Abstract
One of the roadblocks to developing effective therapeutics for Huntington disease (HD) is the lack of animal models that develop progressive clinical traits comparable to those seen in patients. Here we report a longitudinal study that encompasses cognitive and motor assessment, and neuroimaging of a group of transgenic HD and control monkeys from infancy to adulthood. Along with progressive cognitive and motor impairment, neuroimaging revealed a progressive reduction in striatal volume. Magnetic resonance spectroscopy at 48 months of age revealed a decrease of N-acetylaspartate (NAA), further suggesting neuronal damage/loss in the striatum. Postmortem neuropathological analyses revealed significant neuronal loss in the striatum. Our results indicate that HD monkeys share similar disease patterns with HD patients, making them potentially suitable as a preclinical HD animal model.
Highlights
Huntington disease (HD) is a devastating autosomal dominant neurodegenerative disease caused by the expansion of polyglutamine residues (>36Q) in exon 1 of the huntingtin (HTT or IT15) gene
Performance at 8 months of age was similar between rHDs6-8 and wild-type non-transgenic (WT) monkeys (Fig 1a–1d; top panel), the former displayed a slightly higher number of perseverations in the difficult trials (Fig 1d) [t = 3.315 with 5 d.f., p = 0.021]
Testing conducted on HD monkeys at 16 months of age revealed a gradual impairment in motor function (Fig 1e–1h; bottom panel)
Summary
Huntington disease (HD) is a devastating autosomal dominant neurodegenerative disease caused by the expansion of polyglutamine (polyQ) residues (>36Q) in exon 1 of the huntingtin (HTT or IT15) gene. A major challenge in the study of HD pathogenesis and the development of effective therapies is that the currently available animal models cannot replicate the full spectrum of HD clinical and pathological features, among them motor symptoms, cognitive behavioral deficits, and neuropathological changes of the striatum [1,2,3,4]. Recent longitudinal neuroimaging studies of HD patients suggested that non-invasive MRI provides an optimal quantitative tool for determining anatomical changes that are highly correlated with the development and progression of cognitive behavioral and motor impairments throughout the course of HD [6,7,8,9]
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