1. When does Huntington’s Disease Begin? Richard Dubinsky, MD, MPH University of Kansas 11/16/12

2. Disclosures  Current  NIH/NCAM and FDA OPD  2CARE  CRESTE  CHDI  ENROLL-HD  Facilitator, redefining HD across the life span  Completed:  NIH: CARE-HD, PHAROS, PREDICT-HD  FDA: RID-HD  HSG: Longitudinal database  CHDI: COHORT

3. HD Gene  Cloned 1993,from the Venezuela project  Trinucleotide repeat, one of the first three described  CAG expansion  Gene product  huntingtin  htt

4. Ross C, Lancet Neurology 2011;10:83-98

5. CAG n Ranges  <26 normal, 17 most common  26-29 rarely expand  30-36 expand, mostly 35 and 36  35-38 unstable expansion  HD in future generations  39 and above: HD  80% of people with 39 repeats will develop HD

6. What happened?  Founder effect, maternal germ cell mosaicism  Maternal transmission rarely changes CAG n  Paternal transmission usually expands  Mean expansion 6.2  Mean contraction 1.3

7. Lee JM. Neurology 2012;78:690-5

8. Onset of HD  Traditionally defined as onset of chorea  Always gradual, never sudden  Cognitive, behavioral and motor changes can precede chorea

9. Determining Clinical Onset  Historical data  Chorea  Other domains:  Behavior  Cognition

10. UHDRS-99 Copyright © HSG Ltd.

11. HD: Juvenile Form  Predominance of dystonic rigidity  Early cognitive problems  Prolonged survival

12. http://promotingexcellence.org/huntingtons/

13. Is the initial symptom disease onset?  Frequent phenoconversion after predictive testing  4 x > normal population suicide rate around phenoconversion  HD is not protective against other disorders

14. HD: Progression  Total Functional Capacity  Five domains  Occupation (3)  Fiscal (3)  Activities of daily living (3)  Household chores (2)  Residence (2) T Slope ~ 0.9/y

15. HD Disease Models Weir Lancet Neurology 2011;10:573-9

16. Ross C, Lancet Neurology 2011;10:83-98

19. Lee JM. Neurology 2012;78:690-5

20. Brinkman R Am J Hum Genet, 1997;60:1202-10

22. Langbehn D, Am J Med Genet B Neuropscyh 2010;153B:397-408

23. PREDICT-HD  Prospective cohort study of gene +, asymptomatic subjects and gene – controls  Near (onset < 9 years)  Mid (onset 9-15 years)  Far (onset > 15 years)  Yearly neuroimaging, cognitive and psychomotor testing

26. Paulsen J, JNNSP 2008;79:874-80

28. Paulsen J, Brain Res Bull 2010;82:201-7

29. Aylward E, JNNSP, 2011;82:405

30. COHORT  Multi-site, international natural history of HD  People with HD, those at risk, family members, some children  2006-2011  Funded by CHDI Dorsey, PLoS 2012

35. Symbol Digit Modality / Stroop red green blue blue green red +(!<&^@) 12345678 @@)^(+!+

37. COHORT: Medication Use Dorsey, PLoS 2012

39. TRACK-HD  Prospective, longitudinal cohort study  Manifest HD  Gene + (pre-manifest HD)  Burden of pathology score  Age x (CAG-35.5)  > 250  Gene -, non-matched controls

40. HD Cohorts  PreHD-A and PreHD-B  Dichotomized at median predicted years to diagnosis (Langbehn score)  HD1 and HD2  Stage 1 TFC 11-13  Stage 2 TFC 7-10

41. TRACK-HD Baseline Characteristics Tabrizi S, Lancet Neurology 2009

44. Tabrizi, S Lancet Neurology. 2012,11:42-35 ∆ in Brain Volume

45. Tabrizi, S Lancet Neurology. 2012,11:42-35 Striatal volumes

46. Tabrizi, S Lancet Neurology. 2012,11:42-35

48. Neuropsychological Tests

49. Tabrizi, S Lancet Neurology. 2012,11:42-35

51. HD Clinical Trials  Completed  CARE-HD  RID-HD  TETRA-HD  TREND-HD  MINOS  CYTE I  PHEND-HD  DIMEBOND 1 & 2  HSG Database  PHAROS  COHORT  Ongoing  2CARE  CRESTE-HD  PRE-CREST  REACH-HD  PREDICT-HD

52. Potential Treatments  RNA Silencing  Anti-sense oligonucleotides  RNA interference

53. Delivery Mechanisms  RNAi injected into CSF  Virus injected into:  CSF  Putamen  Virus inserted into bone marrow  Inserted via nanotube and heavy metal through the olfactory bulbs

54. Bone Marrow Transplantation?  Mutant htt expressed in many cells  Inflammatory markers before and at phenoconversion  Bone marrow derived cells get into the brain

55. Lancet 2004;363:1432-7

58. Aronin N NEJM 2012;367-1753

59. Conclusion  Changes that lead to HD start > 10 years before ‘phenoconversion’  Redefining the onset  Research  Clinical diagnosis  Implications

60. Huntington Study Group

61. Sleep and HD  Insomnia is very common  Sun downing  Delusions of not sleeping