CHDI Advisory Board Meeting, Princeton, 9-10 March 20091

Huntington’s Disease Sleep Medical Advisory Meeting9-10 March 2009Princeton, NJ

Report prepared by Susanna J Dodgson BSc(Hons), PhD
Principal, Emerald Pademelon Press, LLC
PO Box 381, Haddonfield, New Jersey 08033
609-792-1571

27 March 2009

Huntington’s Disease Sleep Medical Advisory Meeting 9-10 March 2009 Princeton, NJ

Table of Contents

Introductions and welcome to the CHDI Clinical Protocol Advisory Board Joseph Giuliano, Director, Clinical Operations

Meeting leader

Advisors

CHDI Attendees

Overview of CHDI Goals and Objectives for Sleep in HD Daniel van Kammen MD, PhD, CHDI Chief Medical Officer

Advisory Board Discussion

Sleep and Circadian Abnormalities in Huntington’s Disease: Clinical Indications and Animal Models Thomas Kilduff PhD, Stanford Research Institute

Advisory Board Discussion

Overview of Clinical Research in Sleep and HD Francis Walker MD, Wake Forest University School of Medicine

Advisory Board Discussion

Clinical studies on sleep in patients living with Huntington’s Disease Anna Goodman PhD, Cambridge Centre for Brain Repair

Overview of Effects of Sleep Deficits on Cognition Phyllis Zee MD, PhD, Northwestern University School of Medicine

Open forum

Tuesday Advisory Board Discussion

Reference 1: Definition of Huntington’s Disease

Reference 2: Riemersma-van der Lek RF, Swaab DF, Twisk J, Hol EM, Hoogendijk WJ, Van Someren EJ. Effect of bright light and melatonin on cognitive and noncognitive function in elderly residents of group care facilities: a randomized controlled trial. JAMA. 2008 Jun 11;299(22):2642-55. Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, Amsterdam, The Netherlands.

Reference 3: Petersén A, Gil J, Maat-Schieman ML, Björkqvist M, Tanila H, Araújo IM, Smith R, Popovic N, Wierup N, Norlén P, Li JY, Roos RA, Sundler F, Mulder H, Brundin P. Orexin loss in Huntington’s disease. Hum Mol Genet. 2005 Jan 1;14(1):39-47. Epub 2004 Nov 3. Department of Physiological Sciences, Section for Neuronal Survival, Lund, Sweden.

Reference 4: Heng MY, Tallaksen-Greene SJ, Detloff PJ, Albin RL. Longitudinal evaluation of the Hdh(CAG)150 knock-in murine model of Huntington’s disease. J Neurosci. 2007 Aug 22;27(34):8989-98. Neuroscience Graduate Program and Department of Neurology, University of Michigan, Ann Arbor, Michigan 48109, USA.

Reference 5: Morton AJ, Lagan MA, Skepper JN, Dunnett SB. Progressive formation of inclusions in the striatum and hippocampus of mice transgenic for the human Huntington’s disease mutation. J Neurocytol. 2000 Sep;29(9):679-702. Departments of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QJ, UK.

Reference 6: Goodman AO, Murgatroyd PR, Medina-Gomez G, Wood NI, Finer N, Vidal-Puig AJ, Morton AJ, Barker RA. The metabolic profile of early Huntington’s disease—a combined human and transgenic mouse study. Exp Neurol. 2008 Apr;210(2):691-8. Epub 2008 Jan 19. Cambridge Centre for Brain Repair, E.D. Adrian Building, Forvie Site, Robinson Way, Cambridge, CB2 2PY, UK.

Reference 7. Morton AJ, Wood NI, Hastings MH, Hurelbrink C, Barker RA, Maywood ES. Disintegration of the sleep-wake cycle and circadian timing in Huntington’s disease. J Neurosci. 2005 Jan 5;25(1):157-63. Erratum in: J Neurosci. 2005 Apr 13;25(15):3994. Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, United Kingdom.

Reference 8. Pallier PN, Maywood ES, Zheng Z, Chesham JE, Inyushkin AN, Dyball R, Hastings MH, Morton AJ. Pharmacological imposition of sleep slows cognitive decline and reverses dysregulation of circadian gene expression in a transgenic mouse model of Huntington’s disease. J Neurosci. 2007 Jul 18;27(29):7869-78. Department of Pharmacology , University of Cambridge, Cambridge CB2 1PD, United Kingdom.

Reference 9. Pallier PN, Maywood ES, Zheng Z, Chesham JE, Inyushkin AN, Dyball R, Hastings MH, Morton AJ. Pharmacological imposition of sleep slows cognitive decline and reverses dysregulation of circadian gene expression in a transgenic mouse model of Huntington’s disease. J Neurosci. 2007 Jul 18;27(29):7869-78. Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, United Kingdom.

Reference 10: Scammell TE, Willie JT, Guilleminault C, Siegel JM; International Working Group on Rodent Models of Narcolepsy. Collaborators: de Lecea L, Erman MK, Guilleminault C, Kelz MB, Kilduff TS, Kubin L, Leonard CS, Mignot E, Mochizuki T, Nishino S, Peever JH, Saper CB, Scammell TE, Siegel JM, Shiromani PJ, Willie JT, Wisor JP. A consensus definition of cataplexy in mouse models of narcolepsy. Sleep. 2009 Jan 1;32(1):111-6. Department of Neurology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215, USA.

Reference 11: Thankachan S, Kaur S, Shiromani PJ. Activity of pontine neurons during sleep and cataplexy in hypocretin knock-out mice. J Neurosci. 2009 Feb 4;29(5):1580-5. West Roxbury Veterans Administration Medical Center and Harvard Medical School, West Roxbury, Massachusetts 02132, USA.

Reference 12: van Duijn E, Kingma EM, Timman R, Zitman FG, Tibben A, Roos RA, van der Mast RC. Cross-sectional study on prevalences of psychiatric disorders in mutation carriers of Huntington’s disease compared with mutation-negative first-degree relatives. J Clin Psychiatry. 2008 Nov;69(11):1804-10. Epub 2008 Nov 4. Department of Psychiatry, Leiden University Medical Center, B1-P, P.O. Box 9600, 2300 RC Leiden, The Netherlands.

Reference 13: Videnovic A, Leurgans S, Fan W, Jaglin J, Shannon KM. Daytime somnolence and nocturnal sleep disturbances in Huntington disease. Parkinsonism Relat Disord. 2008 Nov 26. [Epub ahead of print] Department of Neurology, Feinberg School of Medicine, Northwestern University, 710 N Lake Shore Drive #1106, Abbott Hall, Chicago, IL 60611, USA.

Reference 14: Buysse DJ, Reynolds CF 3rd, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res. 1989 May;28(2):193-213.Department of Psychiatry, University of Pittsburgh School of Medicine, PA.

Reference 15: Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep. 1991 Dec;14(6):540-5. Sleep Disorders Unit, Epworth Hospital, Melbourne, Victoria, Australia.

Reference 16: Arnulf I, Nielsen J, Lohmann E, Schiefer J, Wild E, Jennum P, Konofal E, Walker M, Oudiette D, Tabrizi S, Durr A, Schieffer, J [corrected to Schiefer, J].Rapid eye movement sleep disturbances in Huntington disease. Arch Neurol. 2008 Apr;65(4):482-8. Erratum in: Arch Neurol. 2008 Nov;65(11):1478. Pathologies du Sommeil, Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris (AP-HP), and U106, University Pierre and Marie Curie, Paris CEDEX 13, France.

Reference 17: Ohayon MM. Difficulty in resuming or inability to resume sleep and the links to daytime impairment: Definition, prevalence and comorbidity. J Psychiatr Res. 2009 Mar 2. [Epub ahead of print] Stanford Sleep Epidemiology Research Center, Stanford University School of Medicine, 3430 W. Bayshore Road, Palo Alto, CA 94303, USA.

Reference 18: Diekelmann S, Wilhelm I, Born J. The whats and whens of sleep-dependent memory consolidation. Sleep Med Rev. 2009 Feb 27. [Epub ahead of print] University of Lübeck, Department of Neuroendocrinology, Haus 23a, Ratzeburger Allee 160, 23538 Lübeck, Germany.

Reference 19: Plihal W, Born J. Effects of early and late nocturnal sleep on declarative and procedural memory Source Journal of Cognitive Neuroscience. 1997 Jul;9(4):534-7. University of Bamberg, FRG.

Reference 20: Campbell IG, Darchia N, Khaw WY, Higgins LM, Feinberg I. Sleep EEG evidence of sex differences in adolescent brain maturation. Sleep. 2005 May 1;28(5):637-43. Department of Psychiatry, University of California Davis Sleep Lab, 1712 Picasso Ave, Suite B, Davis, CA 95616, USA.

Reference 21: Antoniadis EA, Ko CH, Ralph MR, McDonald RJ. Circadian rhythms, aging and memory. Behav Brain Res. 2000 Sep;114(1-2):221-33. Corrected and republished from: Behav Brain Res. 2000 Jun 15;111(1-2):25-37. Departments of Psychology and Zoology, University of Toronto, 100 St George Street, Ont., M5S 3G3, Toronto, Canada.

Reference 22. Mellman TA, Pigeon WR, Nowell PD, Nolan B. Relationships between REM sleep findings and PTSD symptoms during the early aftermath of trauma. J Trauma Stress. 2007 Oct;20(5):893-901. Department of Psychiatry, Howard University, Washington, DC 20059, USA.

Reference 23: De Marchi N, Daniele F, Ragone MA. Fluoxetine in the treatment of Huntington’s disease. Psychopharmacology (Berl). 2001 Jan 1;153(2):264-6. Institute of Psychiatry, Second University of Naples, Italy.

Reference 24: Chae KY, Kripke DF, Poceta JS, Shadan F, Jamil SM, Cronin JW, Kline LE. Evaluation of immobility time for sleep latency in actigraphy. Sleep Med. 2008 Dec 20. [Epub ahead of print]Scripps Clinic Sleep Center, W207, 10666 N Torrey Pines Road, La Jolla, CA 92037, USA; Department of Pediatrics, School of Medicine, Pochon CHA University, South Korea.

Reference 25: Weydt P, Pineda VV, Torrence AE, Libby RT, Satterfield TF, Lazarowski ER, Gilbert ML, Morton GJ, Bammler TK, Strand AD, Cui L, Beyer RP, Easley CN, Smith AC, Krainc D, Luquet S, Sweet IR, Schwartz MW, La Spada AR. Thermoregulatory and metabolic defects in Huntington’s disease transgenic mice implicate PGC-1alpha in Huntington’s disease neurodegeneration. Cell Metab. 2006 Nov;4(5):349-62. Epub 2006 Oct 19. Department of Laboratory Medicine, University of Washington, Seattle, Washington 98195, USA.

Reference 26: Blackwell AD, Paterson NS, Barker RA, Robbins TW, Sahakian BJ. The effects of modafinil on mood and cognition in Huntington’s disease. Psychopharmacology (Berl). 2008 Jul;199(1):29-36. Epub 2008 Jun 1. Department of Psychiatry, School of Clinical Medicine, University of Cambridge, Addenbrooke’s Hospital, Hills Road, Cambridge, CB2 2QQ, UK.

Reference 27: Klöppel S, Chu C, Tan GC, Draganski B, Johnson H, Paulsen JS, Kienzle W, Tabrizi SJ, Ashburner J, Frackowiak RS; PREDICT-HD Investigators of the Huntington Study Group. Automatic detection of preclinical neurodegeneration: presymptomatic Huntington disease. Neurology. 2009 Feb 3;72(5):426-31.Department of Psychiatry and Psychotherapy, Freiburg Brain Imaging, University Clinic Freiburg, Germany.

Reference 28: Leproult R, Van Onderbergen A, L’hermite-Balériaux M, Van Cauter E, Copinschi G. Phase-shifts of 24-h rhythms of hormonal release and body temperature following early evening administration of the melatonin agonist agomelatine in healthy older men. Clin Endocrinol (Oxf). 2005 Sep;63(3):298-304. Centre d’Etude des Rythmes Biologiques (CERB) and Laboratoire de Physiologie, Université Libre de Bruxelles, Brussels, Belgium.

Eszopiclone Package Insert extract:

Alprazolam Package Insert extract:

Agomelatine Prescribing Information extract:

Introductions and welcome to the CHDI Clinical Protocol Advisory BoardJoseph Giuliano, Director, Clinical Operations

The meeting leader welcomed the Advisory Board, introduced all advisors and CHDI attendees, and described the program for the next 2 days.

Meeting leader

Joseph Giuliano, Director, Clinical Operations

Advisors

Derk-Jan Dijk, PhD, University of Surrey

Anna Goodman, PhD, Cambridge Centre for Brain Repair

Andrew D. Krystal, MD, DukeUniversityMedicalCenter

Wallace Mendelson, MD, The University of Chicago

Thomas Kilduff, PhD, Stanford Research Institute

Francis Walker, MD, WakeForestUniversitySchool of Medicine

Kathleen M. Shannon, MD, RushUniversitySchool of Medicine

Ken Evans, PhD, Ontario Cancer Biomarker Network

Phyllis Zee, MD, PhD, Northwestern UniversitySchool of Medicine

CHDI Attendees

Beth Borowsky, PhD, Director, Translational Medicine

Susanna J Dodgson PhD, Medical writer

Allan Tobin, PhD, Senior Scientific Advisor

Daniel van Kammen, MD, PhD, Chief Medical Officer

John Warner, PhD, Director, Biostatistics

Overview of CHDI Goals and Objectives for Sleep in HD Daniel van Kammen MD, PhD, CHDI Chief Medical Officer

Dan set the tone for the meeting by describing the mission of CHDI: to serve a patient population with Huntington’s Disease.(1)

Reference 1: Definition of Huntington’s Disease

Huntington's disease is a familial disease caused by a mutation in the huntington (sic) gene. Each child of a parent with a mutation in the huntingtin gene has a 50-50 chance of inheriting the mutation. As a result of carrying the mutation, an individual's brain cells fail and die leading to cognitive and physical impairments that, over the course of the disease, significantly impair the individual's quality of life and ultimately causes death. Symptoms of Huntington's disease, which generally develop in midlife and become progressively more debilitating as time passes, can also develop in infancy or old age. Once overt symptoms start, patients live for about 15 to 20 years. One person in 10,000 is believed to carry a mutation in the huntingtin gene. There is currently no way to delay the onset of symptoms or slow the progression of Huntington's disease.
From CHDI Press Release 29 Oct 2008

Persons living with Huntington’s Disease have only one thing in common: their defect in a single gene on the short end of chromosome 4. The symptoms are not uniform for each patient at each stage of the disease and cover the range of having no symptoms that are identifiable with the disease, the pre-manifest population.

He explained that this meeting was called to prepare a protocol to run a clinical trial to determine whether early intervention in the pre-manifest, can improve the quality of their lives. Pre-manifest are the population of patients who have not yet developed the motor dysfunction that leads to clinical diagnosis of Huntington’s Disease.

Dan explained in a slide that the motor dysfunction is a small part of diagnosed Huntington’s Disease, he called it “the tip of the iceberg” because the motor dysfunction can be seen by everyone. Motor symptoms include motor impersistence, chorea, bradykinesia, walking difficulties, eye movements, dysarthria, dysphagia. Appearing before diagnosis of Huntington’s Disease are the psychiatric symptoms (depression, apathy, irritability, aggression, obsessive compulsive symptoms, dysphoria, mood swings, anxiety, psychosis, suicidality) and cognitive impairment, attention, fluency, executive function,working memory, visuo-spatial memory,emotion recognition, judgment, reaction time).

Symptoms in persons living with diagnosed Huntington’s Disease can include severe motor dysfunction and severe psychiatric illness, Dan told the Advisory Board that the psychiatric symptoms cause stress and anxiety in the patient, and in the patient’s caregivers, and that any treatment that can lessen the psychiatric symptoms should be considered because persons can live with Huntington’s Disease 20 to 50 years, and improving their quality of life over that lifespan is huge.

Dan directed the attention of the Advisory Board to a paper from Holland in which the therapeutic combination of bright lights and melatonin improved both cognitive and noncognitive function in elderly patients.(2)

Reference 2: Riemersma-van der Lek RF, Swaab DF, Twisk J, Hol EM, Hoogendijk WJ, Van Someren EJ. Effect of bright light and melatonin on cognitive and noncognitive function in elderly residents of group care facilities: a randomized controlled trial. JAMA. 2008 Jun 11;299(22):2642-55. Netherlands Institute for Neuroscience, Royal NetherlandsAcademy of Arts and Sciences, Amsterdam, The Netherlands.

CONTEXT: Cognitive decline, mood, behavioral and sleep disturbances, andlimitations of activities of daily living commonly burden elderly patients withdementia and their caregivers. Circadian rhythm disturbances have been associatedwith these symptoms. OBJECTIVE: To determine whether the progression of cognitiveand noncognitive symptoms may be ameliorated by individual or combined long-term application of the 2 major synchronizers of the circadian timing system: brightlight and melatonin. DESIGN, SETTING, AND PARTICIPANTS: A long-term,double-blind, placebo-controlled, 2 x 2 factorial randomized trial performed from1999 to 2004 with 189 residents of 12 group care facilities in the Netherlands;mean (SD) age, 85.8 (5.5) years; 90% were female and 87% had dementia. INTERVENTIONS: Random assignment by facility to long-term daily treatment withwhole-day bright (+/- 1000 lux) or dim (+/- 300 lux) light and by participant to evening melatonin (2.5 mg) or placebo for a mean (SD) of 15 (12) months (maximum period of 3.5 years). MAIN OUTCOME MEASURES: Standardized scales for cognitiveand noncognitive symptoms, limitations of activities of daily living, and adverseeffects assessed every 6 months. RESULTS: Light attenuated cognitivedeterioration by a mean of 0.9 points (95% confidence interval [CI], 0.04-1.71)on the Mini-Mental State Examination or a relative 5%. Light also ameliorateddepressive symptoms by 1.5 points (95% CI, 0.24-2.70) on the Cornell Scale forDepression in Dementia or a relative 19%, and attenuated the increase infunctional limitations over time by 1.8 points per year (95% CI, 0.61-2.92) onthe nurse-informant activities of daily living scale or a relative 53%difference. Melatonin shortened sleep onset latency by 8.2 minutes (95% CI,1.08-15.38) or 19% and increased sleep duration by 27 minutes (95% CI, 9-46) or6%. However, melatonin adversely affected scores on the Philadelphia GeriatricCentre Affect Rating Scale, both for positive affect (-0.5 points; 95% CI, -0.10 to -1.00) and negative affect (0.8 points; 95% CI, 0.20-1.44). Melatonin alsoincreased withdrawn behavior by 1.02 points (95% CI, 0.18-1.86) on the MultiObservational Scale for Elderly Subjects scale, although this effect was not seenif given in combination with light. Combined treatment also attenuated aggressivebehavior by 3.9 points (95% CI, 0.88-6.92) on the Cohen-Mansfield Agitation Indexor 9%, increased sleep efficiency by 3.5% (95% CI, 0.8%-6.1%), and improvednocturnal restlessness by 1.00 minute per hour each year (95% CI, 0.26-1.78) or9% (treatment x time effect). CONCLUSIONS: Light has a modest benefit inimproving some cognitive and noncognitive symptoms of dementia. To counteract theadverse effect of melatonin on mood, it is recommended only in combination withlight.

Dansaid they are not looking at sleep apnea, but in the inability to stay asleep when a patients wakes during the sleep phase of the sleep-wake cycle. He explained the need for a clinical trial not going on too long, because subjects will stop participating, either because of loss of interest or because of advancing disease.

He said the studies have not shown conclusively whether patient deterioration from disease progression can be slowed with sufficient sleep. CHDI scientists do not know if improved sleep will delay disease progression, but are hoping it will.

Advisory Board Discussion

The concerns from Dan’s presentation were whether these findings are reproducible in a population that is a mouse model of Huntington’s Disease, and whether the light-melatonin combination will work for persons living with Huntington’s Disease.

According to Phyllis, this combination is needed for sleep disorders related to circadian rhythms because melatonin improves sleep but ruins mood, and light improves mood. According to Dan, no interventions have been found that can revert a person diagnosed with Huntington’s Disease to being pre-manifest and no publications are available that report that intervening with sleep and circadian rhythm in revert persons diagnosed with Huntington’s Diseaseto being pre-manifest.

Sleep and Circadian Abnormalities inHuntington’s Disease:Clinical Indications and Animal ModelsThomas Kilduff PhD, Stanford Research Institute

Tom was the first speaker from the Advisory Board, he told us his task was to explain the scientific research that had been done about sleep. He explained that a pivotal study came from Sweden in 2004, from Dr Asa Petersen and his group who reported that hypocretin (which is also called orexin)is lost in Huntington’s disease.(3)

Huntington’s disease (HD) is a devastating neurodegenerative disorder caused byan expanded CAG repeat in the gene encoding huntingtin, a protein of unknownfunction. Mutant huntingtin forms intracellular aggregates and is associated withneuronal death in select brain regions. The most studied mouse model (R6/2) of HDreplicates many features of the disease, but has been reported to exhibit onlyvery little neuronal death. We describe for the first time a dramatic atrophy andloss of orexin neurons in the lateral hypothalamus of R6/2 mice. Importantly, we also found a significant atrophy and loss of orexin neurons in Huntingtonpatients. Like animal models and patients with impaired orexin function, the R6/2mice were narcoleptic. Both the number of orexin neurons in the lateralhypothalamus and the levels of orexin in the cerebrospinal fluid were reduced by 72% in end-stage R6/2 mice compared with wild-type littermates, suggesting thatorexin could be used as a biomarker reflecting neurodegeneration. Our results show that the loss of orexin is a novel and potentially very important pathology in HD.