Rate and acceleration of whole-brain atrophy in premanifest and early Huntington's disease.
Huntington's disease (HD) produces progressive and ultimately widespread impairment of brain function. Neostriatal atrophy alone cannot account for whole-brain losses seen postmortem, and the mutant huntingtin protein and its neuropathologic sequelae are evident throughout the brain. Whole-brain atrophy quantification encompasses the totality of mutant huntingtin's effects on brain volume and may be useful in tracking progression in trials. We studied whole-brain atrophy in HD using a 2-year follow-up design, with three annual MRI scans. We recruited 20 control subjects, 21 premanifest mutation carriers, and 40 patients with early HD and used the brain boundary shift integral to study rate and acceleration of atrophy. Among subjects with an acceptable quality 2-year scan pair, age- and gender-standardized mean brain atrophy rate was greater (P < 0.001) in the patients with HD (n = 21; 0.88%/yr; 95% confidence interval: 0.62-1.13%/yr) than that in controls (n = 13; 0.16%/yr; 0.00-0.32%/yr). In the 12 patients with early HD in whom acceleration could be directly assessed there was evidence (P= 0.048) of acceleration year-on-year (mean acceleration = 0.69% yr(-2); 95% confidence interval: 0.01% yr(-2) to 1.37% yr(-2)), although this was not formally significantly different from that in controls (n = 7, P = 0.055). Statistically significantly increased atrophy rates and acceleration were not seen overall in the premanifest group, who were on average 18 years from predicted disease onset. We conclude that the study of whole-brain atrophy has the potential to inform our understanding of the neurobiology of HD and warrants further study as one means of assessing the outcomes of future clinical trials.
Wild
Edward J
EJ
Dementia Research Centre, UCL Institute of Neurology, London, United Kingdom.
Henley
Susie M D
SM
Hobbs
Nicola Z
NZ
Frost
Chris
C
MacManus
David G
DG
Barker
Roger A
RA
Fox
Nick C
NC
Tabrizi
Sarah J
SJ
D000328:Adult; D017668:Age of Onset; D001284:Atrophy / Q000453:epidemiology / Q000473:pathology; D001921:Brain / Q000473:pathology*; D015331:Cohort Studies; D018450:Disease Progression; D005260:Female; D006801:Humans; D006816:Huntington Disease / Q000453:epidemiology / Q000235:genetics / Q000473:pathology*; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D017354:Point Mutation / Q000235:genetics; D011446:Prospective Studies; D012720:Severity of Illness Index
Neurology. 2005 May 10;64(9):1563-72
15883317
J Neurol. 2009 Feb;256(2):203-12
19266143
Clin Genet. 2004 Apr;65(4):267-77
15025718
Arch Neurol. 1993 Jan;50(1):17-9
8418795
Mov Disord. 2009 Apr 30;24(6):932-6
19243073
Neurology. 1981 Oct;31(10):1333-5
6125919
Mov Disord. 1996 Mar;11(2):136-42
8684382
Clin Sci (Lond). 2006 Jan;110(1):73-88
16336206
IEEE Trans Med Imaging. 1997 Oct;16(5):623-9
9368118
Lancet. 2004 Jan 31;363(9406):392-4
15074306
Hum Mol Genet. 1999 May;8(5):813-22
10196370
Neurology. 2005 Feb 8;64(3):548-50
15699394
J Neurol Neurosurg Psychiatry. 2008 Aug;79(8):874-80
18096682
IEEE Trans Med Imaging. 1998 Feb;17(1):87-97
9617910
Mov Disord. 2000 May;15(3):552-60
10830423
Comput Methods Programs Biomed. 1997 May;53(1):15-25
9113464
AJNR Am J Neuroradiol. 2001 Sep;22(8):1483-9
11559495
Neurology. 2004 Jul 13;63(1):66-72
15249612
J Comput Assist Tomogr. 1998 Jan-Feb;22(1):139-52
9448779
Neurology. 2005 Sep 13;65(5):745-7
16157910
J Neurosci. 1999 Apr 1;19(7):2522-34
10087066
Expert Opin Med Diagn. 2008 Jan;2(1):47-62
23485116
Cell. 2000 Mar 31;101(1):57-66
10778856
Neuron. 1995 Nov;15(5):1193-201
7576661
Neurology. 2003 May 27;60(10):1615-20
12771251
Neurology. 2005 Jul 12;65(1):119-24
16009896
J Exp Med. 2008 Aug 4;205(8):1869-77
18625748
Lancet Neurol. 2006 Sep;5(9):724-5
16914400
Neurology. 2006 Aug 22;67(4):694-6
16924028
J Neurol Neurosurg Psychiatry. 1993 Jan;56(1):98-100
8429330