Neurovascular abnormalities in humans and mice with Huntington's disease.

Cerebral microvascular aberrations have recently become recognized as a source of pathologies in neurodegenerative disorders, but this concept has not been fully examined with respect to Huntington's disease (HD). A novel in vivo technique, three-dimensional microscopic magnetic resonance angiography (μMRA), allows visualization of the neurovascular system in exquisite detail and provides quantitative structural and functional information. This technique was applied in the present study, in parallel with immunohistological analysis and behavioral assessment, to a well-characterized mouse model of HD (R6/2). Dynamic contrast-enhanced magnetic resonance imaging was used to examine the integrity of the blood-brain barrier (BBB). The μMRA findings revealed an increase in vessel volume fraction and cerebral blood volume in the brains of R6/2 mice at the age of 7weeks when no apparent motor dysfunction was detected. Collagen IV immunostaining disclosed an enhancement in vessel density, but not in vessel size of the microvasculature in the mouse HD brain. This change in neurovasculature worsened with disease progression, with no apparent disruption in the BBB. Most importantly, immunohistological assays of human tissues revealed that the vessel densities in the cortex, caudate/putamen, and substantia nigra were higher in HD patients than in non-HD human subjects. The early onset of such vessel aberrations could be used as a biomarker for the early diagnosis of HD.