Volume 6

Meet the Compound: Coenzyme Q10

coq10Molecular Formula: C59H90O4

Molecular Weight: 863.34 g/mol

Mechanism of Action: CoQ10 occurs naturally in the body, an important antioxidant in the mitochondrial electron transport chain1. It has been shown to decrease the abnormally high lactate-pyruvate levels in cerebrospinal fluid in HD2.

CoQ10 has been explored as a neuroprotective in PD and HD (Table 1). Although the QE3 trial of CoQ10 in PD showed no significant benefits,3 studies in HD have shown more promising results. Dr. Flint Beal, Professor of Neurology and Neuroscience at Weill Medical College of Cornell University, told HD Insights that the failure of CoQ10 in PD has an unknown impact on its use in HD. “I am still hoping that the results in HD will be beneficial,” he said. Dr. Karl Kieburtz, Director of the Clinical and Translational Science Institute at the University of Rochester, told HD Insights that the evidence for a modest benefit of CoQ10 in HD is greater than in the case of PD. The CARE-HD study of high dose CoQ10 and remacemide in HD demonstrated a trend toward slowing functional decline4. Dr. Kieburtz suggested that these results may indicate that the benefits of long-term CoQ10 are detectable only in a clinical trial setting. Further exploration of CoQ10 is important, he said, because it is a low-cost, readily available intervention that people at risk for HD can take at low risk for a long time, while some more potent therapies that target specific biological processes may demonstrate high toxicities. This exploration is currently being undertaken in the 2CARE study, a multi-center, randomized, double-blind, placebo-controlled study of high-dose CoQ10, conducted by the Huntington Study Group (HSG) under the direction of Drs. Merit Cudkowicz, Michael McDermott, and Karl Kieburtz. 2CARE aims to identify the effects of CoQ10 on functional decline in HD, as well as its long-term safety and tolerability5.

coq10 table

The PREQUEL study represents the first randomized, controlled trial of CoQ10 in premanifest HD, under the direction of Drs. Christopher Ross of Johns Hopkins University, and Kevin Biglan of the University of Rochester. The results of PREQUEL will be presented at this year’s HD Clinical Research Symposium. Dr. Ralf Reilmann (see “Selected by Chance,” p. 1) said, “I think PREQUEL is one of the most fantastic studies. This was a proof-of-concept study, and I think we are transitioning from a phase where such trials were unrealistic, to a phase where we can actually consider doing challenging, disease-modifying trials in both manifest HD and premanifest HD.”


1 Chaturvedi RK, Beal MF. Mitochondria targeted therapeutic approaches in Parkinson’s and Huntington’s diseases. Mol Cell Neurosci. 2013 Jul; 55:101-14.

2 Koroshetz WJ, Jenkins BG, Rosen BR, Beal MF. Energy metabolism defects in Huntington’s disease and effects of coenzyme Q10. Ann. neurol. 1997;41(2):160-5. Epub 1997/02/01. doi: 10.1002/ana 410410206. PubMed PMID: 9029064.

3 National Institute of Neurological Disorders and Stroke (NINDS). Statement on the termination of QE3 study [Internet]. [Updated 2011 June 2; cited 2013 Sep 19]. Available from ninds.nih.gov/disorders/clinical_trials/CoQ10-TrialUpdate.htm.

4 Kieburtz K, Koroshetz W, McDermott M, et al. A randomized, placebo-controlled trial of coenzyme Q10 and remacemide in Huntington’s disease. Neurol. 2001 Aug 14; 57(3):397-404.

5 ClinicalTrials.gov. Coenzyme Q10 in Huntington’s Disease (HD) (2CARE) [Internet]. [Cited 2013 Sep 19]. Available from clinicaltrials.gov/ct2/show/NCT00608881?term=2CARE +Huntington&rank=1.

6 Hyson HC, Kieburtz K, Shoulson I, et al. Safety and tolerability of high-dosage coenzyme Q10 in Huntington’s disease and healthy subjects. Mov Disord. 2010;25(12):1924-8.

7 Schults CW, Oakes D, Kieburtz K, et al. Effects of coenzyme Q10 in early Parkinson d isease: Evidence of slowing of the functional decline. Arch Neurol. 2002 Oct; 59(10):1541-50.

8 Kieburtz K, Ravina B, Galpern W, et al. A randomized clinical trial of coenzyme Q10 and GPI-1485 in early Parkinson Disease. Neurol. 2007 Jan 2;68(1):20-28.

9 Beal MF. A phase III clinical trial of coenzyme Q10 (QE3) in early Parkinson’s disease: Parkinson Study Group QE3 Investigators [Abstract]. Mov Disord. 2012 Jun 17-21; 27 Suppl 1:346.

Research Round-Up

By: Lise Munsie, PhD

In the lab…

Caron and colleagues describe properties of the huntingtin protein based on sensitive fluorescent sensors and using Förster resonance energy transfer (FRET) 1. They describe the intramolecular proximity between the domains flanking the polyglutamine tract, the N-terminus of huntingtin, and the polyproline region. Pathogenic CAG repeat lengths alter the ability of huntingtin to fold, and to interact with itself and other proteins. This may be part of the mechanism of disease, and the FRET assay may act as a read-out for altered huntingtin function. An early event in HD pathogenesis is activation of caspase-6 in the central nervous system. Ehrnhoefer and colleagues explored the role of caspase-6 in peripheral phenotypes such as the muscle wasting observed in HD2. They found that activity of p53, a transcriptional activator of caspase-6, is increased in neuronal and peripheral tissues of HD patients and mouse models of HD, leading to the activation of caspase-6. This implies that peripheral dysfunction in HD may stem from the same pathways that cause neurodegeneration. Murmu and colleagues examined the kinetics of dendritic spine alterations and synaptic plasticity in the R6/2 mouse model of HD, using long-term two-photon imaging through a cranial window3. By tracking individual dendrites and spines over six weeks, they show that a decrease in spine density and survival is associated with disease progression, and is evident before behavioral change and neuronal loss. In the mouse model there is increased spine turnover, and newly formed spines are less likely to mature. Future therapies should examine ways to stabilize dendritic spines and modulate spine turnover.

In the scanner…

round upThe Australia-based IMAGE-HD group is using MRI imaging to investigate functional changes in the macro and microstructure of HD brains over time. Their recent study published in PloS ONE used a 3T MRI scanner to observe differences in premanifest and early symptomatic HD patients4. Longitudinal change in caudate volume discriminates between groups at all stages of the disease. Caudate atrophy is present before onset of symptoms and is one of the most sensitive measures that may work as a biomarker. Recent data suggests that changes in HD brains extend to the white matter tract. A second study published in PLoS ONE used diffusion tensor imaging (DTI) and tractography to investigate mechanisms that underlie regional specific changes in white matter during the course of HD5. This study focused on the corpus callosum, associating changes in subregions of this structure with motor and cognitive outputs. The study found that demylenation and axon damage is likely to occur before onset of HD symptoms, and that abnormal structural connectivity is associated with HD progression and the number of CAG repeats. Neurovascular abnormalities are increasingly shown to have connections with neurodegenerative diseases such as HD. Lin and colleagues report on a novel fMRI technique called 3-dimensional microscopic magnetic resonance angiography, and their use of this technique to assess neurovascular changes in the R6/2 mouse model of HD6. Their work showed that disease progression is associated with an increase in vessel volume function and cerebral blood volume. This data correlates with immunostaining of human tissues that looks at microvascular morphology. The paper suggests that these changes could be used as a biomarker for early diagnosis of HD.

In the clinic…

In a recent issue of Nature Genetics, Mason and colleagues describe a new therapeutic lead for HD7. Using a genomewide over-expression suppressor screen in yeast, the group defines genes that suppress cell toxicity that is induced by mutant huntingtin fragment expression. The paper focuses on genes that encode glutathione peroxidases (GPxs), which are antioxidant enzymes. These enzymes do not inhibit autophagy like many other antioxidants, and the group found that genetic or pharmacological manipulation of GPx can rescue many HD phenotypes in yeast, fly and mammalian models. GPx therapy shows promise, and well-tolerated GPx mimetics are readily available for trials. Another experimental antioxidant therapy was explored in a PLoS ONE article that looked at protective effects of glial conditioned medium (GCM) in the R6/1 mouse model of HD8. GCM is enriched with antioxidants and neurotrophic factors, and is hypothesized to have therapeutic effects. Perucho and colleagues infused GCM into the left striatum of R6/1 mice and found positive effects on cell survival and inclusion formation. Another group is looking at new ways to specifically target the cognitive deficits in HD. Saavedra and colleagues investigated the involvement of the neuronal nitric oxide synthase/3′,5′-cyclic guanosine monophosphate (nNOS/cGMP) hippocampal pathway in HD cognitive decline9. They found a decreased level of cGMP in the HD mouse hippocampus, and found that injecting sildenafil, a phosphodiesterase (PDE5) inhibitor that increases cGMP levels, leads to memory improvement. Targeting this pathway may slow cognitive decline in HD.


1 Caron NS, Desmond CR, Xia J, Truant R. Polyglutamine domain flexibility mediates the proximity between flanking sequences in huntingtin. Proc Natl Acad Sci USA. 2013 Jul 3; 110:14610-5.

2 Ehrnhoefer DE, Skotte NH, Ladha S, et al. P53 increases caspase-6 expression and activation in muscle tissue expressing mutant huntingtin. Hum Mol Genet. 2013 Sep 18; doi:10.1093/hmg/ddt458.

3 Murmu RP, Li W, Holtmaat A, Li JY. Dendritic spine instability leads to progressive neocortical spine loss in a mouse model of Huntington’s disease. J Neurosci. 2013 Aug 7; 33(32):12997-3009. doi: 10.1523/JNEUROSCI.5284-12.2013.

4 Domínguez D JF, Egan GF, Gray MA, et al. Multi-modal neuroimaging in premanifest and early Huntington’s disease: 18 month longitudinal data from the IMAGE-HD study. PLoS ONE. 2013 Sep 16;8(9):e74131. doi:10.1371/journal.pone.0074131.

5 Phillips O, Sanchez-Castaneda C, Elifani F, et al. Tractography of the corpus callosum in Huntington’s disease. PLoS ONE. 2013 Sep 3; 8(9):e73280. doi:10.1371/journal.pone.0073280.

6 Lin CY, Hsu YH, Lin MH, et al. Neurovascular abnormalities in humans and mice with Huntington’s disease. Exp. Neurol. 2013 Sep 10. pii: S0014-4886(13)00268-9. doi: 10.1016/j.expneurol. 2013.08.019. [Epub ahead of print].

7 Mason RP, Casu M, Butler N, et al. Glutathione peroxidase activity is neuroprotective in models of Huntington’s disease. Nat Genet. 2013 Oct ;45(10):1249-54.

8 Perucho J, Casarejos MJ, Gomez A, et al. Striatal infusion of glial conditioned medium diminishes Huntingtin pathology in R6/1 mice. PLoS ONE. 2013 Sep 13; 8(9):e73120. doi:10.1371/ journal.pone.0073120.

9 Saavedra A, Giralt A, Arumi H, et al. Regulation of hippocampal cGMP levels as a candidate to treat cognitive deficits in Huntington’s disease. PLoS ONE. 2013 Sep 5; 8(9):e73664. doi: 10.1371/journal.pone.0073664.

Highlights from the 2013 World Congress on Huntington’s Disease

By: Débora Palma Maia, MD

brazilThe 2013 World Congress on Huntington’s Disease in Rio de Janeiro, Brazil, brought together physicians, scientists, health professionals, patients, family members and support groups to share new knowledge, with the goal of improving the management of HD.

Congress activities began with talks by members of various HD patient organizations. Mr. Rodrigo Osorio, president of Agrupación Chilena de Huntington, described the Red Latinoamericana de Huntington, a network of HD clinics in Latin America (see HD Insights, Vol. 5). It is estimated that 40,000 Latin Americans have HD. This large number of HD patients could help professionals, patients and families to better understand the disease. Mr. Matt Ellison, founder of the HD Youth Organization (HDYO), tackled the challenges faced by young people at risk for HD. He described how the HDYO website may help reduce the stigma of HD by educating young people and families.

In the “Basic Science” session, Dr. Elena Cattaneo described the emergence of huntingtin 800 million years ago, noting that this protein plays a crucial role in the development of brain cells through the formation of structures called rosettes. According to Dr. Marcy MacDonald, the development of HD is a lifelong process, unrelated to prions or prion-like processes. Finally, Dr. Ignacio Muñoz-Sanjuan described how PDE10A inhibitors can reduce the overexcitable properties of medium spiny neurons (see HD Insights, Vol. 5).

The second day of the Congress focused on premanifest HD. Drs. Alexandra Durr and Karl Kieburtz shared their experiences in TRACK-HD and PREDICT-HD, which found that brain imaging is a powerful technique for measuring HD progression. Cognitive tests such as the Symbol Digit Modalities Test are also good measures of progression. Dr. Ralf Reilmann, a movement disorders specialist, reviewed quantitative motor assessment, and argued that movement changes in premanifest subjects can be detected many years before symptoms begin, and are good measures of HD progression (see “Selected by Chance,” p. 1). However, he pointed out that some early movement changes in carriers of the HD mutant gene do not mean that individuals with these movement changes are sick. Prof. Julie Stout reported similar findings for cognitive functions.

Dr. Peggy Nopoulos discussed clinical findings in juvenile HD, and Dr. Francisco Cardoso spoke about the differential diagnosis of HD. He explained that in around 1% of cases, genetic testing does not reveal a CAG expansion. These cases are called HD-like disorders. One of them, HD-like-2, has a phenotype very similar to HD and it is more common in people of African descent. He reminded attendees, however, that these conditions are rare.

Dr. James Gusella presented genetic factors that could influence the age of symptom onset in individuals who are carriers of the HD mutant gene. He believes that understanding the mechanism of the manifestation of symptoms could make it possible to delay their onset. Dr. Laura Jardim discussed the genetic aspects of HD specific to Latin America, a continent with a complex genetic background derived from the population’s Indigenous, European and African genetic ancestries.

Drs. Sarah Camargos and Mônica Haddad presented ENROLL-HD, a global observational study of HD that aims to enroll as many people as possible. They discussed the importance of sharing data, and argued that ENROLL-HD may help to further understanding of the disease, and to educate health professionals around the world about better methods of care for HD patients.

The last Congress session discussed novel therapies. Dr. Douglas MacDonald told the Congress, that there is a “rich pipeline of therapeutics” advancing into the clinic. Dr. MacDonald’s group is working in particular with antisense oligonucelotides to silence the Huntingtin gene, and he told the Congress about emerging gene silencing techniques (see HD Insights, Vol. 3). Dr. Neil Aronin presented his group’s efforts to use deactivated viruses to silence the mutant HD gene. These gene-silencing approaches have shown great promise for the near future. Dr. Bernhard Landwehrmeyer gave an update on clinical trials in HD, while Dr. David Craufurd discussed drug treatment for psychiatric symptoms that is often necessary, and Dr. Binit Shah described deep brain stimulation in HD. At the end of the Congress, Dr. Joaquim Ferreira offered an encouraging reminder that while there is currently no cure for HD, there are a number of treatments that help patients, and many more that show great promise are on the horizon.

Selected by Chance: An Interview with Ralf Reilmann

Dr. Ralf Reilmann

Dr. Ralf Reilmann


CURRENT POSITION: Founding Director of the George Huntington Institut, Münster, Germany. Member, HD Insights Editorial Board.

EDUCATION: MD, Westfälische WilhelmsUniversität Münster (University of Münster), Münster, Germany; Postdoctoral Research Fellowship, Columbia University, New York, NY.

HOBBIES: Jogging, traveling, and discovering the world through the eyes of his seven-year-old daughter. Dr. Ralf Reilmann

HD INSIGHTS: Dr. Reilmann, you recently founded the George Huntington Institute in Münster, Germany. What is the vision of the Institute?

REILMANN: We want to be a dynamic factor in the development and translation of approaches to treating HD. We want to contribute to finding a cure, while providing the best possible, research-based care for patients and their relatives. We also want to foster international collaboration and friendship among HD researchers, and could potentially be a harbor for those who find it problematic to survive in their current settings doing HD research. We also want to directly connect the people in this region to our mission. The institute gives us the opportunity to educate people, including patients, about what’s going on in research, and gives them the opportunity to participate in trials. With a critical mass of people working together— physicians, neuropsychologists, study nurses, researchers— it’s a much more stimulating environment. Development in HD is by no means driven by any one person. It’s a continual pleasure to see what collaboration and international research support can bring about, and I’m glad to be a part of it. Unfortunately, neurodegenerative diseases like HD are very badly reimbursed in the national health schemes of Germany and other European countries, and it’s quite difficult to find support for HD research and care in a large hospital setting. So, the impetus for our formation was to create an infrastructure that allows us to offer Huntington’s patients the optimum level of care, and support our research efforts.

REILMANN: Patients are now coming to us from many hundreds of kilometers away. We have space for different physicians to see patients, with nicely equipped rooms, a big waiting area, a kitchen, and a conference room. We have a lot more resources for our work on HD. And we have the potential to grow: we have planned to pursue the founding of an external large animal facility, to support initiatives like the transgenic pig project we have just started with funding from CHDI, which would give us the opportunity to do research much more dynamically.

HD INSIGHTS: How did you become interested in HD?

REILMANN: Actually, I was drawn into HD research by chance. While I was completing my preclinical studies in medical school, I decided that I wanted to do a thesis in neurology with two of my friends. Our topic was assessment of neurotransmitters in epilepsy, HD, and PD, and my friends insisted that we draw lots. I drew HD! At first, I was disappointed, because I had attended a really interesting course on epilepsy by one of our professors. But when I travelled to Düsseldorf to work with Dr. Herwig Lange, who founded the first inpatient HD ward in Germany, I became fascinated by HD. While I was still analyzing my thesis research, the HD gene was discovered. With a grant from a German scholarship foundation, I joined a lab in Germany that was part of the international team that had discovered the gene. After medical school I went to Queen’s Square in London and studied with David Marsden, the founder of the Movement Disorder Society, who got me interested in quantifying movement disorders more objectively. He urged me to go to Columbia University in New York to pursue my interest, so after two years of neurology residency, I went to New York with a grant from the German government. I could have worked on the quantitative motor (Q-motor) idea in other diseases, but Karen Marder, who ran this big HD center at Columbia, and Carol Moskowitz, dragged me into HD again. I began to validate my Q-motor idea in HD patients. When I returned to Europe in 2001, Bernhard Landwehrmeyer asked me to join the European HD Network initiative and guide the motor working group. I have taken up the project of developing the UHDRS-TMS online certification program, with videos and to develop the Q-motor assessments. I suppose that really gave me the impetus to found the George Huntington Institute and pursue my way, totally focused on HD.

HD INSIGHTS: Could you comment on challenges and improvements in HD research?

REILMANN: The dream I had when I went into HD research is still driving me: to find a cure for HD. We must find a treatment that hits the causal mechanism of this disease. On top of that, we have the opportunity to introduce this treatment in the premanifest stage. This is something very new in medicine: currently, you need to show a benefit to the patient to get regulatory approval to use new drugs. We are challenged to leave this paradigm, because we have the potential to treat people before they become ill. The big studies like TRACK-HD1 and PREDICT-HD2 have quite successfully shown that we do have clinical trial endpoints that work in symptomatic HD, and we have gained a better understanding of how endpoints such as the Q-motor and UHDRS work even in premanifest stages. We have also learned how imaging can contribute to evaluating novel therapies, and we have opportunities to develop novel endpoints that will give us the chance to move therapies into the premanifest domain. This, I think, is the most exciting opportunity we have, above and beyond even HD: we could potentially do clinical trials that would allow us to introduce new therapies before people become sick. The HD community gives us the support of thousands of people who are keen to be involved in research. I think there is great potential for successfully completing clinical development programs and delivering novel therapies to HD patients.

HD INSIGHTS: You are involved in a number of HD clinical trials. Which do you find most promising?

REILMANN: I think a couple of promising compounds are around the corner. The HD field has attracted a lot of recent attention from different sponsors. Pridopidine has shown a potential benefit for motor disability in HD3. The drug has a very benign safety profile, so we are currently planning to start a new trial involving 50 centers and around 400 participants in North America, Europe and Australia, which will increase the dose of the drug compared to previous trials. Unfortunately, this is necessary because the first two trials were formally negative, as the primary endpoint did not reach its predefined significance level. But, it is nice to see this drug get another chance, because currently, we only have drugs available for lowering the amount of involuntary movements. Pridopidine would fill a gap that we have not been able to address in a positive way. We have other compounds for which we expect clinical trial results sometime soon. There’s the exploration of slow-release forms of tetrabenazine, which may create additional benefit to patients and lower potential side effects. And there are a number of other compounds currently being considered for symptom relief, such as PDE10A inhibitors (see HD Insights, Vol. 5). Then there is the buproprion trial in Europe, which is trying to address the problem of apathy in HD. And of course we are expecting the results of the large HSG trials with CoQ10, which will be interesting to hear. We have other sponsors looking into microglial activation patterns that could potentially be ameliorated, and we could also potentially have treatment trials with sRNA addressing the lowering of mutant huntingtin in HD patients. This was the target of a trial with Selisistat for which I was the PI with Siena Biotech, the results of which will soon be available. We will have to see which of these approaches will contribute to our long-term aim to actually change the disease progression of HD.

HD INSIGHTS: Dr. Reilmann, thank you for your time, and for your continuing dedication to HD care and research.

A logo worth a thousand words:

logoOur logo has an interesting story, which encapsulates the excitement about the Institute among the HD community here in Münster. One of the participants in my research is a graphic designer with premanifest HD. When I told him about the Institute, he was so excited that he asked to design a logo for us. I wanted something very traditional, like a seal that we could put on documents, but he had another vision. The logo he designed symbolizes the autosomal dominant inheritance pattern between two generations. Imagine that above the second ‘G’ of ‘George’ is an individual with the HD gene and a recessive normal gene, and on the other side, another individual with two normal genes. The lines symbolize four offspring, two of whom have inherited the disease. When I received the email from him, describing the philosophy behind this logo, I was quite moved. And I think it tells us a lot about what patients are thinking: they are thinking about how this disease affects the next generation.


1 Tabrizi SJ, Reilmann R, Roos RA, et al. Potential endpoints for clinical trials in premanifest and early Huntington’s disease in the TRACK-HD study: analysis of 24 month observational data. Lancet Neurol. 2012 Jan; 11(1):42-53.

2 Biglan KM, Zhang Y, Long JD, et al. Refining the diagnosis of Huntington disease: the PREDICT-HD study. Front Aging Neurosci. 2013 Apr 2;5:12.

3 Reilmann R. The pridopidine paradox in Huntington’s disease. Mov Disord. 2013 Sep; 28(10):1321-4. doi: 10.1002/mds. 25559. Epub 2013 Jul 11. PubMed PMID: 23847099.

Editor’s Letter

Welcome to the latest edition of HD Insights, timed for release at the HSG 2013 Annual Conference and Clinical Research Symposium in Charlotte, NC. HD Insights continues to bring the latest in HD research to the HD community, and we are grateful to the HSG, our sponsors, and our more than 1500 subscribers for their continuing support of this mission.

In this issue, we are pleased to bring you an interview with Dr. Ralf Reilmann, founder of the George Huntington Institute in Münster, Germany, and a longtime friend of the HSG. Dr. Reilmann shares the story of his new Institute and describes the most promising new therapies on the horizon for HD. For those who were unable to make it to Rio de Janeiro last month, Dr. Débora Maia brings us highlights from the 2013 World Congress on Huntington’s Disease. Dr. Lise Munsie gives us a roundup of current HD research in the lab, in the scanner, and in the clinic, and the HD Insights team updates you on HD clinical trials. We explore the current research on coenzyme Q10 in HD and PD, speaking with Drs. M. Flint Beal and Karl Kieburtz about their hopes for the ongoing 2CARE trial, and with Dr. Reilmann about the PREQUEL trial, the results of which will be presented at this year’s Clinical Research Symposium. Finally, PhD candidate Isaac Adanyeguh brings us the very latest from the Institut du Cerveau et de la Moelle Épinière (the Brain and Spine Institute) in Paris, where novel imaging techniques are helping to identify biomarkers of brain energy metabolism for use in clinical trials.

The HD community is fortunate to benefit from the increasing number of sponsors developing novel therapies for HD. HD Insights brings those sponsors—their leaders, their compounds, and their research—to more than 1500 readers around the globe. We rely on the support of these firms to continue to bring HD Insights to the community. If you are interested in becoming a supporter, please look for me at the HSG Meeting (I’m almost as tall as Ralf), or contact me at editor@hdinsights.org

We are always looking for new contributors, topics to cover, and suggestions for how we can better serve you, the HD research community. If you or someone you know is interested in contributing to HD Insights, or if you have ideas that you would like to share with 1500 HD researchers and clinicians around the world, please contact me at editor@hdinsights.org . And finally, subscription to HD Insights is always free: simply send us an email at subscribe@hdinsights.org .









Ray Dorsey, MD




Editorial Board Members

Ray Dorsey, MD — Editor, University of Rochester

Donald Kennedy, PhD — Stanford University

Nobuyuki Nukina, MD, PhD — Riken Brain Science Institute

Rodrigo Osorio — Agrupación Chilena de Huntington

Bernard Ravina, MD — Biogen Idec

Ralf Reilmann, MD, PhD — George Huntington Institute

Sarah Tabrizi, MBChB, PhD — University College London

Leslie Thompson, PhD — University of California Irvine

Huntington Study Group

Shari Kinel, JD — HSG Executive Director

Liz McCarthy, BA — HSG Administrative Manager


Isaac Adanyeguh, PhD Candidate

Débora P. Maia, MD L

Lise Munsie, PhD

Publication Staff

Meredith Achey, BM — Deputy Editor

Robin Taylor — Production Editor

Martin Holmes — Technical Editor

Todd Bernhard — Copy Editor

Dave Kolko — Distribution Specialist


For more information on HD Insights, or to receive a free subscription, please visit us at www.hdinsights.org  or email us at editor@hdinsights.org .

HD Research Around the World: France

franceImaging Brain Metabolic Markers at the Institut du Cerveau et de la Moelle Épinière (ICM), Paris

By: Isaac M. Adanyeguh

In addition to the well-known neurological phenotype, HD presents with non-neurological symptoms that suggest hyper-catabolism in the early stage of the disease, leading to significant weight loss1. Metabolic dysfunction is therefore a major focus of HD research and may be easily amenable to therapeutic intervention2. Our team has shown that dietary anaplerotic therapy can improve peripheral energy metabolism in HD patients3. We also emphasized the potential of non-invasive 31- phosphorus magnetic resonance spectroscopy (31P MRS) in biomarker identification3. However, a sensitive biomarker of brain energy metabolism in HD patients has yet to be identified. Our team at ICM, Hôpital Pitié- Salpêtrière in Paris, led by Prof. Alexandra Durr and Dr. Fanny Mochel, is therefore interested in identifying biomarkers that reflect brain energy metabolism that could be used in therapeutic trials in HD patients.

To identify sensitive brain metabolic markers based on the results obtained in muscle3, we recruited 15 HD patients in the early stage of HD, but who were without significant cognitive impairment, and 15 age- and sex-matched controls, as subjects for brain 31P MRS on a 3T Siemens Magnetom Trio system. We targeted the visual cortex for the single-voxel functional MRS because it is easily stimulated and has high energy metabolism (Figure 1a). It is also very close to the scalp, giving an increased sensitivity to the small surface coils. A 6 cm 31P transmit/receive surface coil (Figure 1b) was used to detect signals (free induction decays – FIDs) from the visual cortex for 4 minutes at rest (baseline), 8 minutes during visual activation, and 8 minutes after visual stimulation (recovery), while limiting signals from other brain regions. A small sphere 10 mm in diameter filled with water and placed below the coil along the coil axis helped to verify and adjust the position of the 31P coil on T1 images (Figure 1a). Visual stimulation was performed with 6 Hz red and black checkerboard flashes (Figure 1c) generated in MATLAB and projected by a video projector onto a screen at the beginning of 8 minutes of stimulation. Subjects were able to focus on the flashes with a nonmagnetic mirror mounted above their eyes.

Figure 1: a) T1-weighted image with highlighted visual cortex showing the position of the sphere filled with water. The black square shows the region used for localized 1H shimming. The dashed white line indicates the sensitive volume of the coil encompassing most of the visual cortex.

Figure 1a:
T1-weighted image with highlighted visual cortex showing the position of the sphere filled with water. The black square shows the region used for localized 1H shimming. The dashed white line indicates the sensitive volume of the coil encompassing most of the visual cortex.

Figure 1: b) The 6 cm 31P transmit/receive coil in a holder with mounted mirror used in the lab.

Figure 1b:
The 6 cm 31P transmit/receive coil in a holder with mounted mirror used in the lab.

Figure 1: c) Red and black checkerboard used for visual stimulation

Figure 1c:
Red and black checkerboard used for visual stimulation.












We obtained 31P spectra from our MRS protocol in the brain (Figure 2). Analysis of the 31P spectra in the time domain using jMRUI software allowed the quantification of energy metabolites ATP, Pi and PCr. The ratio of Pi/PCr was then calculated to determine the brain response to cortical activation. The Pi/PCr ratio has been linked to mitochondrial activation and it provides an index of mitochondrial oxidative regulation4. At rest, there was no significant difference in Pi/ PCr ratio between HD patients and control subjects. Visual stimulation allowed us to analyse the evolution of the Pi/PCr ratio in HD and control subjects. The Bonferroni-corrected Wilcoxon signed-rank test indicated an 11% increase in Pi/PCr ratio between rest and activation (P = 0.024), followed by a decrease between activation and recovery (P = 0.012) in controls (Figure 3). In contrast, no difference was found between the three stages for the HD group for Pi/PCr ratio (Figure 3).

Figure 2: Representative 31P spectrum obtained at 3T with well-defined high-energy phosphate metabolites from the visual cortex of a control subject.

Figure 2:
Representative 31P spectrum obtained at 3T with well-defined high-energy phosphate metabolites from the visual cortex of a control subject.

Figure 3: Pi/PCr ratio before, during and after visual stimulation of 15 HD patients and 15 age- and sex-matched controls. Bonferroni-corrected Wilcoxon signedrank test indicated increased Pi/PCr between rest and activation (p = 0.024a) followed by a decrease between activation and recovery (p = 0.012b). No change was observed in patients (p > 0.05).

Figure 3:
Pi/PCr ratio before, during and after visual stimulation of 15 HD patients and 15 age- and sex-matched controls. Bonferroni-corrected Wilcoxon signedrank test indicated increased Pi/PCr between rest and activation (p = 0.024a) followed by a decrease between activation and recovery (p = 0.012b). No change was observed in patients (p > 0.05).












Because the observed changes were relatively small, a subsequent study will allow us to further explore the use of Pi/ PCr ratio as an outcome measure in HD clinical trials. Recruiting patients from the previous study will allow us to test the reproducibility of the initial findings in the same patient population and measure longitudinal changes. New patients at the early stage of the disease will also be recruited to validate our findings in an independent study population. In addition, we wish to include premanifest individuals to assess whether an abnormal brain energy profile can be identified before onset of overt HD symptoms, which is essential for development of future therapies.


1 Mochel F, Charles P, Seguin F, et al. Early energy deficit in Huntington disease: identification of a plasma biomarker traceable during disease progression. PLoS ONE. 2007 Jul 25; 2(7):e647. doi:10.1371/journal.pone.0000647.

2 Mochel F, Haller RG. Energy deficit in Huntington disease: why it matters. J Clin Invest. 2011 Feb 1;121(2):493–499. doi: 10.1172/JCI45691.

3 Mochel F, Duteil S, Marelli C, et al. Dietary anaplerotic therapy improves peripheral tissue energy metabolism in patients with Huntington’s disease. Eur J Hum Genet. 2010 Sep; 18(9):1057-60. doi: 10.1038/ejhg.2010.72. Epub 2010 May 26.

4 Weiner DH, Fink LI, Maris J, et al. Abnormal skeletal muscle bioenergetics during exercise in patients with heart failure: role of reduced muscle blood flow. Circulation. 1986 Jun; 73(6):1127-36.

HD Insights Volume 6 (PDF)