Distinct brain volume changes correlating with clinical stage, disease progression rate, mutation size, and age at onset prediction as early biomarkers of brain atrophy in Huntington's disease.
Searching brain and peripheral biomarkers is a requisite to cure Huntington's disease (HD). To search for markers indicating the rate of brain neurodegenerative changes in the various disease stages, we quantified changes in brain atrophy in subjects with HD. We analyzed the cross-sectional and longitudinal rate of brain atrophy, quantitatively measured by fully-automated multiparametric magnetic resonance imaging, as fractional gray matter (GM, determining brain cortex volume), white matter (WM, measuring the volume of axonal fibers), and corresponding cerebral spinal fluid (CSF, a measure of global brain atrophy), in 94 gene-positive subjects with presymptomatic to advanced HD, and age-matched healthy controls. Each of the three brain compartments we studied (WM, GM, and CSF) had a diverse role and their time courses differed in the development of HD. GM volume decreased early in life. Its decrease was associated with decreased serum brain-derived-neurotrophic-factor and started even many years before onset symptoms, then decreased slowly in a nonlinear manner during the various symptomatic HD stages. WM volume loss also began in the presymptomatic stage of HD a few years before manifest symptoms appear, rapidly decreasing near to the zone-of-onset. Finally, the CSF volume increase began many years before age at onset. Its volume measured in presymptomatic subjects contributed to improve the CAG-based model of age at onset prediction. The progressive CSF increase depended on CAG mutation size and continued linearly until the last stages of HD, perhaps representing the best marker of progression rate and severity in HD (R(2)= 0.25, P < 0.0001).
Squitieri
Ferdinando
F
Neurogenetics Unit, IRCCS Neuromed & Centre for Rare Diseases, Località Camerelle, Pozzilli (IS), Italy. squitieri@neuromed.it
Cannella
Milena
M
Simonelli
Maria
M
Sassone
Jenny
J
Martino
Tiziana
T
Venditti
Eugenio
E
Ciammola
Andrea
A
Colonnese
Claudio
C
Frati
Luigi
L
Ciarmiello
Andrea
A
D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D001284:Atrophy; D001921:Brain / Q000473:pathology*; D018450:Disease Progression; D005260:Female; D006801:Humans; D006816:Huntington Disease / Q000235:genetics / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D018911:Trinucleotide Repeats