All posts by Sepehr Asgari

Updates in HD Research: January-March 2021

The following is a brief survey of HD-related research published during January-March 2021:

 

Advances in Understanding HD

Biomarkers

Biomarkers are defined as a measurable biological trait that can be used to indicate the presence of a disease.  Biomarkers are incredibly helpful tools for physicians in order to diagnose and monitor the progression of diseases.  As such, research on quantitative biomarkers for HD is an incredibly important medical need.

 

In a February report published in Movement Disorders, a group of German researchers investigated the use of novel biomarkers for HD.1   The researchers measured the levels of the  potential target, PDYN‐derived peptides, in relation to a standard biomarker for neurodegenerative diseases, neurofilament light chain.  The rationale behind this choice is based on prior research demonstrating that brain expression of PDYN is decreased in mouse models of HD.  The group measured the levels of PDYN-derived peptides and neurofilament light chain in the cerebrospinal fluid of HD patients, controls, and patients with other neurodegenerative disorders.  They found that PDYN‐derived peptide levels were significantly decreased specifically in HD patients, whereas neurofilament light chain levels were increased nonspecifically in all neurodegenerative disorders.  These promising findings suggest that PDYN-derived peptide levels could be a more specific biomarker for HD compared to neurofilament light chain, although more research is needed to validate PDYN-derived peptide measurements as a marker for HD progression.

 

In a February report published in Free Radical Biology and Medicine, Naia and colleagues investigated the role of a mitochondrial protein called NAD-dependent deacetylase sirtuin-3 (SIRT3) in HD.2   It has been previously demonstrated that SIRT3 levels and activity is increased in HD.  The study expanded on this knowledge by finding that loss of SIRT3 is correlated with increased oxidative stress, which can cause mitochondrial dysfunction.  Conversely, the researchers found that SIRT3 overexpression led to enhanced mitochondrial function.  In a fly model of HD, SIRT3 overexpression protected against neurodegeneration and extended the lifespan of the flies.  These findings can help inform future research investigating novel therapeutic strategies for HD.

 

Statistical Modeling 

Computational methods have and continue to play an increasingly important role in improving our understanding of the pathophysiology of HD and discovering novel therapeutic strategies.  

 

The composite Unified Huntington’s Disease Rating Scale (cUHDRS) is a metric used to track  the progression of HD and is heavily relied upon in clinical trials.  In a January study published in Movement Disorders, Estevez‐Fraga and colleagues aimed to statistically analyze how well the cUHDRS correlates with imaging biomarkers to track the progression of HD.3   This was done in order to validate cUHDRS as a relevant metric for HD progression.  Using two techniques called voxel-based morphometry and tract-based spatial statistics, the researchers looked at the correlation between cUHDRS scores, gray & white matter volumes, and structural connectivity metrics.  The group found strong evidence supporting the correlation between cUHDRS scores and longitudinal volume in regions of the brain called the occipito-parietal cortex, centrum semiovale, and the basal ganglia and structural connectivity metrics.  These findings support the use of cUHDRS as a valid measurement tool for HD progression.

 

Genetic Risk

Given the genetic nature of HD, there exists the possibility for predictive testing.  Those who are at risk of HD have the option to choose whether or not to get genetically tested.  Learning about genetic predisposition to HD comes with significant psychological burden, including the fear of genetic discrimination.  Understanding the sociology behind this phenomenon is an important step in reducing the stereotypes and stigma surrounding genetic diseases like HD. 

In a February study published in the European Journal of Human Genetics, two Belgian researchers aimed to better understand why individuals at risk for HD worry about genetic discrimination despite the existence of genetic non-discrimination regulations, and how these individuals cope with their concerns.4   The researchers analyzed semi-structured, in-depth interviews with individuals at risk for HD to fuel their findings.  With regards to why these individuals fear genetic discrimination, the study found that these concerns were largely grounded in family backgrounds.  These individuals often witnessed symptomatic relatives suffering from discrimination and stigmatization on numerous occasions, fueling their own concerns.  The researchers also identified two distinct coping strategies- keeping genetic risk a secret, or explicitly choosing to be transparent.  These findings help us gain a better understanding of the social aspects of being at risk for HD.

 

 

 

  1. Al Shweiki, R., et al., “Cerebrospinal Fluid Levels of Prodynorphin‐Derived Peptides are Decreased in Huntington’s DiseaseMovement Disorders. []
  2. Naia, L., et al., “Mitochondrial SIRT3 confers neuroprotection in Huntington’s disease by regulation of oxidative challenges and mitochondrial dynamics” Free Radical Biology and Medicine. []
  3. Estevez‐Fraga, C., et al., “Composite UHDRS Correlates With Progression of Imaging Biomarkers in Huntington’s DiseaseMovement Disorders. []
  4. Wauters and Hoyweghan, “Normalizing life at risk of Huntington’s disease. A qualitative study of backgrounds and coping strategies of fears of genetic discrimination” European Journal of Human Genetics. []
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Updates in HD Research: October-December 2020

The following is a brief survey of HD-related research published during October-December 2020:

 

Therapeutic Advances

Stem Cell Therapy

Stem cell therapy refers to a method that promotes the repair response of diseased tissue using stem cells, or cells with the potential to differentiate into many different types.  This therapy has attracted a lot of interest as a potential therapeutic strategy.

 

In a study published in December in Neuroscience Research, a group of Iranian researchers explored the use of stem cells derived from dental pulp in treating HD in rats. 1 Using administration of a chemical called 3-nitropropionic acid that results in progressive locomotor decline, the group created a rat model of HD disease.  Then, the researchers implanted dental pulp stem cells to investigate potential ameliorative effects.  Their findings were promising; the transplants were well accepted and improved motor skills.  Using a process called histological analysis, where thin slices of tissue are stained and examined under a microscope, the researchers observed that the stem cells hindered shrinkage of the striatum in the rat brains.  Additionally, stem cell implants decreased the expression of pro-inflammatory cytokines responsible for brain damage in HD rats.  This study demonstrates the potential for dental pulp stem cells in the treatment of HD, but significant investigation is still required.     

 

Advances in Understanding HD

Gut Dysbiosis

Gut dysbiosis refers to an imbalance of intestinal microorganisms.  These microorganisms are vital to our health, and such imbalances can have implications towards overall health.  In addition to the classic HD clinical symptom triad of cognitive, motor, and behavioral disturbances, gastrointestinal disturbances such as diarrhea and gastritis (stomach inflammation) are recognized as clinical attributes of HD.  There is growing interest in the role that the gut microbiome, or collection of microorganisms, plays in HD manifestation.

 

In an October study published in Nature Scientific Reports, a group of Swedish researchers investigated the role of tight junction (TJ) proteins in maintaining the barrier between the intestines and systemic circulation (the blood supply) in a mouse model of Huntington’s Disease. 2 Normally, TJ proteins play the vital role of preventing bacteria moving from the intestines to the rest of the body.  However, it has been established that in Parkinson’s patients, this barrier is weakened, leading to leaky gut syndrome.  The resulting imbalance in gut bacteria can cause a lot of issues.  This group of researchers aimed to see if a similar phenomenon can be observed in a mouse model of HD.  They found that although TJ protein levels were normal in HD mice, there was an observable increase in gut permeability and significantly altered gut bacteria levels.  Their results indicate the relevance of increased intestinal permeability and dysbiosis in HD; however, further studies are needed to examine the clinical effects of such changes.

 

Statistical Modeling

Computational methods have and continue to play an increasingly important role in improving our understanding of the pathophysiology of HD and discovering novel therapeutic strategies.  One such method involves statistical analysis on gene expression measurements over time in order to identify genes that are associated with specific HD disease metrics (such as severity).  This technique greatly increases our understanding of the genetic basis of how HD works and has the potential to inform specialized therapeutic strategies.  However, a significant impediment to obtaining useful information from such analyses surfaces when different technologies are used to measure gene expression at different time points, creating data inconsistencies.

 

In a December study published in Biometrical Journal, Fuady and colleagues tackled this problem by developing a novel method of modeling associations between gene expression and disease indicators in cases where two different technologies were used to obtain data at different time points. 3  Using their technique, the research group was able to successfully identify specific genes that were expressed in correlation with severity of HD.  Their technique opens up possibilities for analyzing gene expression data that was suboptimally collected. 

 

Genetic Risk 

Given the genetic nature of HD, there exists the possibility for predictive testing.  Those who are at risk of HD have the option to choose whether or not to get genetically tested.  When testing protocols were first developed, it was predicted that a significant proportion of at-risk individuals would undergo the test, however, testing rates have remained unexpectedly low across cultural contexts.  This phenomenon prompted a group of French scientists to explore a comparison of familial attitudes towards testing over the past 20 years in a recent December study. 4 While the percentage of the population seeking testing has remained relatively constant, the researchers found significant differences in the motivations to do so.  20 years ago, the main reason for getting tested was to prevent genetic transmission to children.  Now, the main motivation is autonomy and the right to know.  These findings offer incredible insight into historical motivations to undergo genetic testing and can inform policy decisions moving forward.

  1. Eskandari, N., et al., “Transplantation of human dental pulp stem cells compensates for striatal atrophy and modulates neuro-inflammation in 3-nitropropionic acid rat model of Huntington’s disease Author links open overlay panel.” Neuroscience Research. []
  2. Loredan, S., et al., “Increased intestinal permeability and gut dysbiosis in the R6/2 mouse model of Huntington’s disease.” Scientific Reports. []
  3. Fuady, A., et al., “Statistical method for modeling sequencing data from different technologies in longitudinal studies with application to Huntington disease.” Biometrical Journal. []
  4. Pierron, L., et al., “Informing about genetic risk in families with Huntington disease: comparison of attitudes across two decades.” European Journal of Human Genetics. []
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Updates in HD Research: July-September 2020

The following is a brief survey of HD-related research published during July-September 2020:

 

Therapeutic Advances

Stem Cell Therapy

Stem cell therapy refers to a method that promotes the repair response of diseased tissue using stem cells, or cells with the potential to differentiate into many different types.  This therapy has attracted a lot of interest as a potential therapeutic strategy for HD.

 

In a July study published in Movement Disorders, Anne‐Catherine Bachoud‐Lévi, on behalf of the Multicentric Intracerebral Grafting in Huntington’s Disease Group reported on the findings of a randomized phase II trial on human fetal cell therapy for HD. 1 The group aimed to determine the safety and efficacy of intrastriatal transplantation of human fetal cells.  Unfortunately, severe adverse events were observed in many of the subjects and no clinical benefits were found from the therapy.  The researchers speculate that the unfavorable outcome was due to the patients’ bodies rejecting the transplant.  This study highlights the difficulties and challenges currently associated with stem cell transplantation as a treatment method.

 

Advances in Understanding HD

Aberrant Development 

Aberrant neuronal development refers to abnormalities in brain cell development and has been implicated in many neurological disorders such as Huntington’s disease.  

 

In an August research article published in Science, a group of French researchers aimed to determine if there are alterations in neurodevelopment among presymptomatic mutation carriers of Huntington’s disease.2  This phenomenon has been previously described in mouse and neuroimaging studies, but this group of researchers hoped to observe it in actual human tissue from fetuses with the HD mutation.  They observed a number of abnormalities, including abnormal ciliogenesis (formation of small outgrowths on cell surfaces) and changes in cell cycle progression.  Their results have far reaching implications, as they seem to suggest more definitively that HD is not only a degenerative disease and also has a neurodevelopmental component.  

 

Gut Dysbiosis

Gut dysbiosis refers to an imbalance of intestinal microorganisms.  These microorganisms are vital to our health, and such imbalances can have implications towards overall health.  In addition to the classic HD clinical symptom triad of cognitive, motor, and behavioral disturbances, gastrointestinal disturbances such as diarrhea and gastritis (stomach inflammation) are recognized as clinical attributes of HD.  There is growing interest in the role that the gut microbiome, or collection of microorganisms, plays in HD manifestation.

 

In a July study published in Brian Communications, Wasser and colleagues investigated the relationship between the gut microbiome, cognitive function, and clinical outcomes in HD.3  Their first objective was to identify if there exists any differences in the gut microbial communities of healthy and HD individuals.  Using rRNA sequencing of fecal samples, the researchers discovered that there were significant differences in the species richness (number of different species) and evenness (a measure of biodiversity) between the control and HD patient population.  Furthermore, the researchers established a correlation between these differences and cognitive performance and clinical outcomes.  These findings indicate the importance of the gut microbiome in HD and could imply the microbiome as a target for therapeutic interventions, although much more research is needed on the topic.

 

Biomarkers

Biomarkers are defined as a measurable biological trait that can be used to indicate the presence of a disease.  Biomarkers are incredibly helpful tools for physicians in order to diagnose and monitor the progression of diseases.  As such, research on quantitative biomarkers for HD is an incredibly important medical need.

 

In a September study published in Oxidative Medicine and Cellular Longevity, a group of researchers from Minzu University of China performed a meta-analysis of blood oxidative stress markers in HD patients and healthy subjects with the hopes of better understanding the biomarker.4  In their comprehensive meta-analysis of 375 HD patients and 447 HC subjects, they discovered that three blood oxidative stress markers, lipid peroxidation products, 8-hydroxyguanosine levels, and glutathione peroxidase activity, were all dramatically elevated in HD patients.  Other biomarkers, such as cholesterol, high-density lipoproteins, low-density lipoproteins, and triglycerides were not significantly different between groups.  This study clarified previously inconsistent and unclear associations between blood oxidative stress markers and HD.  

 

  1. Bachoud‐Lévi, A.C., “Human Fetal Cell Therapy in Huntington’s Disease: A Randomized, Multicenter, Phase II Trial”. Movement Disorders. []
  2. Barnat, M., et al., “Huntington’s disease alters human neurodevelopment”. Science. []
  3. Wasser, C., et al., “Gut dysbiosis in Huntington’s disease: associations among gut microbiota, cognitive performance and clinical outcomes”. Brain Communications. []
  4. Tang, Q., et al., “Blood Oxidative Stress Marker Aberrations in Patients with Huntington’s Disease: A Meta-Analysis Study”. Oxidative Medicine and Cellular Longevity. []
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Updates in HD Research: April-June 2020

The following is a brief survey of HD-related research published during April-June 2020:

 

Therapeutic Advances

Antisense Oligonucleotides 

Antisense oligonucleotides are short strands of DNA that interact with messenger RNA, the precursors of proteins.  Researchers have been investigating the use of antisense oligonucleotides (ASOs) to prevent the production of certain maladaptive proteins that cause disease and the technique has shown great promise for HD, which is caused by a mutant HTT protein. 

 

In an April study published in Neurology, Hawellek and colleagues investigated the effects of treatment with an antisense oligonucleotide called RG6042 on patients with early manifest HD.1  They monitored changes in brain activity using a technique called electroencephalography that records electrical activity in the brain.  The researchers found that RG6042 treatment caused an increase in brain electrical activity signal power in a frequency range that was depressed in the HD patients.  These results indicate that RG6042 may mediate recovery of brain activity in HD patients, but more research as to whether this translates into a therapeutic benefit is needed.

 

Small Molecule Inhibitors

A June report published in ACS Chemical Neuroscience aimed to investigate the ability of several small molecules to hinder Huntingtin protein aggregation, a major aspect of Huntington’s disease.2  Direct blocking of aggregate formation is an under-investigated approach to therapeutic discovery for HD, making this study particularly exciting.  Using a method called fluorescence resonance energy transfer, or FRET, Lo and colleagues engineered two biosensors that could be utilized to monitor aggregation of Huntingtin protein in live cells.  They then used high-throughput screening, an automated method of testing of large numbers of potential drugs, in order to discover effective candidates.  They found six small molecules that displayed a decreased FRET of the biosensors, indicative of aggregate breakage.  Furthermore, these compounds were also found to reduce aggregate-induced cell death in affected cells.  While these results are promising, considerable work needs to be done before these small molecules can be recognized as viable therapeutic options for HD.

 

Drug Delivery

A major challenge for ASOs as a viable treatment is the difficulties in effective delivery to the brain.  As such, determining better methods for drug delivery is an incredibly important area in HD research.  

 

In an April study published in Neurology, Leavitt and colleagues investigated intrathecal drug administration of RG6042, the same experimental ASO for Huntington’s disease investigated by Hawellek and colleagues.3  The group of researchers used two clinical studies to derive insights on best practice for intrathecal drug administration, or injection of therapeutics into the spinal canal, in Huntington’s disease.  The researchers reported gaining substantial insights into the real-world considerations of intrathecal administration via lumbar puncture.  Their findings are a considerable step towards making intrathecal administration of HD therapeutics more feasible in the clinical setting.

 

Cognitive Training

Progressive cognitive disturbances are a defining clinical characteristic of HD.  Cognitive training is a promising therapeutic strategy in order to slow cognitive decline.  However, its efficacy, specifically for HD patients, is not well understood and current research aims to clarify its impact. 

 

In a June report published in Pilot and Feasibility Studies, Yhnell and colleagues aimed to investigate the feasibility and acceptability of a home-based computerized executive function training program called CogTrainHD.4  The researchers found that many of the participants did not strongly adhere to the intervention, indicating that CogTrainHD is not feasible in its current state.  In future studies, the research group aims to rectify the shortcomings of this study.

 

Another June study published in Pilot and Feasibility Studies looked at the feasibility of mindfulness-based cognitive therapy (MBCT) for people with the HD genetic mutation.5  Specifically, Eccles and colleagues were looking to determine if eligible persons would be willing to participate in a randomized controlled trial to analyze the effect of MBCT on people with the HD mutation, either pre-manifest or in an early disease stage.  The group concluded that difficulties in recruiting and relative rarity of HD makes an in-person MBCT randomized controlled trial highly improbable.  The researchers are currently looking at online methods of administration in order to make a randomized controlled trial feasible.

  1. Hawellek, D., et al., “Changes in Brain Activity with Antisense Oligonucleotide RG6042 Treatment in Early Manifest Huntington’s Disease (HD)”. Neurology. []
  2. Lo, C., et al., “Discovery of Small Molecule Inhibitors of Huntingtin Exon 1 Aggregation by FRET-Based High-Throughput Screening in Living Cells”. ACS Publications. []
  3. Leavitt, B., et al., “Intrathecal Drug Delivery of Antisense Oligonucleotides in Huntington’s Disease: Experience of Ionis/Roche RG6042 Development Programme and Best Practice Considerations for Real-World Use”. Neurology. []
  4. Yhnell, E., et al., “A randomised feasibility study of computerised cognitive training as a therapeutic intervention for people with Huntington’s disease (CogTrainHD)”. Pilot and Feasibility Studies. []
  5. Eccles, F., et al., “A feasibility investigation of mindfulness-based cognitive therapy for people with Huntington’s disease”. Pilot and Feasibility Studies. []
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Dental Care and HD

Dental Care and HD

Significance of Dental Care

Adequate dental care is an integral part of maintaining healthy teeth and gums, which are vital not only for eating, but also for social communication.  As a result, poor dental health can have both physical consequences (i.e. tooth decay, gum disease) and mental consequences (i.e. low self-esteem).  Huntington’s Disease (HD) can often make dental care difficult for patients.  The classic HD triad of motor, cognitive, and psychiatric clinical symptoms adversely impact the ability of patients to take care of their teeth and gums, leading to many dental and psychological issues.   

 

Challenges In Dental Care for HD Patients

There is no genetic basis behind why HD increases the susceptibility of teeth to decay.  However, largely due to the inhibiting symptoms of HD, HD patients have a higher clinical incidence of dental issues than normal.  To this point, as HD progresses, there is an increase in the risk for cavities and periodontal disease, or infections of the structures around the teeth- such as the gums.  

 

There are a variety of factors that contribute to this increased risk.  For one, research has demonstrated that many HD patients benefit from a high-energy diet.  Such a diet lends itself to high sugar intake.  This sugar is processed by bacteria on the surface of teeth, and turned into acid that dissolves the tooth and causes tooth decay.  Furthermore, as noted by the Huntington’s Association New South Wales, toxins freed by these bacteria can cause progressively worse irritation in the gums and eventually gum disease.  These problems are exacerbated by a decrease in dexterity that patients with HD might experience, making it difficult to operate a toothbrush and dental floss.

 

Involuntary movements typical in HD patients can lead to bruxism, or grinding and clenching of teeth, which can cause them to deteriorate over time.  Additionally, involuntary movements can make it difficult to stand still. As the disease progresses, patients might not be able to fully open their mouths, further complicating dental care.  Dysphagia, or difficulty swallowing, may also develop with the progression of the disease and can make brushing teeth difficult.

 

Other factors can also contribute to HD patients not receiving or having access to adequate dental care.  Common symptoms of HD, such as apathy and resentment, may contribute to HD patients not prioritizing their dental hygiene.  Additionally, transportation to appointments, access to facilities, and the financial burden of dental care may pose substantial barriers for some people to access adequate treatment.  

 

Furthermore, routine oral surgeries such as root canals can present with unique difficulties in HD patients.  The use of anesthesia for surgeries generally presents with a higher risk for pulmonary aspiration (inhalation of the stomach contents) in HD patients due to chorea.  As a result, any dental surgery requiring anesthesia requires careful consideration of many factors by the physician.  This problem is accentuated by the tendency for HD to require anesthesia even for routine treatments that usually wouldn’t require it.  A notable example is with routine dental fillings.  They typically do not require anesthesia, but can be difficult to perform without anesthesia in late stage HD patients because of the chorea and behavioral complications that they may experience.  

 

What Can Be Done? 

While HD patients do experience unique challenges in dental care, poor dental health does not necessarily need to be a hallmark of the disease.  There are many things patients and caretakers can do to maintain great dental health.  For example, The Huntington Society of Canada advocates for preventative care in order to mitigate risks.  This includes the continued support of caregivers, starting good habits early, and using alternatives to conventional dental care if need be. 

 

Sources and Further Reading:

“Dental Care in Huntington Disease.” Huntington Society of Canada.

Lane and Manley, “The oral health and dental treatment of adults with Huntington’s disease.” Journal of Neurology, Neurosurgery & Psychiatry.

Manley et al., “Guideline for oral healthcare of adults with Huntington’s disease.” Neurodegenerative Disease Management.

“Oral Implications of Huntington’s Disease.” drcairo.com.

Rada, R., “Comprehensive Dental Treatment of a Patient With Huntington’s Disease: Literature Review and Case Report.” Special Care in Dentistry.

Saft el al., “Oral and dental health in Huntington‘s disease – an observational study.” BMC Neurology.

“The Importance of Dental Care in Huntington Disease.” Huntington’s New South Wales.

 

 

 

 

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Updates in HD Research: January-March 2020

Updates in HD Research: January-March 2020

The following is a brief survey of HD-related research published during January-March 2020:

 

Therapeutic Advances

Gene Therapy

Gene therapy refers to the delivery of genetic material to cells in order to treat disease and is an area of active HD research. 

In a February study published in Nature Communications, Wu and colleagues from Pennsylvania State University investigated the use of gene therapy to convert a type of glial cell called astrocytes into neurons in a mice model of HD.1  Mice treated with this novel therapy had a significantly longer life span and improved motor functions.  These results indicate that gene therapy conversion of glia to neurons could be a feasible way to treat HD.

 

Antisense Oligonucleotides 

Antisense oligonucleotides are short strands of DNA that interact with messenger RNA, the precursors of proteins.  Researchers have been investigating the use of antisense oligonucleotides (ASOs) to prevent the production of certain maladaptive proteins that cause disease and the technique has shown great promise for HD, which is caused by a mutant HTT protein.  However, a major challenge for ASOs as a viable treatment is the difficulties in effective delivery to the brain.  

In a January study published in Angewandte Chemie, a group of Japanese researchers investigated a method of ASO delivery to the brain that is less invasive than current methods.2  Their method involves the passage of ASOs across the blood-brain barrier, a very difficult-to- cross barrier between circulating blood and the brain, using careful glycemic control.  Using glucose-coated polymeric nanocarriers, the researchers demonstrated efficient accumulation in brain tissue after intravenous injection and significant inhibition of non-coding RNA in mice.  Their results show a novel method of ASO delivery to the brain in a noninvasive manner.

 

Autophagy Induction

Autophagy refers to a cellular process that works to maintain homeostasis by eliminating unwanted and damaged molecules such as proteins.  Researchers have been interested in utilizing this natural process in order to clear aggregates of misfolded proteins common in many neurodegenerative diseases.  In the case of Huntington’s disease, many different genetic and pharmacological mechanisms have been used by scientists to induce autophagy and clear harmful aggregates of huntingtin protein.3

In a January report published in Cells, a group of Italian scientists mainly from the University of Milan demonstrated a new way to induce autophagy and clear aggregates of huntingtin.4  Their study showed that regulation of an enzyme called glutamine synthetase 1 (GS1) is able to induce autophagy in a fruit fly model of Huntington’s disease and improve neuronal survival.  These findings open up the opportunity for the development of new therapeutics for HD targeting GS1 in future research.

 

Advances in Understanding HD

Aberrant Development 

Aberrant neuronal development refers to abnormalities in brain cell development and has been implicated in many neurological disorders such as Huntington’s disease.  

A March report published in Stem Cell Reports by Smith-Geater and colleagues investigated aberrant development in adult-onset HD.5  Using induced pluripotent stem cells (iPSCs) from HD patients and controls, the researchers identified a mechanism that promotes aberrant neurodevelopment as well as preliminary evidence that specific components of a particular signaling pathway could be a counteractive therapeutic target.

 

Exercise

In a January report, a group of scientists from the University of Southern California investigated the effects of treadmill exercise on a mouse model of HD.6  They found that the treadmill exercise resulted in increases in nitric oxide levels as well as improved mitochondrial function.  These changes were also associated with improved motor performance.  Their findings suggest that in a mouse model of HD, exercise could have a beneficial effect on motor behavior by counteracting deficits in mitochondrial function.

 

HD and Cardiac Arrhythmias

In recent years, there has been increasing evidence that HD patients could be at an increased risk for cardiac arrhythmias.  

In a February study published in Human Molecular Genetics, Zhu and colleagues aimed to investigate this phenomenon in a mouse model of HD.7  Their findings were consistent with prior knowledge, indicating that mutant Huntintin protein (mHTT) can cause problems in cardiac conduction systems, increasing susceptibility to arrhythmias and sudden cardiac death.  As a result, the authors suggest that it is beneficial to monitor heart rhythm in HD patients, even when there are no prior signs of heart disease.

 

Multidisciplinary Rehabilitation

The loss of grey matter in a brain region called the hypothalamus has been well-documented in HD, and is believed to contribute to circadian rhythm and habitual sleep disturbances.  

In a January study published in the Journal of Neurological Sciences, a group of Australian and British scientists investigated the impact of multidisciplinary rehabilitation therapy on hypothalamic grey matter loss and circadian rhythm and habitual sleep disturbances in a group of individuals with preclinical HD.8  The nine month-long study found that a specialized rehabilitation therapy designed by a team of exercise scientists, cognitive training, sleep, and circadian rhythm specialists, neuroscientists, and a neuropsychiatrist was able to reduce hypothalamic grey matter volume loss.  However, the scientists did not observe any significant changes in sleep disturbances.

  1. Wu, Z., et al., “Gene therapy conversion of striatal astrocytes into GABAergic neurons in mouse models of Huntington’s disease”. Nature Communications. []
  2. Hyun Su Min et al., “Systemic Brain Delivery of Antisense Oligonucleotides across the Blood–Brain Barrier with a Glucose‐Coated Polymeric Nanocarrier”. Angewandte Chemie. []
  3. Boland, B. et al., “Promoting the clearance of neurotoxic proteins in neurodegenerative disorders of ageing”. Nature Reviews Drug Discovery. []
  4. Vernizzi, L. et al., “Glutamine Synthetase 1 Increases Autophagy Lysosomal Degradation of Mutant Huntingtin Aggregates in Neurons, Ameliorating Motility in a Drosophila Model for Huntington’s Disease”. Cells. []
  5. Smith-Geater, C. et al., “Aberrant Development Corrected in Adult-Onset Huntington’s Disease iPSC-Derived Neuronal Cultures via WNT Signaling Modulation”. Stem Cell Reports. []
  6. Caldwell, C. et al., “Treadmill exercise rescues mitochondrial function and motor behavior in the CAG140 knock-in mouse model of Huntington’s disease”. Chemico-Biological Interactions. []
  7. Zhu, Y. et al., “Progressive cardiac arrhythmias and ECG abnormalities in the Huntington’s disease BACHD mouse model”. Human Molecular Genetics. []
  8. Bartlett, D. et al., “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. []
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COVID-19 and HD

COVID-19 and HD

The current COVID-19 (coronavirus) crisis presents with unprecedented challenges and uncertainties for all.  In this article, we hope to contribute to increasing awareness and knowledge about COVID-19.  While the information and resources provided below are by no means exhaustive, we hope that they can be helpful for HD patients and their caretakers.

COVID-19 General Info

COVID-19, which stands for coronavirus disease 2019, is a highly contagious viral infection caused by a newly identified virus called SARS-CoV-2.1  The World Health Organization (WHO) declared COVID-19 a global pandemic on March 11, 2020.2  While scientists are still researching the transmission of the virus, it is believed that COVID-19 is primarily spread among people through close contact and respiratory droplets.3  Symptoms can vary from person to person and start 2-14 days after exposure, but common symptoms include dry cough, shortness of breath/difficulty breathing, fever, chills, repeated shaking with chills, muscle pain, headache, sore throat, and new loss of taste or smell.4  According to the WHO, approximately 80% of people with COVID-19 recover without any need for special medical treatment, but 1 in 6 develop breathing difficulties and become seriously ill.5

Click here to view the preventative measures described by the Centers for Disease Control and Prevention (CDC).

COVID-19 and Huntington’s 

According to the European Huntington Association, Huntington’s disease itself does not necessarily put HD patients at a higher risk of contracting COVID-19.  However, among HD patients that are symptomatic, there may be an increased risk of developing pneumonia as a result of being bedridden and undernourished.  HD patients may also be at a higher risk of developing symptoms if exposed to COVID-19 and having a more serious illness.6

Resources

Below are some potentially helpful resources for HD patients and their caregivers:

COVID-19 information:

Lifestyle resources:

Virtual support groups and social support:

Other Helpful Resources:

A starter guide on how to navigate the popular video calling platform, Zoom

Device designed to help seniors connect with loved ones

Video calling app for android devices

A tool that crowdsources wait times for local stores and can be useful for avoiding crowds

 

  1. Subraminiam, V., “Information About COVID-19 for Huntington’s Disease Patients”. Huntington’s Disease News. []
  2. Cucinotta, D. and Vanelli, M., “WHO Declares COVID-19 a Pandemic”. Acta BioMedica. []
  3. Brosseau, L., “COMMENTARY: COVID-19 transmission messages should hinge on science”. Center for Infectious Disease Research and Policy. []
  4. Symptoms of Coronavirus”. Centers for Disease Control and Prevention. []
  5. Readfearn, G., “What happens to people’s lungs when they get coronavirus?”. The Guardian. []
  6. Subraminiam, V., “Information About COVID-19 for Huntington’s Disease Patients”. Huntington’s Disease News. []
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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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