Douglas R Langbehn1, Steven Hersch2,3. 1. Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA. 2. Voyager Therapeutics, Inc., Cambridge, Massachusetts, USA. 3. Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA.
Abstract
BACKGROUND: Huntington's disease (HD) develops in individuals with extended cytosine-adenine-guanine (CAG) repeats within the huntingtin (HTT) gene, causing neurodegeneration and progressive motor and cognitive symptoms. The inclusion of mutant HTT carriers in whom overt symptoms are not yet fully manifest in therapeutic trials would enable the development of treatments that delay or halt the accumulation of significant disability. OBJECTIVES: The present analyses assess whether screening prediagnosis (preHD) individuals based on a normalized prognostic index (PIN) score would enable the selection of prodromal preHD subjects in whom longitudinal changes in established outcome measures might provide robust signals. It also compares the relative statistical effect size of longitudinal change for these measures. METHODS: Individual participant data from 2 studies were used to develop mixed effect linear models to assess longitudinal changes in clinical metrics for participants with preHD and PIN-stratified subcohorts. Relative effect sizes were calculated in 5 preHD studies and internally normalized to evaluate the strength and consistency of each metric across cohorts. RESULTS: Longitudinal modeling data demonstrate the amplification of effect sizes when preHD subcohorts were selected by PIN score thresholds of >0.0 and >0.4. These models and relative effect sizes across 5 studies consistently indicate that the Unified Huntington's Disease Rating Scale total motor score exhibits the greatest change in preHD. CONCLUSIONS: These analyses suggest that the employment of PIN scores to homogenize and stratify preHD cohorts could improve the efficiency of current outcome measures, the most robust of which is the total motor score.
BACKGROUND:Huntington's disease (HD) develops in individuals with extended cytosine-adenine-guanine (CAG) repeats within the huntingtin (HTT) gene, causing neurodegeneration and progressive motor and cognitive symptoms. The inclusion of mutant HTT carriers in whom overt symptoms are not yet fully manifest in therapeutic trials would enable the development of treatments that delay or halt the accumulation of significant disability. OBJECTIVES: The present analyses assess whether screening prediagnosis (preHD) individuals based on a normalized prognostic index (PIN) score would enable the selection of prodromal preHD subjects in whom longitudinal changes in established outcome measures might provide robust signals. It also compares the relative statistical effect size of longitudinal change for these measures. METHODS: Individual participant data from 2 studies were used to develop mixed effect linear models to assess longitudinal changes in clinical metrics for participants with preHD and PIN-stratified subcohorts. Relative effect sizes were calculated in 5 preHD studies and internally normalized to evaluate the strength and consistency of each metric across cohorts. RESULTS: Longitudinal modeling data demonstrate the amplification of effect sizes when preHD subcohorts were selected by PIN score thresholds of >0.0 and >0.4. These models and relative effect sizes across 5 studies consistently indicate that the Unified Huntington's Disease Rating Scale total motor score exhibits the greatest change in preHD. CONCLUSIONS: These analyses suggest that the employment of PIN scores to homogenize and stratify preHD cohorts could improve the efficiency of current outcome measures, the most robust of which is the total motor score.
Authors: Jane S Paulsen; Jeffrey D Long; Christopher A Ross; Deborah L Harrington; Cheryl J Erwin; Janet K Williams; Holly James Westervelt; Hans J Johnson; Elizabeth H Aylward; Ying Zhang; H Jeremy Bockholt; Roger A Barker Journal: Lancet Neurol Date: 2014-11-03 Impact factor: 44.182
Authors: Ralf Reilmann; Andrew McGarry; Igor D Grachev; Juha-Matti Savola; Beth Borowsky; Eli Eyal; Nicholas Gross; Douglas Langbehn; Robin Schubert; Anna Teige Wickenberg; Spyros Papapetropoulos; Michael Hayden; Ferdinando Squitieri; Karl Kieburtz; G Bernhard Landwehrmeyer Journal: Lancet Neurol Date: 2018-12-15 Impact factor: 44.182
Authors: Sarah J Tabrizi; Rachael I Scahill; Gail Owen; Alexandra Durr; Blair R Leavitt; Raymund A Roos; Beth Borowsky; Bernhard Landwehrmeyer; Chris Frost; Hans Johnson; David Craufurd; Ralf Reilmann; Julie C Stout; Douglas R Langbehn Journal: Lancet Neurol Date: 2013-05-09 Impact factor: 44.182
Authors: Jane S Paulsen; Jeffrey D Long; Hans J Johnson; Elizabeth H Aylward; Christopher A Ross; Janet K Williams; Martha A Nance; Cheryl J Erwin; Holly J Westervelt; Deborah L Harrington; H Jeremy Bockholt; Ying Zhang; Elizabeth A McCusker; Edmond M Chiu; Peter K Panegyres Journal: Front Aging Neurosci Date: 2014-04-22 Impact factor: 5.750
Authors: Georg B Landwehrmeyer; Cheryl J Fitzer-Attas; Joseph D Giuliano; Nilza Gonçalves; Karen E Anderson; Francisco Cardoso; Joaquim J Ferreira; Tiago A Mestre; Julie C Stout; Cristina Sampaio Journal: Mov Disord Clin Pract Date: 2016-06-22