When does Huntingtons Disease Begin Richard Dubinsky MD

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

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

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

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

CAGn 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

What happened? § Founder effect, maternal germ cell mosaicism § Maternal transmission rarely changes CAGn § Paternal transmission usually expands § Mean expansion 6. 2 § Mean contraction 1. 3

Lee JM. Neurology 2012; 78: 690 -5

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

Determining Clinical Onset § Historical data § Chorea § Other domains: § Behavior § Cognition

HD: Juvenile Form § Predominance of dystonic rigidity § Early cognitive problems § Prolonged survival

http: //promotingexcellence. org/huntingtons/

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

HD: Progression § Total Functional Capacity Slope ~ 0. 9/y § Five domains § Occupation (3) § Fiscal (3) T § Activities of daily living (3) § Household chores (2) § Residence (2)

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

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

Lee JM. Neurology 2012; 78: 690 -5

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

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

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

Paulsen J, JNNSP 2008; 79: 874 -80

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

Aylward E, JNNSP, 2011; 82: 405

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

Dorsey, PLo. S 2012

Symbol Digit Modality / Stroop + ( ! < & ^ @ ) 1 2 3 4 5 6 7 8 @ @ ) ^ ( + ! + red green blue green red

COHORT: Medication Use Dorsey, PLo. S 2012

Dorsey, PLo. S 2012

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

HD Cohorts § Pre. HD-A and Pre. HD-B § Dichotomized at median predicted years to diagnosis (Langbehn score) § HD 1 and HD 2 § Stage 1 TFC 11 -13 § Stage 2 TFC 7 -10

TRACK-HD Baseline Characteristics Tabrizi S, Lancet Neurology 2009

Tabrizi S, Lancet Neurology 2009

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

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

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

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

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

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 § § § 2 CARE CRESTE-HD PRE-CREST REACH-HD PREDICT-HD

Potential Treatments § RNA Silencing § Anti-sense oligonucleotides § RNA interference

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

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

Lancet 2004; 363: 1432 -7

Aronin N NEJM 2012; 367 -1753

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

Huntington Study Group

Sleep and HD § Insomnia is very common § Sun downing § Delusions of not sleeping