![Page 1: PREQUEL Multicenter Phase II Therapeutic Trial in …hdsa.org/wp-content/uploads/2015/02/11449.pdfPREQUEL Multicenter Phase II Therapeutic Trial in Pre-symptomatic ... parietal cortex](https://reader031.vdocuments.us/reader031/viewer/2022011802/5b0cbb3c7f8b9a8b038ca586/html5/thumbnails/1.jpg)
PREQUEL Multicenter Phase II Therapeutic Trial in Pre-symptomatic (“pre-manifest”) HD
Christopher A. Ross MD PhD-PIKevin Biglan MD-co-PI
HDSA ConventionJune 7, 2008
--Many slices adapted from Kevin Biglan
![Page 2: PREQUEL Multicenter Phase II Therapeutic Trial in …hdsa.org/wp-content/uploads/2015/02/11449.pdfPREQUEL Multicenter Phase II Therapeutic Trial in Pre-symptomatic ... parietal cortex](https://reader031.vdocuments.us/reader031/viewer/2022011802/5b0cbb3c7f8b9a8b038ca586/html5/thumbnails/2.jpg)
The information provided by speakers in workshops, forums, sharing/networking sessions and any other educational presentation made as part of the 2008 HDSA convention program is for informational use only.
HDSA encourages all attendees to consult with their primary care provider, neurologist or other healthcare provider about any advice, exercise, medication, treatment, nutritional supplement or regimen that may have been mentioned as part of any presentation.
Huntington’s Disease Society of America
![Page 3: PREQUEL Multicenter Phase II Therapeutic Trial in …hdsa.org/wp-content/uploads/2015/02/11449.pdfPREQUEL Multicenter Phase II Therapeutic Trial in Pre-symptomatic ... parietal cortex](https://reader031.vdocuments.us/reader031/viewer/2022011802/5b0cbb3c7f8b9a8b038ca586/html5/thumbnails/3.jpg)
Huntington’s Disease
• Selective neuronal degeneration in Basal Ganglia--Caudate and putamen, but also cerebral cortex and other regions
• CAG expansion mutation: longer CAG repeats have earlier onset and more widespead degeneration
CAG-CAG-CAG (DNA)
CAG-CAG-CAG (RNA)
Gln---Gln---Gln (Protein)(Q) (Q) (Q)
![Page 4: PREQUEL Multicenter Phase II Therapeutic Trial in …hdsa.org/wp-content/uploads/2015/02/11449.pdfPREQUEL Multicenter Phase II Therapeutic Trial in Pre-symptomatic ... parietal cortex](https://reader031.vdocuments.us/reader031/viewer/2022011802/5b0cbb3c7f8b9a8b038ca586/html5/thumbnails/4.jpg)
CAG Repeat length and Age of Onset of HD
• CAG repeats of 35 or less do not cause HD
• Incomplete penetrance (delayed onset) for CAG 36 to 40
• Longer expansions result in earlier onset ages—thus can roughly predict onset age
• Determinants of the rate of progression are still unknown
--Ranen et al Am. J. Hum. Genet. 1995, and Margolis et al Arch. Gen. Psychiat. 1999
![Page 5: PREQUEL Multicenter Phase II Therapeutic Trial in …hdsa.org/wp-content/uploads/2015/02/11449.pdfPREQUEL Multicenter Phase II Therapeutic Trial in Pre-symptomatic ... parietal cortex](https://reader031.vdocuments.us/reader031/viewer/2022011802/5b0cbb3c7f8b9a8b038ca586/html5/thumbnails/5.jpg)
Quantification of Caudate Volumes: Regions of Interest
--Aylward et al Neurology 2004
control
HD
![Page 6: PREQUEL Multicenter Phase II Therapeutic Trial in …hdsa.org/wp-content/uploads/2015/02/11449.pdfPREQUEL Multicenter Phase II Therapeutic Trial in Pre-symptomatic ... parietal cortex](https://reader031.vdocuments.us/reader031/viewer/2022011802/5b0cbb3c7f8b9a8b038ca586/html5/thumbnails/6.jpg)
Caudate Atrophy in Pre-Symptomatic HD:Longitudinal Study in Hopkins Cohort
--Aylward et al, Neurology 2004
![Page 7: PREQUEL Multicenter Phase II Therapeutic Trial in …hdsa.org/wp-content/uploads/2015/02/11449.pdfPREQUEL Multicenter Phase II Therapeutic Trial in Pre-symptomatic ... parietal cortex](https://reader031.vdocuments.us/reader031/viewer/2022011802/5b0cbb3c7f8b9a8b038ca586/html5/thumbnails/7.jpg)
Predict-HD MulticenterHD Presymptomatic Study
-35 -30 -25 -20 -15 -10 -5
Estimated Years From Diagnosis
3132
3334
3536
Tota
l Cor
rect
(out
of 4
0)
Odor Identification
-35 -30 -25 -20 -15 -10 -5
Estimated Years From Diagnosis
2426
2830
Tota
l Cor
rect
(out
of 3
6)
Word List Learning
-35 -30 -25 -20 -15 -10 -5
Estimated Years From Diagnosis
0.00
360.
0038
0.00
400.
0042
0.00
440.
0046
0.00
480.
0050
0.00
52
Tapp
ing
Rat
e (ta
ps/m
sec)
Speeded Finger Tapping
-35 -30 -25 -20 -15 -10 -5
0.01
50.
020
0.02
50.
030
Tapp
ing
Con
sist
ency
(1/S
D, i
n m
sec-1
)
Self-Timed Finger Tapping
Estimated Years From Diagnosis-35 -30 -25 -20 -15 -10 -5
Estimated Years From Diagnosis
1213
1415
1617
18
cubi
c cm
Striatal Volume
-35 -30 -25 -20 -15 -10 -5
Estimated Years From Diagnosis
24
68
1012
Tota
l Sev
erity
Sco
re
Motor Exam Score
--Paulsen and REDICT-HD 2007
![Page 8: PREQUEL Multicenter Phase II Therapeutic Trial in …hdsa.org/wp-content/uploads/2015/02/11449.pdfPREQUEL Multicenter Phase II Therapeutic Trial in Pre-symptomatic ... parietal cortex](https://reader031.vdocuments.us/reader031/viewer/2022011802/5b0cbb3c7f8b9a8b038ca586/html5/thumbnails/8.jpg)
White Matter Alterations in HD Mutation-Positive Pre-Symptomatic Individuals
• Fractional anisotropy measure of white matter integrity
• SPM map of significant differences—blue and green represent HD Pre-Sx less than control
--Reading, Mori et al 2005
• DTI: Water diiffusion for fiber tract directionality
![Page 9: PREQUEL Multicenter Phase II Therapeutic Trial in …hdsa.org/wp-content/uploads/2015/02/11449.pdfPREQUEL Multicenter Phase II Therapeutic Trial in Pre-symptomatic ... parietal cortex](https://reader031.vdocuments.us/reader031/viewer/2022011802/5b0cbb3c7f8b9a8b038ca586/html5/thumbnails/9.jpg)
fMRI Alterations in HD Mutation-Positive Pre-Symptomatic Individuals
• 7 Pre-Symptomatic HD• 7 controls• Stroop interference type task
• SPM subtractive analysis– Baseline from active (by group)– Pre-Sx from controls
Between-group differences of BOLD response with the “active” condition of the task
--Reading et al Ann Neurol 2004
![Page 10: PREQUEL Multicenter Phase II Therapeutic Trial in …hdsa.org/wp-content/uploads/2015/02/11449.pdfPREQUEL Multicenter Phase II Therapeutic Trial in Pre-symptomatic ... parietal cortex](https://reader031.vdocuments.us/reader031/viewer/2022011802/5b0cbb3c7f8b9a8b038ca586/html5/thumbnails/10.jpg)
Diagnostic (motor) threshold
0102030405060708090
20 25 30 35 40 45 50 55
Age
Neu
robi
olog
ical
mar
ker
(arb
itrar
y un
its)
CAG < 30 CAG > 39 Untreated
HD Over the Lifetime
![Page 11: PREQUEL Multicenter Phase II Therapeutic Trial in …hdsa.org/wp-content/uploads/2015/02/11449.pdfPREQUEL Multicenter Phase II Therapeutic Trial in Pre-symptomatic ... parietal cortex](https://reader031.vdocuments.us/reader031/viewer/2022011802/5b0cbb3c7f8b9a8b038ca586/html5/thumbnails/11.jpg)
Diagnostic (motor) threshold
0102030405060708090
20 25 30 35 40 45 50 55
Age
Neu
robi
olog
ical
mar
ker
(arb
itrar
y un
its)
CAG < 30 CAG > 39 Untreated CAG > 39 Treated:hypothetical
Design of Therapeutic Trials for Pre-Symptomatic HD
Beginning of treatment
![Page 12: PREQUEL Multicenter Phase II Therapeutic Trial in …hdsa.org/wp-content/uploads/2015/02/11449.pdfPREQUEL Multicenter Phase II Therapeutic Trial in Pre-symptomatic ... parietal cortex](https://reader031.vdocuments.us/reader031/viewer/2022011802/5b0cbb3c7f8b9a8b038ca586/html5/thumbnails/12.jpg)
Study in Pre-manifest HD of Coenzyme Q10(Ubiquinone) Leading to preventive trials
(PREQUEL)
DEFINITION: “A literary, dramatic, or cinematic work whose narrative takes place before that of a preexisting work or a sequel”1
ORIGIN: George Lucas2
First known use: Press materials for the Godfather II2
Popularized in American culture by the Star Wars trilogy prequel (episodes 1-3)2
1http://dictionary.reference.com2http://en.wikipedia.org/wiki/Prequel
![Page 13: PREQUEL Multicenter Phase II Therapeutic Trial in …hdsa.org/wp-content/uploads/2015/02/11449.pdfPREQUEL Multicenter Phase II Therapeutic Trial in Pre-symptomatic ... parietal cortex](https://reader031.vdocuments.us/reader031/viewer/2022011802/5b0cbb3c7f8b9a8b038ca586/html5/thumbnails/13.jpg)
Long Term Objective
• Development of future preventive therapeutic trials in pre-manifest expansion positive individuals (with Coenzyme Q10 and/or other compounds?)
![Page 14: PREQUEL Multicenter Phase II Therapeutic Trial in …hdsa.org/wp-content/uploads/2015/02/11449.pdfPREQUEL Multicenter Phase II Therapeutic Trial in Pre-symptomatic ... parietal cortex](https://reader031.vdocuments.us/reader031/viewer/2022011802/5b0cbb3c7f8b9a8b038ca586/html5/thumbnails/14.jpg)
Primary Aim
• To determine the highest dosage of Co-Enzyme Q10 (amongst 600 mg/day, 1200 mg/day, 2400 mg/day) that is well tolerated in a pre-manifest mutation positive cohort in the context of a randomized, double-blind, parallel group trial.
![Page 15: PREQUEL Multicenter Phase II Therapeutic Trial in …hdsa.org/wp-content/uploads/2015/02/11449.pdfPREQUEL Multicenter Phase II Therapeutic Trial in Pre-symptomatic ... parietal cortex](https://reader031.vdocuments.us/reader031/viewer/2022011802/5b0cbb3c7f8b9a8b038ca586/html5/thumbnails/15.jpg)
Secondary Aim
• To establish the biological activity of CoQ10 in this population by assessing changes in serum levels of CoQ10, 8OHdG/8OHrG
![Page 16: PREQUEL Multicenter Phase II Therapeutic Trial in …hdsa.org/wp-content/uploads/2015/02/11449.pdfPREQUEL Multicenter Phase II Therapeutic Trial in Pre-symptomatic ... parietal cortex](https://reader031.vdocuments.us/reader031/viewer/2022011802/5b0cbb3c7f8b9a8b038ca586/html5/thumbnails/16.jpg)
Additional Objectives
• To assess the feasibility of designing and implementing a therapeutic trial in a pre-manifest population
• To assess the relationship between serum levels of CoQ, measures of oxidative stress (8OHdG/8OHrG), DNA repair mechanisms (OGG1)
• To further validate functional measures of disease in a pre-manifest population
![Page 17: PREQUEL Multicenter Phase II Therapeutic Trial in …hdsa.org/wp-content/uploads/2015/02/11449.pdfPREQUEL Multicenter Phase II Therapeutic Trial in Pre-symptomatic ... parietal cortex](https://reader031.vdocuments.us/reader031/viewer/2022011802/5b0cbb3c7f8b9a8b038ca586/html5/thumbnails/17.jpg)
Significance
• First trial to evaluate potential therapy in participants 100% at-risk for HD
• Allow selection of dosage that is tolerable (and biologically active?)
• Provide insight into process and feasibility of trials in pre-symptomatic participants
![Page 18: PREQUEL Multicenter Phase II Therapeutic Trial in …hdsa.org/wp-content/uploads/2015/02/11449.pdfPREQUEL Multicenter Phase II Therapeutic Trial in Pre-symptomatic ... parietal cortex](https://reader031.vdocuments.us/reader031/viewer/2022011802/5b0cbb3c7f8b9a8b038ca586/html5/thumbnails/18.jpg)
Why Coenzyme Q10?
![Page 19: PREQUEL Multicenter Phase II Therapeutic Trial in …hdsa.org/wp-content/uploads/2015/02/11449.pdfPREQUEL Multicenter Phase II Therapeutic Trial in Pre-symptomatic ... parietal cortex](https://reader031.vdocuments.us/reader031/viewer/2022011802/5b0cbb3c7f8b9a8b038ca586/html5/thumbnails/19.jpg)
HD Cell Biology
Jean Marx, Science 2005
![Page 20: PREQUEL Multicenter Phase II Therapeutic Trial in …hdsa.org/wp-content/uploads/2015/02/11449.pdfPREQUEL Multicenter Phase II Therapeutic Trial in Pre-symptomatic ... parietal cortex](https://reader031.vdocuments.us/reader031/viewer/2022011802/5b0cbb3c7f8b9a8b038ca586/html5/thumbnails/20.jpg)
Intersection of Transcription and Metabolism
--Ross and Thompson Nature Medicine 2006
![Page 21: PREQUEL Multicenter Phase II Therapeutic Trial in …hdsa.org/wp-content/uploads/2015/02/11449.pdfPREQUEL Multicenter Phase II Therapeutic Trial in Pre-symptomatic ... parietal cortex](https://reader031.vdocuments.us/reader031/viewer/2022011802/5b0cbb3c7f8b9a8b038ca586/html5/thumbnails/21.jpg)
Preclinical Efficacy in R6/2 HD Mouse Model
K.M. Smith et al. BBA. 2006;
![Page 22: PREQUEL Multicenter Phase II Therapeutic Trial in …hdsa.org/wp-content/uploads/2015/02/11449.pdfPREQUEL Multicenter Phase II Therapeutic Trial in Pre-symptomatic ... parietal cortex](https://reader031.vdocuments.us/reader031/viewer/2022011802/5b0cbb3c7f8b9a8b038ca586/html5/thumbnails/22.jpg)
CARE-HD: Suggestive Evidence in Manifest HDDose of 600 mg/day for 30 Months
HSG. Neurology. 2001;57:397-404
![Page 23: PREQUEL Multicenter Phase II Therapeutic Trial in …hdsa.org/wp-content/uploads/2015/02/11449.pdfPREQUEL Multicenter Phase II Therapeutic Trial in Pre-symptomatic ... parietal cortex](https://reader031.vdocuments.us/reader031/viewer/2022011802/5b0cbb3c7f8b9a8b038ca586/html5/thumbnails/23.jpg)
CoQ in PD (-Schults 2002)
• 80 PD patients, randomized, double blind, 16 months• Placebo, 300, 600, 1200 mg/ day• 300 or 600 mg/ day modestly beneficial• 1200 mg/ day –more benefit• --suggestive, not conclusive
![Page 24: PREQUEL Multicenter Phase II Therapeutic Trial in …hdsa.org/wp-content/uploads/2015/02/11449.pdfPREQUEL Multicenter Phase II Therapeutic Trial in Pre-symptomatic ... parietal cortex](https://reader031.vdocuments.us/reader031/viewer/2022011802/5b0cbb3c7f8b9a8b038ca586/html5/thumbnails/24.jpg)
Rationale for Safety and Tolerability
• Healthy subjects• Long exposures• Lower tolerability threshold in non-ill participants?
– Suggestion of differential tolerability of CoQ in healthy vs. manifest HD (Pre2care)
![Page 25: PREQUEL Multicenter Phase II Therapeutic Trial in …hdsa.org/wp-content/uploads/2015/02/11449.pdfPREQUEL Multicenter Phase II Therapeutic Trial in Pre-symptomatic ... parietal cortex](https://reader031.vdocuments.us/reader031/viewer/2022011802/5b0cbb3c7f8b9a8b038ca586/html5/thumbnails/25.jpg)
8OHDG: A biomarker of DNA oxidative damage
• Stable in serum and may be useful biomarker of oxidative damage
• Increased in caudate, parietal cortex in HD post-mortem brains
• Increased in R6/2 mouse model
• Increased in ALS and Friedreich’s Ataxia
Hersch et al. Neurology.2006;66:250-252
![Page 26: PREQUEL Multicenter Phase II Therapeutic Trial in …hdsa.org/wp-content/uploads/2015/02/11449.pdfPREQUEL Multicenter Phase II Therapeutic Trial in Pre-symptomatic ... parietal cortex](https://reader031.vdocuments.us/reader031/viewer/2022011802/5b0cbb3c7f8b9a8b038ca586/html5/thumbnails/26.jpg)
Trial Population
• 90 Pre-manifest participants (Diagnostic confidence ≤ 3)• Previously tested expansion (HD mutation) positive
through standard pre-manifest testing programs• No concomitant medication restrictions• No unstable medical/psychiatric illness
![Page 27: PREQUEL Multicenter Phase II Therapeutic Trial in …hdsa.org/wp-content/uploads/2015/02/11449.pdfPREQUEL Multicenter Phase II Therapeutic Trial in Pre-symptomatic ... parietal cortex](https://reader031.vdocuments.us/reader031/viewer/2022011802/5b0cbb3c7f8b9a8b038ca586/html5/thumbnails/27.jpg)
Design
• 1:1:1 Randomized to 600 mg/day, 1200 mg/day, or 2400 mg/day • Double-blind parallel group trial• Titrated over 4 weeks to assigned dosage• Followed for 20 weeks after randomization• Primary outcome is tolerability
![Page 28: PREQUEL Multicenter Phase II Therapeutic Trial in …hdsa.org/wp-content/uploads/2015/02/11449.pdfPREQUEL Multicenter Phase II Therapeutic Trial in Pre-symptomatic ... parietal cortex](https://reader031.vdocuments.us/reader031/viewer/2022011802/5b0cbb3c7f8b9a8b038ca586/html5/thumbnails/28.jpg)
Outcomes
• Primary Outcome– Tolerability: ability to complete study on randomized
treatment assignment• Secondary Outcomes
– Additional tolerability: ability to complete study on active drug, AEs, # of dosage reductions
– Safety: serum chemistries, UA, CBC, EKG– Serum CoQ levels– Serum 8OHdG/8OHrG levels and OGG1 levels– HD clinical and functional scales
![Page 29: PREQUEL Multicenter Phase II Therapeutic Trial in …hdsa.org/wp-content/uploads/2015/02/11449.pdfPREQUEL Multicenter Phase II Therapeutic Trial in Pre-symptomatic ... parietal cortex](https://reader031.vdocuments.us/reader031/viewer/2022011802/5b0cbb3c7f8b9a8b038ca586/html5/thumbnails/29.jpg)
Power Analysis
• Sample Size of 30 per group• Observed tolerability compare to a tolerability that would
be unacceptably low (<75%)• 90% power to correctly detect dosage as tolerable• 20% probability of incorrectly identifying dosage as
tolerable if dosage is actually intolerable
![Page 30: PREQUEL Multicenter Phase II Therapeutic Trial in …hdsa.org/wp-content/uploads/2015/02/11449.pdfPREQUEL Multicenter Phase II Therapeutic Trial in Pre-symptomatic ... parietal cortex](https://reader031.vdocuments.us/reader031/viewer/2022011802/5b0cbb3c7f8b9a8b038ca586/html5/thumbnails/30.jpg)
Sites
Mira Guzijan, MAMichael Geschwind, MD, PhDUC San Francisco73
Dawn Radtke, RN, CCRCMartha Nance, MDHennepin County Medical Center
71
Margaret Sanders, BSVicki L. Wheelock, MDUniversity of California Davis Medical Center
61
Dawn Miracle, BS, MS Rajeev Kumar, MD Colorado Neurological Institute52
Jo Belden, LPN, CCRCJoanne M. Wojcieszek, MDIndiana University45
Joan M. Harrison, MNClaudia Testa, MD, PhDEmory32
Claire WelshRussell Margolis, MDJohns Hopkins University28
Stacey K. Barton, MSW, LCSW Joel S. Perlmutter, MDWashington University27
William H. Adams, BALeigh J. Beglinger, PhDUniversity of Iowa24
Christine Hunter, RNJoseph Jankovic, MDBaylor College of Medicine7
Amy M. Chesire, LCSW-R, MSGPeter Como, PhDUniversity of Rochester1
CoordinatorInvestigator Site NameSite #
![Page 31: PREQUEL Multicenter Phase II Therapeutic Trial in …hdsa.org/wp-content/uploads/2015/02/11449.pdfPREQUEL Multicenter Phase II Therapeutic Trial in Pre-symptomatic ... parietal cortex](https://reader031.vdocuments.us/reader031/viewer/2022011802/5b0cbb3c7f8b9a8b038ca586/html5/thumbnails/31.jpg)
Study Sites
• University of Rochester• Baylor College of Medicine• University of Iowa• Washington University• Johns Hopkins University• Indiana University
• Colorado Neurological Institute• University of California—Davis• Hennepin County Medical
Center• University of California—San
Francisco
![Page 32: PREQUEL Multicenter Phase II Therapeutic Trial in …hdsa.org/wp-content/uploads/2015/02/11449.pdfPREQUEL Multicenter Phase II Therapeutic Trial in Pre-symptomatic ... parietal cortex](https://reader031.vdocuments.us/reader031/viewer/2022011802/5b0cbb3c7f8b9a8b038ca586/html5/thumbnails/32.jpg)
HD Drugs in the “Pipeline”
--Jean Marx Science 2005
![Page 33: PREQUEL Multicenter Phase II Therapeutic Trial in …hdsa.org/wp-content/uploads/2015/02/11449.pdfPREQUEL Multicenter Phase II Therapeutic Trial in Pre-symptomatic ... parietal cortex](https://reader031.vdocuments.us/reader031/viewer/2022011802/5b0cbb3c7f8b9a8b038ca586/html5/thumbnails/33.jpg)
Diagnostic (motor) threshold
0102030405060708090
20 25 30 35 40 45 50 55
Age
Neu
robi
olog
ical
mar
ker
(arb
itrar
y un
its)
CAG < 30 CAG > 39 Untreated CAG > 39 Treated:hypothetical
Design of Therapeutic Trials for Pre-Symptomatic HD
Beginning of treatment
![Page 34: PREQUEL Multicenter Phase II Therapeutic Trial in …hdsa.org/wp-content/uploads/2015/02/11449.pdfPREQUEL Multicenter Phase II Therapeutic Trial in Pre-symptomatic ... parietal cortex](https://reader031.vdocuments.us/reader031/viewer/2022011802/5b0cbb3c7f8b9a8b038ca586/html5/thumbnails/34.jpg)
![Page 35: PREQUEL Multicenter Phase II Therapeutic Trial in …hdsa.org/wp-content/uploads/2015/02/11449.pdfPREQUEL Multicenter Phase II Therapeutic Trial in Pre-symptomatic ... parietal cortex](https://reader031.vdocuments.us/reader031/viewer/2022011802/5b0cbb3c7f8b9a8b038ca586/html5/thumbnails/35.jpg)
![Page 36: PREQUEL Multicenter Phase II Therapeutic Trial in …hdsa.org/wp-content/uploads/2015/02/11449.pdfPREQUEL Multicenter Phase II Therapeutic Trial in Pre-symptomatic ... parietal cortex](https://reader031.vdocuments.us/reader031/viewer/2022011802/5b0cbb3c7f8b9a8b038ca586/html5/thumbnails/36.jpg)
![Page 37: PREQUEL Multicenter Phase II Therapeutic Trial in …hdsa.org/wp-content/uploads/2015/02/11449.pdfPREQUEL Multicenter Phase II Therapeutic Trial in Pre-symptomatic ... parietal cortex](https://reader031.vdocuments.us/reader031/viewer/2022011802/5b0cbb3c7f8b9a8b038ca586/html5/thumbnails/37.jpg)
HD Cell Biology
Jean Marx, Science 2005
![Page 38: PREQUEL Multicenter Phase II Therapeutic Trial in …hdsa.org/wp-content/uploads/2015/02/11449.pdfPREQUEL Multicenter Phase II Therapeutic Trial in Pre-symptomatic ... parietal cortex](https://reader031.vdocuments.us/reader031/viewer/2022011802/5b0cbb3c7f8b9a8b038ca586/html5/thumbnails/38.jpg)
Predict-HD MulticenterHD Presymptomatic Study
--Paulsen and Predict-HD in preparation
![Page 39: PREQUEL Multicenter Phase II Therapeutic Trial in …hdsa.org/wp-content/uploads/2015/02/11449.pdfPREQUEL Multicenter Phase II Therapeutic Trial in Pre-symptomatic ... parietal cortex](https://reader031.vdocuments.us/reader031/viewer/2022011802/5b0cbb3c7f8b9a8b038ca586/html5/thumbnails/39.jpg)
Caudate Atrophy Predates Disease Onset
E.H. Aylward, et al. Neurology. 2004;63:66-72