Progression of structural neuropathology in preclinical Huntington’s disease: a tensor based morphometry study

• Published in: Journal of neurology, neurosurgery and psychiatry Vol. 76; no. 5; pp. 650 - 655
• Main Authors: Kipps, C M, Duggins, A J, Mahant, N, Gomes, L, Ashburner, J, McCusker, E A
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group Ltd 01.05.2005; BMJ Publishing Group LTD; BMJ Group
• Subjects: Adult; Atrophy; Atrophy - pathology; Brain - pathology; Caudate Nucleus - pathology; Disease Progression; Female; Follow-Up Studies; Genetic testing; Globus Pallidus - pathology; globus pallidus externa; GM segment; GPe; grey matter segment; Humans; Huntington Disease - epidemiology; Huntington Disease - genetics; Huntington Disease - pathology; Huntingtons disease; Huntington’s disease; Hypotheses; Incidence; longitudinal imaging; Magnetic Resonance Imaging; Male; Mesencephalon - pathology; MNI; Montreal Neurologic Institute; MRI; Mutation; Neuropathology; Pathophysiology; Point Mutation - genetics; Putamen - pathology; small volume correction; SNr; Substantia Nigra - pathology; substantia nigra pars reticulata; SVC; TBM; tensor based morphometry; Trinucleotide Repeats - genetics; UHDRS; United Huntington’s Disease Rating Scale; VBM; voxel based morphometry; white matter segment; WM segment
• ISSN: 0022-3050; 1468-330X
• DOI: 10.1136/jnnp.2004.047993

Background and objectives: Regional cerebral atrophy occurs in carriers of the Huntington’s disease (HD) gene mutation before clinical diagnosis is possible. The current inability to reliably measure progression of pathology in this preclinical phase impedes development of therapies to delay clinical onset. We hypothesised that longitudinal statistical imaging would detect progression of structural pathology in preclinical carriers of the HD gene mutation, in the absence of measurable clinical change. Methods: Thirty subjects (17 preclinical mutation positive, 13 mutation negative) underwent serial clinical and magnetic resonance imaging (MRI) assessments over an interval of 2 years. Statistically significant changes in regional grey and white matter volume on MRI were analysed using tensor based morphometry (TBM). This technique derives a voxel-wise estimation of regional tissue volume change from the deformation field required to warp a subject’s early to late T1 images. Results: Over 2 years, there was progressive regional grey matter atrophy in mutation-positive relative to negative subjects, without significant clinical progression of disease. Significant grey matter volume loss was limited to bilateral putamen and globus pallidus externa (GPe), left caudate nucleus, and left ventral midbrain in the region of the substantia nigra. Conclusions: While these results are consistent with previous cross sectional pathologic and morphometric studies, significant progression of atrophy in HD before the onset of significant clinical decline is now demonstrable with longitudinal statistical imaging. Such measures could be used to assess the efficacy of potential disease modifying drugs in slowing the progression of pathology before confirmed clinical onset of HD.