Volume 2

HD Insights Volume 2 (PDF)

Meet the Journal


Leslie Thompson, PhD

Leslie Thompson, PhD

Blair Leavitt, MD

Blair Leavitt, MD


NAME: Journal of Huntington’s Disease

EDITORS-IN-CHIEF: Blair Leavitt, MD and Leslie Thompson, PhD

PUBLISHERLeslie Thompson, PhD: IOS Press

SUBSCRIPTION MODEL: Subscription and open access

SUBMISSION SITE: http://www.iospress.nl/journal/journal-of-huntingtons-disease/.

Please email info@isopress.nl with questions regarding manuscript submission.


The Journal of Huntington’s Disease launches in early 2012. The journal has a renowned editorial board and is currently accepting papers for peer review. Manuscripts will be published online and in quarterly print publications. At the 2011 Huntington Disease Clinical Research Symposium in Indianapolis, IN, Dr. Blair Leavitt sat down with HD Insights to discuss the new journal. Dr. Leslie Thompson also shared her thoughts on the new journal via email correspondence.

INSIGHTS: Why a new journal for HD?

THOMPSON: We want to have a single source bringing together all the various aspects of basic and clinical HD research. The field has grown significantly and we feel this would be of great benefit to HD researchers, clinicians, and other HD community members.

LEAVITT: We think there is a niche and a need for this. Given the number of publications each year in the field of HD, it was time for a journal dedicated specifically to HD.

INSIGHTS: How will the Journal of Huntington’s Disease be different from Movement Disorders, or Neurology or other journals that publish articles related to HD?

THOMPSON: The journal will also include meeting announcements, editorials, special interest pieces and reviews.

INSIGHTS: Why has it taken so long for a journal to be developed focused on HD?

LEAVITT: This journal has evolved out of sister journals that have really been quite successful, such as the Journal of Alzheimer’s Disease and the Journal of Parkinson’s Disease. Dr. Patrik Brundin, the editor-in-chief of the Journal of Parkinson’s Disease, was the first to suggest that we should do this for HD. We think the field is ready for it.

THOMPSON: The field has grown over time to include hundreds of researchers, and interest in pharmaceutical development has grown. With the known mutation for the disease comes the opportunity for HD to serve as a paradigm for other neurodegenerative diseases.

INSIGHTS: What should reviewers expect?

THOMPSON: Clinical, basic science, patient care, and historical perspective manuscripts. We are working with the editorial board with the goal of reviewing high quality manuscripts.

LEAVITT: Reviewers should also expect fast but rigorous peer review, and rapid online publication.

INSIGHTS: What should readers expect?

LEAVITT: A one-stop journal, where they can see important and timely articles on all aspects of HD. In the same issue they can expect to see articles addressing issues of ethics, and issues relating to genetic testing. At the same time, they might see an article about basic molecular biology, or pathogenic studies on HD. They might also see an article looking at transgenic mouse models right beside one that looks at a similar study in humans.

INSIGHTS: Thank you for speaking with us, and good luck with the new journal.

Highlights from the 2011 Huntington Study Group Meeting

By: David Shprecher, DO, MS

The two-day meeting and scientific symposium was held in Indianapolis, Indiana

The two-day meeting and scientific symposium was held in Indianapolis, Indiana

In November 2011, the Huntington Study Group hosted its annual meeting and the Fifth Annual Huntington Disease Clinical Research Symposium.

Huntington Study Group Meeting

NIH Endeavors

Elizabeth Thompson, DNSc, RN, CGC, FAAN discussed special genetic research considerations, including consent, reporting results, and data sharing. The Database of Genotype & Phenotype (dbGaP) has been developed to improve dissemination of results and data sharing.1


Elizabeth Aylward, PhD overviewed the PREDICT-HD team’s identification of potential neuroimaging biomarkers that are reliable across sites, and that show cross-sectional outcomes associated with disease burden.2

Christopher Ross, MD, PhD discussed considerations for the use of neuroimaging biomarkers, including MR spectroscopy and functional MRI. Early in HD, findings of altered glutamate levels or functional connectivity patterns could reflect cell dysfunction rather than cell death.

Bernhard Landwehrmeyer, MD presented imaging data from the TRACK-HD team.3 Brain atrophy, which is a reliably detectable change in HD gene mutation carriers, was less distinct in carriers furthest from the projected onset of manifest HD symptoms.4

Fifth Annual Huntington Disease Clinical Research Symposium

Mary Edmondson, MD discussed how her career as a neurologist was influenced by her father, HC Canning, who lost his battle with HD in 1995.

Karen Anderson, MD reviewed behavioral changes associated with HD. Suicide in HD patients may be prevented by delaying a patient’s actions to allow impulsive thoughts or rage to pass.


Mark Groves, MD discussed a treatment algorithm, developed from an international survey of clinicians, for pharmacological treatment of irritability and perseverative behaviors in HD patients. 5 6

Eric Epping, MD PhD and Kevin Biglan, MD MPH presented PREDICT-HD data findings. 7 HD symptoms are reported more frequently by companions than by patients, and this apparent loss of patient insight into their symptoms worsens following diagnosis of manifest symptoms. Identifying and clinically defining disease onset is a challenge; multidimensional diagnosis results in earlier diagnosis and allows for identification of clinical phenotypes that are predominantly cognitive or predominantly behavioral.

Karen Marder, MD MPH reviewed the role of diet and exercise in HD. There is evidence for metabolic defects in HD. Individuals can maintain their weight with increased caloric intake.

Steve Hersch, MD PhD presented data on the transcriptional modulator H2A histone family member Y.8 This is a biomarker, expressed in both blood and brain, that completely distinguishes HD expansion carriers from non-carriers.

Research Round-Up

By: Lise Munsie and Mahmoud Pouladi, PhD

In the scanner…

Huntington disease (HD) imaging data is providing new insights into the mechanism of disease, and is also providing sensitive biomarkers. Identification of biomarkers is critical to the success of clinical trials of disease-modifying therapeutic agents. Imaging techniques include magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS) and functional MRI (fMRI). The TRACK-HD team led by Prof. Sarah Tabrizi has now published its 24-month data, which supports the 12-month data from the team’s previous report, showing that imaging markers are the most effective method to detect disease-related group differences in premanifest and early HD patient groups.1 The team’s data also indicates that striatal and total white matter atrophy are the most sensitive anatomical measures of premanifest HD. Di Paola and colleagues used MRI to investigate changes in the corpus callosum, which has the largest white matter tract in the human brain.2 Their findings complement those of the TRACK-HD study; white matter changes in the corpus callosum in premanifest and early HD suggest that the corpus callosum may be a key structure in the development of the neuropathology of HD. MRI-observable changes in corpus callosum white matter may be a biomarker in the progression of HD. Zacharoff and colleagues published data on the R6/2 mouse model of HD.3 They used MRS to investigate changes in brain metabolites, and MRI to assess changes in brain volume. They found that changes in brain metabolites manifest before changes in brain volume. This data aids in validating HD mouse models for use in drug discovery and target design.

 In the lab…

Two studies in the December 2011 issue of Nature highlight Sirt1, an NAD-dependent protein deacetylase implicated in the regulation of cellular metabolism, as a potential therapeutic target for HD.

Jiang and colleagues demonstrated that mutant huntingtin (mHTT) inhibits Sirt1 deacetylase activity, which alters the acetylation status of a number of its substrates such as FoxO3a, and influences their function.4 Knockdown of Sirt1 in vitro exacerbated mHTT-mediated toxicity, whereas overexpression of Sirt1 restored the concentrations of acetylated FoxO3a and p53 to baseline levels and protected against mHTT toxicity. The authors reported that in N171-82Q and BACHD mice, overexpression of Sirt1 improved motor function and reduced neuropathology, including striatal and cortical atrophy. In N171-82Q mice some metabolic parameters were improved, including improved insulin sensitivity as shown by attenuated hyperglycaemia and decreased plasma insulin levels; improved glucose tolerance; and attenuated body weight loss. Jeong and colleagues examined the effect of modulation of Sirt1 levels in R6/2 mice.5 Brainspecific knockdown of Sirt1 worsened motor dysfunction and exacerbated striatal atrophy. Conversely, global overexpression of Sirt1 attenuated striatal atrophy and was associated with restoration of BDNF levels. Although there is a disconnect in the impact of Sirt1 overexpression on survival, body weight, and mHTT aggregates in the N171-82Q and R6/2 mice, these studies highlight a role for Sirt1 in the pathogenesis of HD. The neuroprotective effects of Sirt1 show that it is a potential therapeutic target for HD.

In the clinic…

Neuropsychiatric disturbances are common in HD patients, and two recent studies explore depression and apathy. Richards and colleagues exploited the richness of the data repository assembled as part of the European Huntington’s Disease Network REGISTRY Study, to examine the discriminant value of items on two depression rating scales, namely the Beck Depression Inventory (BDI), and the Hamilton Rating Scale for Depression (HAM-D).6 Using a discriminant analysis method, the authors found that items from the BDI were more likely than items from the HAM-D to discriminate depressed mood HD patients from those without depressed mood. Loss of interest, guilt, and suicidal thoughts were the best discriminators of depressed mood. Weight loss, measures of sleep disturbances, and irritability were poor discriminators of depressed mood. This study can assist in the development of refined measures of depression in HD patients. Reedeker and colleagues examined the incidence, course and predictors of apathy in HD in a prospective study.7 Patients were assessed using a modified version of the Apathy Evaluation Scale at baseline, and re-assessed after two years. Of the patients who completed the study, 14% who were free of apathy at baseline later developed apathy. The development of apathy in these patients was associated with a lower baseline Mini-Mental State Exam score, supporting a role for cognitive dysfunction in the development of apathy in HD. Of 34 patients with apathy at baseline, 14 subjects were no longer apathetic at follow-up, indicating that apathy in HD is reversible, and suggesting that targeting treatable causes of apathy may aid in combating apathy in HD.


1 Tabrizi SJ, Reilman R, Roos RAC, 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; 11(1): 42-53.

2 Di Paola M, Luders E, Cherubini A, et al. Multimodal MRI analysis of the corpus callosum reveals white matter differences in presymptomatic and early Huntington’s disease. Cerebral Cortex. 2012 Jan 5 [Epub] doi:10.1093/ cercor/bhr360

3 Zacharoff L, Tkac I, Song Q, et al. Cortical metabolites as biomarkers in the R6/2 model of Huntington’s disease. Journal of Cerebral Blood Flow & Metabolism. 2011 1-13.

4 Jiang M, Wang J, Fu J, et al. Neuroprotective role of Sirt1 in mammalian models of Huntington’s disease through activation of multiple Sirt1 targets. Nat Med. 2011 Dec 18; 18(1):153-8.

5 Jeong H, Cohen DE, Cui L, Supinski A, et al. Sirt1 mediates neuroprotection from mutant huntingtin by activation of the TORC1 and CREB transcriptional pathway. Nat Med. 2011 Dec 18; 18(1):159-65.

6 Rickards H, Souza JD, Crooks J, et al. Discriminant Analysis of Beck Depression Inventory and Hamilton Rating Scale for Depression in Huntington’s Disease. J Neuropsychiatry Clin Neurosci. 2011 Sep 1;23(4):399-402.

7 Reedeker N, Bouwens JA, van Duijn E, et al. Incidence, Course, and Predictors of Apathy in Huntington’s Disease: A Two-Year Prospective Study. J Neuropsychiatry Clin Neurosci. 2011 Sep 1; 23(4):434-41.

Inside the NINDS with Dr. Walter Koroshetz

Dr. Walter Koroshetz became Deputy Director of the National Institute of Neurological Disorders and Stroke (NINDS) in 2007. He received his medical degree from the University of Chicago and trained in neurology at Massachusetts General Hospital (MGH). After completing his residency, he was introduced to the HD Center without Walls at MGH and Boston University. He started seeing patients with HD and became involved in the first pre-symptomatic testing for HD. Dr. Koroshetz was also involved in early HD imaging research, and helped discover the effect of HD on lactic acid levels in the brain.1

At the 2011 Huntington Disease Clinical Research Symposium in Indianapolis, Indiana, Dr. Koroshetz sat down with HD INSIGHTS to discuss his role as Deputy Director of NINDS and the NIH’s new project, NeuroNEXT.


walter korshetz

Walter Koroshetz, MD

NAME: Walter Koroshetz, MD

CURRENT POSITION: Deputy Director of the National Institute of Neurological Disorders and Stroke

PREVIOUS POSITIONS: Vice Chair of the Neurology Service at Massachusetts General Hospital; Director of Stroke and Neurointensive care at Massachusetts General Hospital; Professor of Neurology at Harvard Medical School

EDUCATION: MD, The University of Chicago

HOBBY: Long-distance bicycle trips. Most recent ride was 50 miles from Arlington, Virginia to Purcellville, Virginia and took 4.5 hours.



INSIGHTS: What motivated your transition from academia to the NIH?

KOROSHETZ: I was at a point in my career where I had done a bunch of things, and there were a number of leadership opportunities opening up. One of them happened to be this job at the NIH, which I thought was unique. There’s only one Deputy Director of NINDS in the country, and you get an experience that is quite unique, that no one else really sees. You get to see neuroscience, neurology, policy and government from a unique vantage point.

INSIGHTS: Has it been interesting?

KOROSHETZ: Yes. It’s like being a kid in a candy shop. If you’re interested in all sorts of different neurologic issues, it’s the best place to be because you see everything. I may have meetings on three different diseases in one day. If you have ADHD for neurology, it’s a great job!

INSIGHTS: Were there any drawbacks?

KOROSHETZ: There’s clearly a big difference when you go from being in an academic institution to being in an administrative job in government. So I certainly miss a lot of the interactions I had with patients, young physicians, residents, fellows, colleagues in the trenches. There’s nobody really in the trenches with me anymore. I’m kind of there by myself.

INSIGHTS: Turning to the NIH funding outlook, it has been a very tough time for the NIH in terms of its budget. In 2011, NIH spent $65 million on research on Huntington disease. Is that enough?

KOROSHETZ: No, but unfortunately, we could say that about every disease. No disease is getting too much, as far as I can see. There are now unique opportunities in neuroscience to make advances in lots of different diseases, and I think the pace at which that happens depends on what resources you have available. We still get quite a bit of money, so the taxpayers’ investment of $31 billion to the NIH is something I think the country can be proud of.

INSIGHTS: Given limited resources, what are your top priorities for Huntington disease?

KOROSHETZ: My thoughts are that we have an opportunity with a penetrant dominant genetic disorder to really try and understand how to block the pathology before it happens. Huntington disease is a nice example of how basic science, disease science, and human studies can come together and hopefully come up with a new treatment that slows down the disease. And the great thing about it is, if we do find something that slows down the disease in patients, we have the opportunity to identify people before they have the disease, and treat even before the disease becomes manifest. From the NIH point of view, Huntington is a very attractive disease.

INSIGHTS: The NIH is trying to facilitate clinical research and clinical trials in neurology with a program called NeuroNEXT. Can you tell us what NeuroNEXT is?

KOROSHETZ: NeuroNEXT is a network of sites throughout the country that have come together to do very innovative biomarker studies and phase two clinical trials in neurological disorders. And there is a really good group of committed principal investigators at the 25 sites. Dr. Merit Cudkowicz, who has been active in the HSG, is the principal investigator of the coordinating center; Dr. Karen Marder is on the steering committee as the principal investigator from Columbia. We have a lot of hope that this group will be able to partner with industry and academicians and be the first to test innovative and exciting treatments in humans.

INSIGHTS: What does it mean for investigators?

KOROSHETZ: For investigators working on therapies, this is a potential avenue by which therapies can get to patients, to test, and see whether they really hit proof-of-principle or target engagement. For industry investigators, there’s a potential mechanism that they could use to test whether their drugs are actually engaging their anticipated targets. For disease organizations who are involved in funding Huntington research in the early stages, if there’s a really promising drug that meets a good score with peer review, this network could be testing those drugs.

INSIGHTS: How can industry work with NeuroNEXT?

KOROSHETZ: We have mechanisms by which the NIH can enter a cooperative research agreement with industry to try and protect their intellectual property as one of their drugs comes into the network for testing. We would be looking for co-funding, in some instances, to get this done. But if we have an efficient network that can really quickly do high-quality studies in patients, then I think that would be of benefit to industry as well.

INSIGHTS: You say co-funding. Does that mean the NIH would help companies investigate their own drugs?

KOROSHETZ: Absolutely. If they think they’re going to make a difference for patients, we’re definitely interested in partnering with industry to do that.

INSIGHTS: A pharmaceutical company might think that working with the NIH means a lot of bureaucracy in a long time horizon that usually isn’t compatible with the pharmaceutical industry’s priorities. How will NeuroNEXT address that?

KOROSHETZ: At NeuroNEXT, we put together mechanisms by which companies come in with an idea, and get a turnaround time that’s very quick with regards to whether there’s interest on the part of the institute and the network to move forward with that proposal. I think for a large number of industry applications, we can really shorten the turnaround time, and still try to compete in terms of going as fast as industry trials could.

INSIGHTS: Thank you Dr. Koroshetz for talking with us today.


  1. Jenkins BG, Rosas HD, Chen YC, Makabe T, Myers R, MacDonald M, Rosen BR, Beal MF, Koroshetz WJ. 1H NMR spectroscopy studies of Huntington’s disease: correlations with CAG repeat numbers. Neurol. 1998; 50(5): 1357-65.