This is the first study to systematically evaluate variable rates of progression in HD using structural neuro-imaging. The most striking finding was that both the rate of progression and the topological distribution of cortical thinning were highly influenced by the age of onset as defined clinically, rather than by the length of the CAG repeat. The rates of change for more than two-thirds of cortical regions demonstrated more rapid thinning in Young than in either Mid or Old.
In Young, we found regional rates of cortical thinning greater than twice those of either Mid or Old in several regions. This was true for sensori-motor cortex, portions of interior frontal, superior parietal, inferior parietal and the cuneus, where the rates of thinning were greater than eight percent. However, even within Young, the rate of cortical thinning was highly heterogenous, with much slower rates of thinning in superior temporal, peri-calcarine, and lingual regions. In contrast, the rates of cortical thinning were considerably slower in Old, where the most rapid changes were on the order of at most, three percent per year, primarily in portions of precentral, superior, middle and inferior temporal and the precuneus; thinning of most other brain regions was much slower. Mid, in general, demonstrated rates of thinning intermediate between Young and Old. It is noteworthy that this pattern was recapitulated in the corpus callosum, the major conduit for information transfer between the cortical hemispheres11
. Total white matter and gray matter volume reductions were also significantly more rapid in Young. Reductions in whole brain volumes, while not significant, were also more rapid in Young subjects than in either Mid or Old subjects. The general implication is that phenotypic variability in Huntington’s disease is, indeed, complex16
and extends to include highly variable rates of progression.
While the numbers of subjects studied was relatively small, the findings in the cortex were recapitulated in the more rapid volume loss in whole brain volumes and in the corpus callosum in Young; rates in Old were significantly slower.
In contrast to cortex, and perhaps surprisingly, the rates of change in subcortical structures were not significantly different amongst the groups. Atrophy rates for the basal ganglia structures were consistent with what has been published previously17
. Of note, the initial volumes measured in Young were significantly smaller than those of the other two groups, suggesting a potential “floor” effect. These findings also independently support an important role of the cortex in clinical progression.
Relationship to CAG repeat length
CAG repeat length appeared to have some influence in the rates of progressive thinning, but in only fewer than eleven percent of cortical regions was the correlation significant. In these regions, each increase in repeat length was associated with a 0.1% faster rate of change; a similar association has been reported with the TFC 2, 18
. CAG repeats were, as expected, larger in Young as compared to Old, but there was considerable overlap with Mid. There was no significant difference in CAGn
between Mid and Old; in spite of this, there was still a difference in the rates of thinning for many cortical regions, suggesting that cortical thinning is not strongly dependent on the CAGn
. It is also important to note that patients with repeat lengths in the ranges that have been associated with juvenile onset, typically larger than 55, were not included in these analyses, as juvenile HD is difficult to equate clinically with adult HD. We suspect that rates of progression in juvenile HD are even faster than our Young group.
We did not find any relationship between CAGn
and the rate of volume loss in any subcortical structure, but did find a relationship between the cross-sectional volume at the baseline scan and CAGn
, as has been reported previously19
. Other studies have put into question the role of the CAGn
in clinical heterogeneity 16
. Our findings suggest that the CAGn
does not appear to play a significant role in the rate
of atrophy for any structure or region, but rather, that once the genetic influence set off the pathogenic cascade, subsequent factors dominate the pathology and influence disease progression much more than CAGn
. Our findings also illustrate the importance of carefully evaluating models developed from cross-sectional data in longitudinal studies.
Relationship to Clinical Progression
It is important to note that the groups were in similar stages of disease at the time of the first assessment, thereby reducing a potential confound due to disease severity; clinical rates of progression may vary according to stage 20
. Nevertheless, the change in the TFC in Young was more than double the change in either Mid or Old. Typically, the TFC has been reported to change by approximately 0.72 units yearly. In our study, Young had a mean reduction of approximately two points over one year, suggesting that Young were also clinically progressing more quickly than expected; change scores in Mid and Old, were closer to expected values. Age, which has been shown to affect cortical changes independently, did not significantly influence regional rates of progression.
Selective vulnerability in the brain in Huntington’s disease remains poorly understood. This selectivity appears to extend to regional cortical rates of progression. One possible explanation is differential transcriptional dysregulation, which is believed to be heterogeneous throughout the brain and may render certain regions more vulnerable21
. Oxidative stress may independently contribute to vulnerability 22–24
. Differentially altered metabolism and cerebral perfusion may also be important; these too have been demonstrated to differ regionally25
. If neither CAG n
. nor age can fully account for the variability in progression, there must be additional environmental, genetic, or epigenetic factors that modulate progression26
. Much remains to be understood about clinical heterogeneity in a disorder defined by a single genetic mutation.
Our findings also have important implications for clinical trials. At present, the high clinical variability in HD necessitates enrolling hundreds of patients who must be followed for years in neuroprotective Phase III studies in which the TFC is the primary outcome measure. The TFC also has little power to provide preliminary evidence of efficacy in early phase studies so it is difficult to either systematically build preliminary data for promising therapies or to terminate them. Our study demonstrates that progression, defined structurally by MRI, is indeed highly variable. However, it also demonstrates that neuro-imaging approaches can objectively and sensitively measure the variability and thus help contain it. Thus, there is great potential for neuro-imaging to enhance our understanding of important phenotypic variability and to provide biomarkers to enhance the efficiency of clinical trials.