dr. Cristina Sampaio of CHDI on the latest in disease-modifying and symptomatic treatments currently in development.

The HD-themed Guided Poster Tour highlighted some particularly compelling posters on HD clinical and basic science, as well as the continuing exploration of biomarkers, imaging changes, and their clinical correlates. Poster presenters ranged from well-known clinicians and investigators to PhD candidates, and hailed from Australia, Europe, and North America. Dr. Sam Frank presented the results of the First-HD study, emphasizing in particular the participant reports of improved global impression throughout the trial (see HD Insights, Vol. 10). Also presenting on clinical trials, Dr. Bernhard Landwehrmeyer discussed a recent analysis of data from MermaiHD and HART suggesting that there was no significant increase in adverse events in participants taking anti-depressants or anti-psychotics and pridopidine. Two posters described novel objective measures of HD symptoms, including a shoe-worn inertial sensor tested at Oregon Health and Sciences University, and the use of a Wii balance board to assess HD progression evaluated at UC San Diego. In addition, Dr. Ashwini Rao described his lab’s work evaluating gait modulation as a marker of HD progression. Two Australian researchers each described novel physiological measures of HD − Ms. Lauren Turner presented her discovery of abnormal electrophysiological responses in pre-manifest HD patients, and suggested that these may represent compensation, while Dr. Fiona Wilkes presented a compelling new analysis of IMAGE-HD imaging data showing callosal thinning with HD disease progression.

The 19th MDS Congress provided many opportunities for HD experts and those new to the field to learn about the latest in clinical and scientific understanding of the disease and its treatment.
Abstracts from the meeting can be accessed at www.mdsabstracts.com.