Tabrizi SJ, Reilmann R, Roos RA, Durr A, Leavitt B, Owen G, Jones R, Johnson H, Craufurd D, Hicks SL, Kennard C, Landwehrmeyer B, Stout JC, Borowsky B, Scahill RI, Frost C, Langbehn DR, . Potential endpoints for clinical trials in premanifest and early Huntington's disease in the TRACK-HD study: analysis of 24 month observational data. Lancet Neurol. 2012 Jan;11(1):42-53. PubMed.
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Johns Hopkins University
This comprehensive and beautifully crafted study presents results from the longitudinal TRACK-HD trial of pre-manifest HD, which, like the complementary PREDICT-HD (Aylward et al., 2011; Paulsen et al., 2010; Biglan et al., 2009) study, is searching for Huntington's disease biomarkers for use in clinical trials. The results of both studies will have important implications for AD and PD as well. HD can serve as a model (Ross and Tabrizi, 2011; Walker, 2007) for these more common diseases, because it is caused by mutations in a single gene. Since the length of the CAG expansion predicts age of onset, predictive testing can determine the approximate time to onset of individuals who are expansion positive but without signs and symptoms sufficient to diagnose manifest disease ("pre-manifest" individuals).
The TRACK-HD findings closely parallel recent results from PREDICT-HD. Both studies find that atrophy in caudate and putamen (corpus striatum of the basal ganglia) long precede diagnosable onset of HD, and that atrophy is measurable longitudinally even in the pre-manifest period. In addition, somewhat unexpectedly, both studies have found that subcortical white matter also is an excellent longitudinal biomarker.
Consistent with the concept that HD is a disease prominently affecting the basal ganglia, which coordinate movement, thought, and emotion, both studies have found that all three functions are affected, and have measureable longitudinal change, though movement and cognition have more consistent change, which is detectible earlier. The particular contribution of TRACK-HD is to report all measures together in a clear and consistent fashion so that effect sizes can be compared. Rather than attempting to choose any single measure as pre-eminent, the TRACK-HD report suggests that several measures together may be most useful for future clinical trials.
HD can provide many lessons for AD, PD, and other progressive brain diseases. In all these diseases, brain atrophy begins many years prior to onset of clinically diagnosable ("manifest") illness. Ideally, therapeutic interventions should also begin early. With appropriate biomarkers, treatments can be identified not just to slow progression of disease after it begins, but to delay—or even conceivably prevent—onset, thus addressing these devastating degenerative diseases with preventive therapy.
References:
Aylward EH, Liu D, Nopoulos PC, Ross CA, Pierson RK, Mills JA, Long JD, Paulsen JS, . Striatal Volume Contributes to the Prediction of Onset of Huntington Disease in Incident Cases. Biol Psychiatry. 2011 Sep 8; PubMed.
Aylward EH, Nopoulos PC, Ross CA, Langbehn DR, Pierson RK, Mills JA, Johnson HJ, Magnotta VA, Juhl AR, Paulsen JS, . Longitudinal change in regional brain volumes in prodromal Huntington disease. J Neurol Neurosurg Psychiatry. 2011 Apr;82(4):405-10. PubMed.
Biglan KM, Ross CA, Langbehn DR, Aylward EH, Stout JC, Queller S, Carlozzi NE, Duff K, Beglinger LJ, Paulsen JS, . Motor abnormalities in premanifest persons with Huntington's disease: the PREDICT-HD study. Mov Disord. 2009 Sep 15;24(12):1763-72. PubMed.
Paulsen JS, Nopoulos PC, Aylward E, Ross CA, Johnson H, Magnotta VA, Juhl A, Pierson RK, Mills J, Langbehn D, Nance M, . Striatal and white matter predictors of estimated diagnosis for Huntington disease. Brain Res Bull. 2010 May 31;82(3-4):201-7. PubMed.
Ross CA, Tabrizi SJ. Huntington's disease: from molecular pathogenesis to clinical treatment. Lancet Neurol. 2011 Jan;10(1):83-98. PubMed.
Walker FO. Huntington's disease. Lancet. 2007 Jan 20;369(9557):218-28. PubMed.
Northwestern University
One of the major hurdles in the development of treatments for neurodegenerative
diseases has been the absence of measurable indicators of disease progression.
This is particularly important in diseases such as Huntington's, where pre-manifest subjects
can be identified with a genetic test and potential treatments could be
instituted many years before disease onset. The study by Tabrizi et al.
demonstrates measurable disease-related changes over 24 months in pre-manifest
and early manifest HD. Neuroimaging markers such as grey matter and white
matter atrophy proved the most sensitive. There was also evidence of
longitudinal cognitive decline in early HD. Importantly, the study suggests an
association between the changes in brain atrophy and clinical progression.
In
comparison with an early HD group, where a range of potential outcomes to track
disease progression were identified, striatal and total white matter atrophy
appeared the most sensitive changes in pre-manifest subjects. It will be
interesting to examine, as part of larger studies, to what extent these brain
imaging changes correlate with disease progression in pre-manifest HD. Such
trials will also provide the opportunity to assess reliability and validity of
these findings across different sites and establish more definitely their
potential as indicators of clinical progression. It is anticipated that the
availability of such outcome measures may dramatically decrease the cost and
duration of therapeutic trials in HD, and therefore allow for testing of a larger
number of therapeutic agents identified in preclinical studies.
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