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

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Presentation on theme: "When does Huntington’s Disease Begin? Richard Dubinsky, MD, MPH University of Kansas 11/16/12."— Presentation transcript:

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  rarely expand  expand, mostly 35 and 36  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

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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

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

20 Brinkman R Am J Hum Genet, 1997;60:

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22 Langbehn D, Am J Med Genet B Neuropscyh 2010;153B:

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

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

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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   Funded by CHDI Dorsey, PLoS 2012

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35 Symbol Digit Modality / Stroop red green blue blue green red

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37 COHORT: Medication Use Dorsey, PLoS 2012

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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  Stage 2 TFC 7-10

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

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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

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48 Neuropsychological Tests

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

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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

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58 Aronin N NEJM 2012;

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

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