An international team led by researchers at the UCL Institute of
Neurology has identified a set of tests that could help identify
whether - and how - Huntington's disease (HD) is progressing in
groups of people who are not yet showing
symptoms.
The latest findings from the TRACK-HD study could be used to
assess whether potential new treatments are slowing the disease up
to 10 years before the development of noticeable
symptoms.
"Currently, the effectiveness of a new drug is decided by its
ability to treat symptoms," said lead author Professor Sarah
Tabrizi. "These new tests could be used in future preventative drug
trials in individuals who are gene positive for HD but are not yet
showing overt motor symptoms.
"These people have the most to gain by initiating treatment
early to delay the start of these overt symptoms and give them a
high quality of life for a longer period of time."
The TRACK-HD investigators have previously reported a range of
tests that could be used in clinical trials to assess the
effectiveness of potential disease-modifying drugs in people who
already show signs of the disease. But in individuals without
noticeable symptoms there was little evidence of a decline in
function over two years, limiting the ability to test new drugs
early in the disease course.
HD is caused by the mutation of a single gene on chromosome 4,
which causes a part of the DNA (known as a CAG motif) to repeat
many more times than it is supposed to. The length of the CAG
repeat is known to be a major determinant of the age at which
symptoms of the disease are likely to start, but its contribution
to progression is unclear.
In this study the TRACK-HD investigators extended the study to a
third year with the aim of identifying some of the earliest
biological changes in individuals with presymptomatic HD, giving
additional power to predict how the disease may progress beyond
that already expected from age and CAG
length.
Over three years, baseline measures derived from brain imaging
were the clearest markers of disease progression and future
diagnosis, above and beyond the effect of age and CAG count, in
gene carriers up to 20 years before they were expected to show
symptoms.
In particular, the investigators suggest that measuring volume
change in white matter and the caudate and putamen regions might be
future endpoints for treatment trials.
In individuals up to 10 years away from developing symptoms
there was also significant deterioration in performance on a number
of motor (movement) and cognitive (intellectual function) tasks
compared with controls, and the frequency of apathy
increased.
Professor Tabrizi said: "A new generation of drugs will be ready
for human trials in the very near future.
"Diagnosis in HD is something of an artificial construct at
onset of motor symptoms, and this study now gives us a number of
other, more well-defined parameters that correlate with disease
progression. Something that suggests we're moving towards a more
biological, as opposed to physical, definition of disease
progression that reduces the importance of an 'onset event' is
great news.
"By extending the reach of clinical trials to include
individuals who are currently free of overt symptoms there is a
realistic future possibility that treatments in the pipeline can
significantly improve the quality of life for patients and
families."
Writing in a linked comment in The Lancet Neurology, Professor
Francis Walker from Wake Forest Medical School in the USA says that
the TRACK-HD investigators have set the standard for observational
studies in other neurodegenerative diseases. He said: "Virtual
roadmaps of disease in the minds of practitioners are good for care
in the framework of the traditional patient encounter, but it takes
substantial effort, teamwork, and genius to turn them into
rigorous, quantifiable timelines that can be used to test efficacy
in future therapeutic trials."
The paper, Predictors of phenotypic progression and disease onset in
premanifest and early-stage Huntington's disease in the TRACK-HD
study: analysis of 36-month observational data, is published
in The Lancet.