Abstract & Commentary
Source: Thieben MJ, et al. The distribution of structural neuropathology in preclinical Huntington’s disease. Brain. 2002;125:1815-1828.
Huntington’s disease (HD) is an autosomal dominant neurodegerative disorder linked to an expanded CAG trinucleotide repeat within the IT15 gene located on chromosome 4. Classical past neuropathologic descriptions of HD emphasized the predilection for involvement of the striatum, particularly the head of the caudate and putamen. Much emphasis was placed on clinical correlation between the degree of striatal pathology and symptoms of chorea and cognitive disturbance. Recently, it has become clear that this view of HD as a disease limited to the basal ganglia is incorrect, grossly underestimating the widespread neuropathologic changes that characterize the disorder. Prior therapeutic approaches have targeted the basal ganglia, for example, transplanting embryonic cells into caudate or putamen, with disappointing results. In order to rationally design therapies that will impact the natural history of this degenerative disorder, it is critical to understand the sequence and distribution of pathologic changes in the brains of HD patients.
In this seminal study, Thieben and colleagues set out to define the structural neuropathology in preclinical HD. Using a population of individuals who had undergone predictive genetic testing, 12 subjects were selected with more than 40 CAG repeats (guaranteeing eventual development of HD), and 5 had between 36 and 39 repeats (at risk for developing HD). A neurologist who was blinded to patients’ genetic status evaluated all patients, and none had evidence of HD on exam. Whole- brain MRIs and voxel-based morphometry were performed using statistical parametric mapping. The advantage of this technique is that it is fully automated and does not rely on region of interest evaluations (which introduce the possibility of investigator bias). Thieben et al observed significant reductions in grey matter volume in the left head and body of the caudate, putamen, and globus pallidus, continuous with volume loss in the nucleus accumbens and orbito-frontal cortex. Volume loss on the right side in the striatum was not statistically significant. They also observed grey matter loss in the tectum of the brainstem, posterior insula and posterior intra-parietal sulcus, and bilateral reduction in periventricular white matter volume in frontal, occipital, and temporal horns of the lateral ventricles.
Commentary
Several interesting and important conclusions can be drawn from this study. Early involvement of the striatum is not surprising given the noted predilection for this structure. However, the asymmetry of involvement was a surprise. Further, striatal volume loss was most severe rostrally and ventrally, in apparent contradiction to previous serial autopsy studies of HD brains. Involvement of the other brain regions correlates well with early clinical features of the illness. Bilateral volume loss of the insular cortex may explain the early loss of facial recognition characteristic of HD patients. Involvement of the intra-parietal sulcus and midbrain tectum may explain the delay in initiation of voluntary saccades that is frequently seen early in the disorder. The unexpected widespread white matter changes preceding clinical symptoms further confirms the idea that the brains of HD carriers are grossly and widely abnormal. Also, they appear well before they show symptoms and signs of the disease. This study suggests that future therapeutic approaches of HD must target all areas of the brain, almost certainly by pharmacologic agents that affect the bioenergetic disturbance underlying this presently untreatable neurodegenerative disorder. —Steven Frucht
Dr. Frucht, Assistant Professor of Neurology, Movement Disorders Division, Columbia-Presbyterian Medical Center, is Assistant Editor of Neurology Alert.
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