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We found that premanifest HD gene carriers had more disrupted sleep, characterized by a fragmented sleep profile, meaning more time spent awake during the night see Figure ; increased objective daytime sleepiness; and alterations in sleep-dependent brain activity as measured by EEG, with a clear association with increasing disease burden. In addition, the development of these abnormalities coincided with the development of cognitive, affective, and subtle motor deficits, and preceded any metabolic alterations.

These new sleep results in patients are in line with reports from transgenic rodent models of HD that report gradually worsening sleep quality from a very early stage, and together raise many interesting questions. What causes these early sleep disturbances? What is their significance in the early cognitive deficits and the onset and progression of the disease? These questions remain to be investigated.

Finally, it remains to be established whether therapeutic sleep quality improvement could help premanifest and manifest patients with HD to reduce the cognitive symptoms or even slow down the disease process, as suggested by earlier studies performed in transgenic animal models of HD.

Sleep, cognition, and normal aging: integrating a half century of multidisciplinary research. Perspect Psychol Psy. Connections between sleep and cognition in older adults. Lancet Neurol. Nat Rev Neurol. Sleep and Alzheimer disease pathology—a bidirectional relationship. Sleep disturbance in mental health problems and neurodegenerative disease. Nat Sci Sleep. Exp Neurol. Rapid eye movement sleep disturbances in Huntington disease.

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Arch Neurol. J Neurol. A Cross-sectional Cohort Study. Nocturnal agitation in Huntington disease is caused by arousal-related abnormal movements rather than by rapid eye movement sleep behavior disorder. Sleep Med. J Neurosci. Curr Neurol Neurosci. J Neurol Neurosur PS. Ann Neurol. Brain Res. Chaired by Dr. Ray Dorsey and co-chaired by Dr.

The 9 th Annual HD Clinical Research Symposium took place in the morning of the final day, followed by a family-oriented educational program for members of the HD community. Working group sessions covering care, education, behavior, and rehabilitation aspects of HD were available to all attendees, enabling both expert and junior researchers to discuss recent developments in their specific fields of interest.

Ray Dorsey discussed the recent progress of the HSG and provided an insight into the directions the group wishes to pursue in the next five years. He acknowledged the success of the Phase III trial for SD, which concluded that the compound not only improved chorea symptoms, but also total motor score, functional, and quality of life measures. Dorsey also highlighted new online initiatives that allow patients, families, and researchers to communicate more freely and easily, including the updated HSG Link website , and recent ventures into social media Twitter and Facebook.

He provided hope to families, stating that HD can become a treatable disease comparable to the management of multiple sclerosis or HIV. Kevin Biglan , Ms. Chandler Swope , and Ms. David Corey , Dr. Lisa Stanek and Prof. Sarah Tabrizi covered the exciting new therapeutic area of gene silencing , introducing attendees to the basic cellular mechanisms, as well as the potential benefits and risks.

Volume 13 – #7 – July 2010

Erika Bjorklund , speaking from her own experiences about how to deal with a diagnosis of HD in the family. Kyle Fink described the prospect of using mesenchymal stem cells as a potential therapy. The keynote address on gene silencing by Dr. Juan Sanchez-Ramos echoed a recurring theme from the conference, expressing optimism that together, the HD community will be able to find a way to stop the progression of this disease.

HD is due to a dominantly inherited CAG trinucleotide repeat expansion in the HTT gene that is both necessary and sufficient to cause clinical manifestations. The size of the expanded CAG repeat largely determines the rate of the pathogenic process that leads to clinical symptoms of HD.

However, the size of the expansion does not perfectly predict individual age at onset of clinical disease, suggesting the existence of genetic and possibly environmental disease modifiers that interact with HTT -driven disease pathogenesis to alter the timing of clinical symptoms of HD. In order to identify human genetic factors capable of delaying or hastening age at onset of motor signs, the GeM-HD Consortium capitalized on the power of genome -wide association GWA analysis by using naturally occurring single-nucleotide polymorphisms SNPs in the DNA as genetic markers.

DNA samples were collected from 4, HD patients to determine genome -wide SNP genotypes and, from corresponding clinical information, the difference between observed and CAG-predicted age at onset i. Subsequent statistical analysis aimed at identifying genetic variations correlated with residual age at onset revealed two genome -wide significant regions representing three independent modifier effects. A region on chromosome 15 harbors two independent modifier association signals in the HD population: one that hastens age at onset by approximately 6 years, and the other that delays it by approximately 1.

A region on chromosome 8 carries a modification signal that delays onset by approximately 1.

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These findings demonstrate that HD can be modified prior to clinical disease onset, supporting the potential of genetic modifier pathways as therapeutic targets. Many additional genetic modifiers may still remain undetected in this 4,person GWA study due to sample size and to the magnitude of individual modifier effects. Observations that HTT participates in a wide variety of cellular functions support the likelihood that there may be numerous genetic modifiers of HD. We strongly advise that the data be interpreted with care; for example, as most SNP signals represent indirect association, the location of the SNP does not necessarily implicate the nearest gene.

Nevertheless, the discovery of significant genetic modifiers of HD provides the proof of principle that disease modification in HD is possible. The GeM MOA website is designed to accelerate the search for targets for development of therapeutic interventions, validated in humans, that are effective before the emergence of clinical disease. J Huntingtons Dis. Edited by Drs. To read about the beginnings of the journal, see HD Insights, Vol. He took a few moments to share his thoughts with HD Insights on the compound, Roche, and the future of HD therapeutics.

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The following is an edited transcript of the conversation. We consider our collaboration with Ionis Pharmaceuticals in HD to be true to this strategy. The particular thing that attracted us is that Ionis has generated a huntingtin antisense oligonucleotide ASO. This is a second-generation antisense therapy—the first to enter clinical development—designed to reduce the production of all forms of HTT , including mHTT. The life-transforming potential of this ASO made it a very attractive opportunity for us.

Can you tell us about that? They are in charge of development until the end of Phase I. The assay has not been widely used, and has never been used in a clinical trial.

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Ed Wild and Dr. Amber Southwell. These assays appear to be ready for prime time. The other exciting aspect of the assays is that they track disease stage, and associate with clinical severity, at least in cross-section. We want to learn more about how those assays perform longitudinally in terms of their test-retest reliability.

A forthcoming study — the HDClarity study — will hopefully elucidate that. That would be a very exciting first-in-human clinical accomplishment. Are there any other major outcomes of interest?

Any other positive outcomes we might observe in Phase I would be a pleasing upside. The treatment duration is probably insufficient to result in disease modification. The sample size is also very small, so I think that any effects we might see on motor or cognitive functioning, or an overall sense of well-being, for example, would be pleasing, but not what we really expect.


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From there, we are looking together towards the future of the program, what an integrated program may look like, as well as clinical development options. I consider this to be a process. We are engaging in collaborative discussions with stakeholders and therapeutic experts.

We are also actively engaged in a disease-modeling effort to help us better design clinical efficacy trials.

mantmepadubul.gq This has been made possible in part through generous sharing of datasets from academic investigators, including Dr. Jane Paulsen of the University of Iowa. We are planning for success now and in the future, but of course we are waiting for the Phase I data to formally trigger planning of later trials. We are mapping it out right now.