All posts by Lauren Hinkley

Cognitive Training in HD

Cognitive Training in HD

Huntington’s Disease (HD) is known to cause degenerative changes in three domains: physical, psychological, and cognitive. Although there are no medications currently approved for treating all three domains of HD effects, there are many medications and therapies that can be prescribed for both physical effects (such as chorea) and psychological changes (such as HD related depression). There are, however, fewer options for treating the cognitive changes that arise as a result of HD. One possible option, however, may be cognitive training, which will be explored in this article as it relates to Huntington’s Disease

What is Cognitive Training?

Cognitive training includes mental, intellectual interventions that are designed to target one or more cognitive domains, which have been used by neuropsychology to assess cognitive performance. As defined by the DSM-5, which is used to define and diagnose mental disorders, these domains include executive function, complex attention, social cognition, learning and memory, language, and perceptual-motor function, each with subdomains that allow physicians to more specifically analyze cognitive deficits. 1 Many people affected by HD experience some cognitive symptoms, which can include difficulties with complex problems, thinking through the steps of a problem, and multitasking. In later stages of HD, it may also include the inability to learn new motor tasks due to cognitive symptoms. 2 As cognitive symptoms may greatly affect someone with HD, making the effort to find a solution to these problems is all the more important. An appropriately targeted cognitive training method is one possibility worth exploring. Although not enough research has been done on cognitive training specifically in HD patients to determine whether cognitive training may be beneficial to this population, there have been many studies of cognitive training in other neurodegenerative diseases that suggest that such a result is possible. 

Cognitive Training in other Neurodegenerative Diseases

Over the last few decades, there have been many studies focusing on the effects of cognitive training in neurodegenerative diseases, including Alzheimer’s Disease (AD), non-Alzheimer’s Dementia, the pre-Alzheimer’s Disease state of Mild Cognitive Impairment, and Parkinson’s Disease. A meta-analysis published in 2014 by researchers at King’s College London looked at thirty-three studies of the effects of cognitive training on Alzheimer’s based dementia. 3 Most of the studies in this analysis showed a statistically significant improvement on the mini-mental state evaluation (MMSE) and Alzheimer’s disease Assessment Scale-Cognition (ADAS-Cog) for those who underwent cognitive training as compared to controls. Both the MMSE and ADAS-Cog are well established and widely used by the psychiatric community to measure cognition. Therefore, an improvement on the performance of these assessments after cognitive training suggests that cognitive training may be effective at improving cognition. However, authors of the meta-analysis point out that these results may not be clinically significant; that is, even though they seemed significant in the calculations, that difference may not translate to a noticeable change in the patients’ real life. 

Other studies have focused on the effects of cognitive training in cases of Mild Cognitive Impairment (MCI). Though there is no specific test to diagnose MCI, it has been used for research purposes as a pre-Alzheimer’s state, as many — though not all — cases of MCI later progress to AD. Researchers consider cognitive training as especially relevant to MCI, as these patients have not yet progressed to clinical AD or dementia, and are therefore in a state in which this training may be maximally effective. A different meta-analysis published in 2011 by Li et al. looked at the results of many studies on the effects of cognitive training in MCI. 4 They looked at seventeen studies which, overall, showed significant improvements in various domains of cognition in those who underwent cognitive training. The domains in which they saw improvement included language, episodic memory, semantic memory, executive functioning/working memory, attention, and more. While these results are encouraging, it is important to note that MCI is unique from other neurodegenerative states as it has not yet — and may never — progress to a clinically diagnosed neurodegenerative disease.

There have also been studies on the effects of cognitive training in Parkinson’s Disease (PD), which is important to consider, as PD is considered the most clinically similar to HD out of the neurodegenerative diseases described in this paper. A 2011 study on the effects of cognitive training in PD patients found that those who underwent cognitive training had significantly improved performance in the areas of attention, information processing speed, executive functioning, and more as opposed to those who did not receive cognitive training. 5 A different study from 2015 found that cognitive training in PD patients resulted in beneficial effects on the cognitive deficits in these patients as well as an increase in their brain-derived neurotrophic factor (BDNF) concentration. 6BDNF is an important protein responsible for maintaining adult nerve cells, and has been studied in relation to Huntington’s Disease (for more information on BDNF, visit this page). However, this study emphasizes that they do not know whether an increase in BDNF is beneficial to damaged nerve cells, like those in both PD and HD. 

While none of the neurodegenerative diseases mentioned have the exact same characteristics as HD and are therefore not completely applicable to HD cognitive training research, they do establish a solid foundation for research on cognitive training in HD. Additionally, these studies and more have done a lot to help researchers understand what cognitive training is, how to study it, and how to employ it in the context of a neurodegenerative disease. 

Cognitive Training in Mice Models of HD

More relevant to HD specifically, there have been a few studies over the past few years with the aim of evaluating the efficacy of cognitive training in mice models of HD. One study conducted by researchers at the Cardiff University School of Biosciences in 2016 used HdhQ111/+ knock-in mice  — in which researchers intentionally add a gene to the mouse genome — to simulate HD symptoms in mice models. 7 They randomized both wild-type control mice and the HdhQ111/+  to three different treatment groups to study the effects of cognitive training on the HD mice vs the controls in the different groups. The first group of control and HD mice received cognitive training that involved an attention based task, the second group received a non-attention based cognitive task as training, and the third group received no cognitive training. This study found that both the control and the HD mice in groups one and two (attention and non-attention based cognitive training) performed better on cognitive tasks than the group that received no training. Additionally, the HD mice that received cognitive training showed improved “HD related behavior.” Since the tasks selected were designed to be a representation of HD related cognitive deficits, these results suggest that cognitive training — either attention or non-attention based — has the potential to help those experiencing the cognitive deficits of HD. 

Another study conducted by Curtin et al. and also published in 2016 performed four experiments to test different aspects of cognitive ability in HD mice. 8 The mice were 28-29 weeks old when they were tested, and the studies compared the abilities of mice who received cognitive training when they were 6-9 weeks old to mice who did not receive cognitive training. Using zQ175 mice — another mouse model for HD — the four cognitive skills that they studied in the different experiments were learning and motivation, response inhibition, cognitive flexibility, and memory deficits. In all four experiments, the HD mice who received cognitive training displayed fewer impairments than those who had not. 

Results from both these studies are encouraging for the use of cognitive training to help manage symptoms for HD patients, though it is important to note that results displayed in animal models do not always translate to human patients. 

Cognitive Training in HD Patients

Though there aren’t many studies specifically looking at the effects of cognitive training in Huntington’s Disease patients, there are a few that shed light on this topic. One of these is a clinical trial named CogTrainHD which began in late 2016 and was conducted by researchers at Cardiff University. This study used computerized cognitive training software to determine whether cognitive training is a feasible way of treating HD symptoms. The results of this study have not been posted, but you can find more information here. 9

In addition to the CogTrainHD clinical trial, there are a few studies which look at specific outcomes beyond cognition as the result of cognitive training. For example, a study published in 2020 by Barlett et al. studied the effects of  multidisciplinary training which included cognitive training on the volume of the hypothalamus, levels of BDNF, circadian rhythm, and habitual sleep in people with Huntington’s Disease. 10 These factors are important to study, as changes to the hypothalamus — a region of the brain important in maintaining homeostasis, or internal equilibrium of body processes — have been noted in HD patients. This study found that the HD patients who underwent the multidisciplinary training experienced a smaller loss of brain matter in their hypothalamus than those who did not have the training. Those who had the training also maintained their levels of BDNF, while those who did not have the training experienced a decline in their BDNF following the study period. Although this study included exercise and social interaction in addition to cognitive training in the multidisciplinary training, it supports that a training regimen including cognitive training may encourage positive results for those with HD. 

A specific type of cognitive training that researchers are looking at for its potential to help those afflicted with HD is neurofeedback training. Neurofeedback training differs from traditional cognitive training because it is done while a patient is receiving a real-time functional MRI (fMRI) scan. The training program can use the participant’s response to modify the way the training is given. For example, if the person consistently enters the wrong or correct answer, the program may select easier or more difficult questions, respectively. A study published in 2020 conducted by Papoutsi et al. looked at the feasibility of using neurofeedback training for HD patients by conducting a controlled trial on thirty-two Huntington’s Disease patients. 11 These participants were split into four groups: two conducting neurofeedback training, each with a focus on a different region of the brain, and two control groups that received no neurofeedback intervention. The study found that while there were no significant differences between the results of the two intervention groups that focused on different regions of the brain, both intervention groups performed better on the neurofeedback tasks than the control groups by the end of the intervention. However, neither the intervention nor control groups displayed any improvement in cognitive functioning outside the neurofeedback tasks.

It is evident that more research is needed to determine whether cognitive training is an effective way to treat the cognitive symptoms displayed in Huntington’s Disease. While many of the results on both human and animal models are encouraging, there are many different types of cognitive training that make it difficult to determine what may be the best solution for the most people. Many factors play into whether or not a cognitive training regimen will be effective for an individual: the individual’s medical and mental history, the type of cognitive training, how often one participates in cognitive training (per day, week, etc.), and how long the training period lasts, which is especially important in a study, because if training is not done for long enough to see a result we may be discounting training that may be effective if done for a longer period of time. All of these factors are important to consider when conducting or learning about cognitive training research, and without consideration of all of them, it is difficult to determine what cognitive training therapies actually work. While there are many studies on cognitive training in other neurodegenerative diseases that may serve to guide similar research for the HD community, it is imperative that more research be done on cognitive training in Huntington’s Disease so that HD patients do not miss out on what could potentially be a beneficial form of therapy. 

  1. American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.). Arlington, VA: Author. []
  2. https://hdsa.org/what-is-hd/cognitive-symptoms/ []
  3. Huntley JD, Gould RL, Liu K, et al. Do cognitive interventions improve general cognition in dementia? A meta-analysis and meta- regression. BMJ Open 2015;5:e005247. doi:10.1136/bmjopen-2014- 005247 []
  4. Li, H., Li, J., Li, N., Li, B., Wang, P., & Zhou, T. (2011). Cognitive intervention for persons with mild cognitive impairment: A meta-analysis. Ageing research reviews, 10(2), 285-296. []
  5. París, A. P., Saleta, H. G., de la Cruz Crespo Maraver, M., Silvestre, E., Freixa, M. G., Torrellas, C. P., … & Bayés, À. R. (2011). Blind randomized controlled study of the efficacy of cognitive training in Parkinson’s disease. Movement Disorders, 26(7), 1251-1258. []
  6. Angelucci, F., Caltagirone, C., & Costa, A. (2015). Cognitive training in neurodegenerative diseases: a way to boost neuroprotective molecules?. Neural regeneration research, 10(11), 1754. []
  7. Yhnell, E., Lelos, M. J., Dunnett, S. B., & Brooks, S. P. (2016). Cognitive training modifies disease symptoms in a mouse model of Huntington’s disease. Experimental neurology, 282, 19-26. []
  8. Curtin, P. C., Farrar, A. M., Oakeshott, S., Sutphen, J., Berger, J., Mazzella, M., … & Brunner, D. (2016). Cognitive training at a young age attenuates deficits in the zQ175 mouse model of HD. Frontiers in behavioral neuroscience, 9, 361. []
  9. https://clinicaltrials.gov/ct2/show/NCT02990676 []
  10. Bartlett, D. M., Lazar, A. S., Kordsachia, C. C., Rankin, T. J., Lo, J., Govus, A. D., … & Cruickshank, T. M. (2020). Multidisciplinary rehabilitation reduces hypothalamic grey matter volume loss in individuals with preclinical Huntington’s disease: A nine-month pilot study. Journal of the neurological sciences, 408, 116522. []
  11. Papoutsi, M., Magerkurth, J., Josephs, O., Pépés, S. E., Ibitoye, T., Reilmann, R., … & Tabrizi, S. J. (2020). Activity or connectivity? A randomized controlled feasibility study evaluating neurofeedback training in Huntington’s disease. Brain Communications. []
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Stanford Huntington’s Disease Patient Care Symposium

By Maria Suarez-Nieto and Sepehr Asgari

On the 2nd of November, 2019, the Stanford University School of Medicine’s Huntington’s Disease Center of Excellence held their inaugural Stanford Huntington’s Disease Patient Care Symposium.  Hosted in Mountain View, California, the event saw the participation of HD patients, caretakers, healthcare professionals, students, and members of the broader HD community. The symposium highlighted the latest advances in HD research from multiple perspectives, providing those in attendance with valuable new information.  

The morning started with Daniel Jarosz, PhD and Assistant Professor of Chemical and Systems Biology and Developmental Biology at Stanford University, who dreams of the day when a treatment for HD exists.  His informational talk focused on highlighting breakthroughs in basic science research for HD and other neurodegenerative diseases. Dr. Jarosz opened by explaining the work of Judith Frydman, who found that a chaperone protein, a type of protein that assists other proteins in carrying out their function, called TriC binds to the ends of Huntingtin protein fibers.  This prevents the Huntingtin protein from aggregating, thereby suppressing the toxic effects of Huntingtin aggregation. Scientists further found that treating Hungtintin rich neurons with TriC helped normalize the structure of the protein. After explaining the methods used to discover that Huntingtin aggregates spreads between cells, Dr. Jarosz shifted his focus to explain how he used novel African turquoise killifish as a model for HD.  Using that model, he identified that aged individuals have a strong enrichment in prion-like character among proteins known to form aggregates, meaning that aggregated proteins can spread similar to how prions do. If these findings are further confirmed, Dr. Jarosz stressed how this could be a new aspect of neurodegenerative disease behavior that we could potentially target.

Afterwards, Sharon Sha, MD, MS, Clinical Associate Professor of Neurology and Neurological Sciences at Stanford University and Co-Director of the Huntington’s Disease Center of Excellence and Ataxia Clinic, gave her talk on “Cognitive challenges in HD and ways to work around them.” Sha opened with an overview of symptoms commonly found in HD patients, which allowed her to introduce the main topic of her talk, cognitive symptoms. She deemed the cognitive impacts of HD “underrecognized,” and continued with explaining how these symptoms manifest in individuals, primarily by affecting their executive function, which could impact individuals years before motor impairments. Her research found that premanifest HD patients (patients in which symptoms have yet to arise) were more aware of presenting executive function problems than early stage HD. Sha proceeded to shift her focus to describing strategies that help treat cognitive problems, along with those that do not; she recommended using memory aids, decreasing multitasking, and being receptive to help. She continued by explaining that Donepezil, a drug commonly used to treat dementia in Alzheimer’s disease, does not work effectively to treat cognitive problems, along with the potential for another drug called Rivastigmine, and closed with addressed the prevalent insurance issues associated with clinical trials. 

The third talk was given by John Barry, MD and professor of psychiatry and behavioral sciences at Stanford Medical Center, on the neuropsychiatric challenges that HD patients face. He opened with explaining how unawareness is hard-wired, not solely deniel. Barry described the disabling psychiatric symptoms often seen in HD patients, such as apathy, denial, depression, irritability, and anger among others; he emphasized that the disease, rather than the individual themselves,  is the cause for these symptoms,.

After a short break, the morning resumed with a moving patient testimonial from Sheila A. She spoke about her own experience being diagnosed, and touched upon the guilt she felt at knowing it is possible that she passed HD down to her children, who were already born when it was discovered that HD is in her family. She explained the lack of resources available to her and her family living in Scotland at the time, along with her experience of her father being misdiagnosed. Sheila continued with her experiences in enrolling and participating in clinical trials that drove her to the US; despite not knowing what treatment group she belongs to, she is hopeful for the future of HD research and treatment, ending on the note that she finally felt “dignified in a really undignified disease”.

Following Sheila’s testimony was Kristina Cotter, PhD, who presented her dissertation research on “Positive attitudes and therapeutic misconception around clinical trials in the Huntington’s disease community.” Using a PACT-22 scale, which is a commonly used metric for clinical trial attitudes, her team developed a survey with two measures to assess clinical trial attitudes and understanding in the HD community. After distributing the survey via emails, flyers, and social media through HD-related organizations and evaluating 73 responses, Cotter and her team found that respondents viewed clinical trials positively and generally viewed trials as safe. She also explained that individuals with prior HD-related research experience were less likely to have negative expectations about trials than those without research experience, and that level of invasiveness was negatively correlated with willingness of an individual to participate. Interestingly, Cotter mentioned how she did not expect to find that individuals with HD were more likely than the other groups to experience therapeutic misconception; she concluded with recommending to use her findings to strengthen informed consent during HD clinical trial recruitment.

The last talk of the morning was a concise yet information-packed update on ongoing HD clinical trials by Brent Bluett, DO, clinical assistant professor in Neurology and the Neurological Sciences and Marcus Parrish, PhD of the Department of Chemical and Systems Biology. He touched briefly on a variety of ongoing drug-related clinical trials, shared contact information for audience members interested in such trials, and described how AMT-130 gene therapy has been found to lower huntingtin protein and improve HD symptoms  in animal models. Bluett continued with emphasizing the ability to use of biomarkers as indicators of the severity and/or presence of HD, and concluded that biomarkers could be clinical trial endpoints for the HD community.

The afternoon began with an educational overview of nutrition, given by, Veronica Santini, MD, MA, and co-director of the Huntington’s Disease and Ataxia Clinic. She explained the higher total energy required for those with HD due to higher movement. She continued to explain healthy and unhealthy recommendations for HD patients; specifically, she mentioned decreasing lactose intake, while increasing the “colors” on a  plate, particularly through vegetables. 

The afternoon continued with a panel discussion about “Support Challenges in Huntington’s Disease” with social workers from the local community.  Moderated by Dr. Sha and Dr. Santini, the panel consisted of Andrea Kahn, MS, CGC, Amee Jaiswal, LCSW, and Betsy Conlan, LCSW of Stanford Health care, among others. Each of these panelists introduced themselves gave attendees the opportunity to ask any questions they may have. They each provided expert answers for all questions from the audience members, which included those on along the topic of insurance protections, trust planning, pre-existing conditions under the Affordable Care Act, and long-term care. Panelists also recommended HD patients and families to enroll in a long term insurance plan prior to getting tested, mentioning the impact which positive results can have on the resources and coverage of an insurance plan.

The event concluded with a talk by Kristin Morris, PT, DPT, NCS, and physical therapist from the Stanford Neuroscience Health Center. She demonstrated examples of physical therapy style movements for those impacted by HD, and offered the opportunity for attendees to join in trying them out.

The first annual iteration of Stanford Patient Care and Research Symposium was a great success, bringing valuable information to and bringing together the HD community.

 

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Gluten and Huntington’s Disease

Summary: Gluten can affect the amount of tissue transglutaminase in the body, which is an important enzyme in the formation of the protein aggregates that are characteristic of HD. 

 

As with many neurodegenerative diseases, the accumulation of misfolded protein in the brain is a hallmark of Huntington’s Disease (HD). In HD, these misfolded proteins are mutant huntingtin protein. While normal huntingtin protein is necessary for healthy cellular functioning, research suggests that the accumulation of mutant huntingtin protein causes a toxic gain of function. Recent studies have begun exploring the relationship between HD and gluten, particularly due to gluten’s ability to affect the amount of tissue transglutaminase in the body, an important enzyme in the formation of protein aggregates that are characteristic of HD (or something). Ultimately, the mechanisms our bodies use to digest gluten and the physiological functions affected by HD may have more in common than researchers initially anticipated.

In Huntington’s Disease, not only is there an excess of mutant huntingtin protein, but it also tends to clump together, or aggregate. When the aggregates are in their intermediate stages, they are thought to be associated with cellular function and disease activity. And though the body has ways to get rid of this unwanted material through a process known as autophagy, this function is typically compromised in people with HD. Due to this interaction between mutant huntingtin aggregates and HD disease activity, it is critical to understand how and why these aggregates form, and any factors that influence their formation.

One important class of enzymes to consider when trying to understand protein aggregates in HD is tissue transglutaminases, which are broadly responsible for creating bonds between specific amino acids. Tissue transglutaminases (TGase) play an important role in both autophagy and apoptosis, or programmed cell death, both of which are key processes in maintaining a healthy cell environment. Additionally, the primary role of TGases is to create very strong bonds between specific amino acids, including glutamine. The expanded polyglutamine encoded by the CAG repeat in individuals with HD may serve as an ideal target for TGase activity, which can create bonds between the polyglutamine to create clumps of protein. 

There have been many studies looking at this relationship between TGase and HD. This includes studies using drugs such as cystamine to inhibit the effects of TGase and observe the effects on the progression of HD in those individuals. From their clinical trial that concluded in 2015, Raptor Pharmaceuticals claimed to have obtained results that were “clinically meaningful and suggest that [cystamine] may play an important role in the treatment of Huntington’s disease.” For more information about this study please click here. This study and others suggest that limiting the functional activity of tissue transglutaminase may by an effective way to treat the symptoms of Huntington’s Disease, though more research in the field is needed to confirm this idea. To read more about cystamine and HD, please visit this HOPES article

However, drugs such as cystamine are not the only way to influence the amounts of TGase acting in one’s body. Research suggests that higher amounts of dietary gluten intake is correlated with higher concentrations of TGase in body tissue, including gut and nervous tissue. This relationship between dietary gluten intake and tissue TGase concentration is indirect, acting through a storage protein in wheat called gliadin. While most other dietary proteins are broken down by human gut proteases, gliadin is not, and it consequently reaches the small intestine still in tact. After binding to a receptor there, gliadin is able to cross the intestinal barrier.

Once on the other side of the intestinal barrier, gliadin is catalyzed by TGase, which resides locally in the body tissue. For those who consume gliadin containing foods (including many gluten products) on a normal basis, their bodies must increase TGase activity in order to keep up with the regular intake of gliadin entering the body. This increased TGase, however, is not specific to acting on gliadin, and could possibly affect the formation of HD protein aggregates. 

To date, there have been no studies specifically looking at the effects of dietary gluten/gliadin on the progression or severity of HD symptoms. Further research is necessary before the scientific community will be able to accurately assess the relationship dietary gluten can play in HD. However, Buchara et al. in 2004 examined the concentrations of antigliadin antibodies (AGAs) in people with and without HD. This study found a significantly higher concentration of AGAs in HD individuals than in those without HD. Elevated AGA concentrations — a measure that is also used as a diagnostic tool for Celiac Disease — means that individuals with HD may be more sensitive to dietary gluten. Despite this, the basis of association between AGAs and HD is still unclear, which reaffirms the need for research on dietary gluten as an environmental modifier of HD. 

For those looking to limit their gluten intake, there are a few options. In addition to replacing gluten containing foods with other healthy alternatives, there are also established diets, such as the Paleo Diet, which are considered gluten free. Please make sure to consult your physician before making any changes to your diet. For more information about diet and HD, please refer to this HOPES webpage

Existing research suggests that dietary gluten intake could increase tissue transglutaminase, which may have unintended consequences for individuals with HD. However, more research in this area is necessary to determine gluten’s role in HD with any degree of certainty. This research provides valuable insight for the HD community, because as science continues to search for holistic treatment and prevention options for HD, methods for treating and delaying the onset of symptoms of HD are valuable for improving quality of life. 

 

Further Reading

Barta, Z., Mekkel, G., & Zeher, M. (2004, August 24). Antigliadin antibodies in Huntington’s disease. Retrieved from https://n.neurology.org/content/63/4/762.2 Click here to read a response to the article Antigliadin Antibodies in Huntington’s Disease, including questions about the article from other scientists and the author’s response. 

Bushara, K. O., Nance, M., & Gomez, C. M. (2004). Antigliadin antibodies in Huntington’s disease. Neurology,62(1), 132-133. doi:10.1212/wnl.62.1.132. Click here to read about a study examining the concentrations of antigliadin and other antibodies in Huntington’s Disease vs non-HD individuals. 

Bushara, K. O. (2005). Neurologic presentation of celiac disease. Gastroenterology, 128(4), S92-S97. Click here to read about the ways in which Celiac’s Disease manifests as a neurological disorder, and the relationship between gluten insensitivity and HD. 

Chin, R. L., & Latov, N. (2005). Peripheral neuropathy and celiac disease. Current treatment options in neurology, 7(1), 43-48. Click here to read about the mechanisms of Celiac’s Disease and how these, particularly transglutaminase, are related to HD. 

Hadjivassiliou, M., Williamson, C. A., & Woodroofe, N. (2004). The immunology of gluten sensitivity: Beyond the gut. Trends in Immunology,25(11), 578-582. doi:10.1016/j.it.2004.08.011. Click here to read about the relationship between antigliadin antibodies and gluten insensitivity from the lens of neurology.

Mastroberardino, P. G., & Piacentini, M. (2010). Type 2 transglutaminase in Huntington’s disease: a double‐edged sword with clinical potential. Journal of internal medicine, 268(5), 419-431. Click here to read about the role of tissue transglutaminase in Huntington’s Disease and the some of the methods researchers are using to target this as a treatment for HD. 

Walker, F. O. (2007). Huntington’s disease. The Lancet, 369(9557), 218-228. Click here to read more about the general pathophysiology of HD, including more on the protein aggregates that are characteristic of the disease. 

 

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Anesthesia and Huntington’s Disease

Anesthesia and Huntington’s Disease

For many years, the question of how to best use anesthesia in people with Huntington’s Disease (HD) has puzzled medical professionals. With an occurance of about 5 cases per 100,000 people in the US and Europe, HD is considered to be rare, and anesthesiologists are not likely to come across patients with HD very often. While the medical and scientific communities are yet to develop standards for anesthetic management in people with HD, research has uncovered certain aspects of HD that must be carefully considered when anesthesia is introduced.

Like any other patient, someone with HD would require anesthesia for many surgical situations. However, HD can cause anesthesia to also be necessary for situations that wouldn’t usually require anesthesia for a non-HD person. An example of this is dental care: for someone with later stage HD, chorea and behavioral changes associated with HD would make it difficult to have a dental filling done without anesthesia.

The most prominent interaction between the physiology of HD and common anesthetic agents happens as a result of the bulbar dysfunction seen in many HD cases. The bulbar region of the brain includes the cerebellum, medulla, and pons, and is responsible for controlling many involuntary functions that keep us alive. Many individuals with HD experience bulbar dysfunction, which typically manifests in the form of chorea, or uncontrollable movements that can affect all muscles, including respiratory muscles. Involuntary movements in the respiratory muscles can increase patients’ risk for pulmonary aspiration, or inhalation of the stomach contents. While pulmonary aspiration can happen to anyone under anesthesia, chorea in HD patients increases this risk, so it is important for an anesthesiologist to consider this when they are anesthetizing someone with HD.

Because of this increased risk, a rapid and safe recovery has been identified as a common goal for using anesthesia in patients with HD. The longer they remain unconscious from the anesthesia, the greater their risk of experiencing pulmonary respiration. Thus, fast-acting agents are generally seen to work well for individuals with HD. An example of a fast-acting and effective anesthetic is sevoflurane, which is used to induce and maintain the effects of general anesthesia. Sevoflurane is often used in combination with desflurane, a substance used to maintain the effects of anesthesia in a patient. It is administered via inhalation in a mixture of nitrous oxide and oxygen, and is effective in HD patients because its effects wear off rapidly after administration is discontinued as compared to other anesthetic agents. This allows for rapid recovery and minimizes HD patients’ risk of pulmonary aspiration. Conversely, anesthetic agents such as sodium thiopental and succinylcholine are reported to cause prolonged apnea in individuals with HD, making them unideal for anesthetizing this population due to the increased risk of pulmonary aspiration after prolonged unconsciousness.

In addition to the complications of bulbar dysfunction, there are also other considerations that anesthesiologists must note when using various anesthetic agents in individuals with HD. Among these considerations are the interactions between drugs commonly prescribed to treat the symptoms of HD with the anesthesia. Tetrabenazine is the only drug currently FDA approved specifically for treating the symptoms of HD — as opposed to drugs that are prescribed to individuals with HD but originally designed to treat something else. Since tetrabenazine primarily treats chorea symptoms in HD patients, it has the potential to interact with the bulbar function and increase the risk of pulmonary aspiration for someone with HD under anesthesia. The official recommendation for those taking tetrabenazine is to consult an anesthesiologist, as the drug could influence how the anesthesia affects the central nervous system. Additionally, many antipsychotic drugs which are commonly prescribed to people with HD, including haloperidol and chlorpromazine, commonly include the side effect of suppressing movements. While this often helps treat chorea as well as psychosis in HD patients, it also has the potential for adverse interactions with various anesthetic agents in ways that have not yet been widely researched.

Other factors to consider while evaluating an individual with HD for anesthetic care include age, nutrition, and their ability to qualify for certain types of anesthesias. Increased frailty is commonly seen in older individuals with HD, and their symptoms often prevent them from being able to fully cooperate with an anesthesiologist, making this an important consideration for anesthesiologists. Malnutrition can be seen in HD patients as they progress into the later stages of the disease, as it can be difficult to eat and/or retain their food. Various levels of under or malnutrition alter the physiology of the body in ways such as: shifting electrolyte and fluid levels, causing metabolic abnormalities, and increasing risk for hypothermia — all of which change the ways in which the body responds to drugs, including anesthesia. Finally, chorea can make it difficult to consider anesthetic options such as spinal anesthesia, as the uncontrollable chorea movements make it difficult to get proper injection placement, which is crucial for patient safety as well as the ability of the anesthesia to work effectively.

Various factors that dictate the proper treatment of those with Huntington’s Disease when using anesthesia have come to light in recent years. Despite this, a consensus on the best practices for anesthetic management of individuals with HD is still yet to be determined. Until further research is conducted, the existing literature suggests a few main factors that anesthesiologists must carefully consider while using anesthesia in patients with HD. The first is the response time of the anesthetic agent to minimize the risk of pulmonary respiration. Next, they must consider the interaction of the anesthesia with other drugs the patient may be taking. Finally, the physical condition of the patient must be taken into consideration, including nutrition level and which options are feasible for each patient. While a firm consensus on the anesthetic management of people with HD may never be reached due to the high variability of considerations between cases, more research on the interactions of HD and anesthesia is necessary to determine how to best treat these individuals.

 

Further Reading

Cangemi Jr, C. F., & Miller, R. J. (1998). Huntington’s disease: review and anesthetic case management. Anesthesia progress, 45(4), 150. Click here to read about the challenges of using anesthesia with HD, and one case study using sodium thiopental and succinylcholine.

Esen, A., Karaaslan, P., Akgün, R. C., & Arslan, G. (2006). Successful Spinal Anesthesia in a patient with Huntington’s Chorea. Anesthesia & analgesia, 103(2), 512-513. Click here to read about the challenges presented by using spinal anesthesia in HD patients and how this was successfully done in one case study.

Kang, J. M., Chung, J. Y., Han, J. H., Kim, Y. S., Lee, B. J., & Yi, J. W. (2013). Anesthetic management of a patient with Huntington’s chorea-A case report. Korean journal of anesthesiology, 64(3), 262. Click here to read a case report using anesthesia in an emergency operation on an HD patient.

MacPherson, P., Harper, I., & MacDonald, I. (2004). Propofol and remifentanil total intravenous anesthesia for a patient with Huntington disease. Journal of clinical anesthesia, 16(7), 537-538. Click here to read about one case study using propofol anesthesia in a HD patient in a dental case.

McConachie, I. (Ed.). (2009). Anesthesia for the high-risk patient. Cambridge University Press. This book includes concerns with using anesthesia in the malnourished, which can be a problem for HD patients.

Nguyen, P. T., Meeks, D., & Liotiri, D. (2017). Anaesthesia and orphan disease: airway and anaesthetic management in Huntington’s disease. BMJ case reports, 2017, bcr-2017. Click here to read about airway management when using anesthesia in HD patients.

Yadava, A., Battacharya, P. K., Jain, R. K., & Agarwa, R. C. (2006). Anaesthesia and huntington’s chorea. Indian J. Anaeth, 50(1), 47-48. Click here to read this article, which describes one particular case of anesthesia in HD, and discusses the risks associated with anesthesia and HD.

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2019 HOPES & HDSA Family Conference

2019 HOPES & HDSA Family Conference

The HD Journey: The Long and Winding Road

 

The 18th Annual HOPES Conference, co-hosted this year by the HDSA as their Annual Northern California Chapter Conference, was a gathering of innovation, advocacy, and community. With distinguished guests from HDSA Center of Excellence, UCSF, UC Davis, Stanford, and the broader HD community, those touched by HD were able to take a step back and reflect while fervently pursuing the future and what it may hold for HD families.

The day began with two back-to-back breakout workshop sessions, each led by experts with a different focus. Some of these sessions included how to manage behavioral changes in HD, the importance of clinical trials in advancing HD treatments, how HD advocacy has impacted one person’s life, perspectives on self-care from a life coach, HD research updates, and a breakout session about living in an HD family. But the common thread throughout each of these workshops was the audience members’ active participation, their thoughtful and intentional questions propelling the presentations and making them even more impactful for everyone present.

During the first session, Jeanette Garcia spoke about her own experience being diagnosed with HD. As one of ten children to a mother with HD, she and four of her siblings have chosen to get tested and answer what she called the “genie question”: if you could know when and how you could die, would you choose to? Out of the five who have been tested, three, including Jeanette, tested positive. Since then, she has taken every opportunity to participate in research studies for HD, even before she began showing symptoms. From clinical trials — where you may or may not be receiving treatment — to observational studies that will help researchers understand this disease, Jeanette sees it as her responsibility to future generations to contribute to scientific progress however she can, and urges others to do the same. She finished with a poem she wrote about her journey of acceptance with her diagnosis as well as a call to action for those in the HD community to be aware of clinical trial options that exist, saying “I did not sign up for this, but I can sign up to end it.”

In the second session, Peter Deng, a doctoral candidate at UC Davis, spoke about updates in HD research. He began by mapping out the different levels at which various therapeutics can target HD: the protein, RNA, or DNA stages. While the CAG extension that causes HD appears in the code of the genetic information, the DNA, Deng pointed out that it wasn’t even until 2017 that we saw a treatment that actually targeted HD at this level. After explaining how various therapeutic agents are working to target buildup of the mutant huntingtin protein that occurs in HD, he then shifted his focus to research seeking to answer what he called “the four to eight million dollar question, depending on who you ask,” and one that many researchers often neglect when developing a treatment: how can it be delivered into patients? For this, he presented two solutions that are currently being developed: lipid nanoparticles and modified adeno-associated viruses. The lipid nanoparticles, while effective at delivering therapeutics in cellular models, are not able to cross the blood-brain barrier, and thus delivered intravenously, would get stuck in the liver and lungs before their transient effects go away. Viruses, however, are able to persist for a long time in cells that aren’t rapidly dividing, such as neurons. Using viral vectors to deliver their protein treatment, Deng’s research group found that treated Huntington’s model mice performed significantly better on a movement test than untreated HD mice, and only slightly worse than wild-type mice.

In the afternoon, everyone gathered in a large lecture hall for a series of presentations broken down into three parts. Stanford student and HOPES co-leader, Cole Holderman, began with the presentation of two awards to outstanding members of the HD community. Roy Nierenberg, an HD patient, advocate, and regular attendee of the Palo Alto support group was recognized as the Joseph P. Roberson Foundation HD Person of the Year 2019 for his positivity, courage, and commitment to others in face of his diagnosis. Roy commented that he is “finding things that I love in my new life…I think I’m as happy as I’ve ever been in my life. I feel positive and enjoy what I’m doing.” Dawn Green, HD partner, caregiver, and advocate was awarded the George and Marna Parks 2019 award for her unrelenting commitment to and presence in the HD community.

The afternoon continued with a panel of speakers with various experiences with HD, moderated by Lisa Kjer-Mooney, LCSW. The panel included:

Each of these panelists had the opportunity to give their take on questions about everything from the best diet for HD, the benefits of exercise for HD persons, when is the time to stop working and take that bucket list vacation, and how to stay present in the moment. Below are some of the summarized focal points presented by the panelists.

  • If you have tested positive for HD, you may benefit from receiving regular care, even if you are not displaying symptoms, as it allows a medical professional to monitor you, and gives you an opportunity to learn about new updates in the HD community (Dr. Khandhar).
  • Many people believe that the Mediterranean Diet may be beneficial for those with HD, but the Mediterranean Diet may seem beneficial because it is accompanied by the Mediterranean lifestyle. It’s not just the diet, it’s the lifestyle that accompanies it — exercise, fresh air, good company, good food (Dr. Khandhar).
  • In late-stage HD, sometimes the best food is whatever you can get down. These individuals are prone to weight loss, so high fat foods are a good option, including ice cream (Dawn Green and Dr. Khandhar).
  • Exercise may be beneficial for patients no matter what stage they are, and there is always something someone can do. The best exercise is something that interests you that you will continue to do, even if it is gardening or folding clothes (Chelsea MacPherson).
  • Roy exercises and has found joy in biking and practicing Qigong (Roy Nierenberg).
  • Huntington’s is not a cookie cutter disease; not only are the symptoms different (behavioral, emotional, and movement), but everyone is at a different point in their life and circumstances and you must find someone who can listen to your needs (Elle Tadina-Siau).
  • Caregivers must make sure they take care of themselves as well and meet their own needs (Elle Tadina-Siau).
  • Staying connected has helped Dawn through her HD journey as a caregiver. Seeing practitioners and social workers outside of the office at events such as the conference provides an opportunity to ask questions and meet people (Dawn Green).
  • For loved ones with mobility issues, video calls for medical appointments can be an easier option and is something that Dawn and her husband use, but had to advocate for (Dawn Green).
  • The HD community is small compared to that for many other diseases, but very familial. There is a lot to learn from each other and must be there for one another (Dr. Khandhar).
  • Roy had a long road in deciding to leave the software company he was president of. His daughter “gave [him] a gift” when she took it over from him. (For more of Roy’s story, click here.)
  • Dawn recommends the book The Precious Present by Spencer Johnson for anyone who is trying to live in the moment and not dwell on the past or future. When Tom was diagnosed, they made a promise to live in the moment, and they have many special memories because of this decision (Dawn Green).
  • Things you want to do now you may not want to do later, so if a bucket list is more like a right now list (Dr. Khandhar).

To close the day, Adreahna Lee, a representative from Roche/Genentech presented an update on the group’s work on HD research. Details on the Generations HD1 phase III clinical study, HD Natural History Study, and Ionis-HTT phase I/IIa Study can be found on the Roche/Genentech website. She closed with some conclusions about the research being done: first, that there is data to date to support further clinical testing of RG6042 in HD, and that safety and efficacy are big questions while doing this research. For more information, the trial information support line at Genentech can be reached at 888-662-6728.

The information and community shared at this year’s conference made it an invaluable experience for patients, caregivers, and researchers alike. Thank you to everyone who attended and contributed to making the event as special as it was.

 

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