Complexity and heterogeneity: what drives the ever-changing brain in Huntington's disease?

Abstract

Significant advances are being made in our understanding of basic pathophyiological and biochemical mechanisms that cause Huntington's disease (HD). There is increasing reason to believe that pathologic alterations occur in the brain for years before symptoms manifest. The "classic" hallmark of neuropathology in HD is selective neurodegeneration in which vulnerable populations of neurons degenerate while less vulnerable populations are spared. While the earliest and most striking neuropathologic changes have been found in the neostriatum, neuronal loss has been identified in many other regions of the brain. We report topologically selective, early, and progressive changes in the cortex, striatum, extrastriatal brain structures, and white matter throughout the spectrum of disease. Our growing understanding of HD underscores the reality that points to the complexity of HD. A single, well-defined, genetic mutation causes a cascade of events whose final result is an aggregate insult of the homeostatic process. We explore possible explanations for the selective vulnerability of the brain in HD. The ultimate goal in HD is to develop disease-modifying therapies that will prevent the onset of clinical symptoms in those individuals who are at risk and slow the progression of symptoms in those individuals already affected with symptoms. Understanding changes in brain morphometry and their relationship to clinical symptoms may provide important and new insights into basic pathophysiological mechanisms at play in the disease.

Figures

Figure 1

Topologically selective thinning occurs in Pre-manifest Huntington’s disease. A. Surface maps of cortical thinning were generated by using a general linear model at each vertex across the entire mantle in 31 gene-carriers without symptoms of HD. Significant cortical thinning was present in sensor-motor, parietal, superior temporal, entorhinal, precuneus, occipital and portions of frontal cortex. B. Thickness maps of individuals greater than 12 years to expected onset; thinning is already present over the portions of superior temporal, motor, precuneus and entorhinal cortical regions. C. Thickness maps of individuals less than 12 years to expected onset; thinning is much more extensive, and begins to involve occipital, parietal, cuneus, posterior frontal cortical areas. Maps are presented on a semi-inflated cortical surface of an average brain. The color scale at the bottom represents the significance of the thickness change, transitioning from red (p<0.05) to yellow (p<0.001).

Figure 2

Topologically selective thinning in Early symptomatic HD: extension of changes seen in Pre-manifest subjects. A. Surface maps of cortical thinning were generated by using a general linear model at each vertex across the entire cortical mantle. In Stage I and Stage II subjects, significant thinning was present in sensor-motor, parietal, posterior superior and middle frontal, enthorhinal, precuneus, cuneus and occipital cortical areas. Maps are presented on a semi-inflated cortical surface of an average brain. The color scale at the bottom represents the significance of the thickness change, transitioning from red (p<0.01) to yellow (p<0.00005). B. After adjusting for striatal volume, significant thinning of the cortex was still present over occipital, parietal, and precuneus, suggesting some degree of independence between striatal and cortical pathology.

Figure 3

Bar-graphs demonstrating changes in the volumes of several other brain regions, spanning from pre-manifest individuals greater than 12 years to estimated onset through Stage III HD. A complex pattern of progressive changes emerges that also demonstrates the extensive involvement of brain structures in HD.