Arches. Photo by Daniel Chia
HOPES: Huntington's Outreach Project for Education, at Stanford

World Congress 2013- Premanifest HD

In September 2013, several HOPES student researchers attended the Huntington’s Disease World Congress, held in Rio de Janeiro, Brazil. Summaries of the all the sessions attended can be found in the Conferences and Conventions section of our site.

The HOPES trip to the 2013 World Congress received partial support from the Bingham Fund for Innovation in the Program in Human Biology.

HD is a unique disease because it is one of few diseases where patients who choose to test and do test positive for the mHTT gene will almost inevitably develop symptoms, making cohorts of premanifest HD subjects a valuable group for scientists to study, because the age of disease onset, severity of symptoms, and progression of the disease varies substantially. While it is valuable to study this population, studies of premanifest HD patients are complicated by the fact the line between pre-symptomatic HD and diagnosed HD is difficult to distinguish at times. So the need for biomarkers and a better description of premanifest and early stage HD needs to be outlined and to reach a consensus among physicians and researchers because the first treatment of HD will likely lie in delaying the onset and reducing the severity of HD rather than finding a cure.

Table of Contents:

1.Premanifest HD (Karl Kieburtz, United States)
2.Motor Assessment Reviewed (Ralph Reilmann, Germany)
3.Neuropsychology in Premanifest HD (Julie Stout, Australia)
4.MRI biomarkers in Premanifest HD (Rachael Scahill, United Kingdom)
5.Overview of pridopidine DRF Study design (Karl Kieburtz, United States and Anna Wickenburg, Sweden)

Premanifest HD (Karl Kieburtz, United States)

One of the first speakers at the Congress began his discussion of the success of other diseases and their associated biomarkers to confirm a diagnosis. One example, autosomal dominant Alzheimer’s disease (ADAD), common in a small population in Colombia has specific biomarkers: amyloid protein aggregation and hippocampal volume. ADAD is similar to HD, since it is a neurodegenerative disease in which the patient’s children have a 50% chance to inherit the disease because the disease is caused by the genes on one of the alleles that the patient possesses. For more on the genetics of HD click here. The amyloid protein aggregates and decreased hippocampal volume indicates the neurodegenerative effects of ADAD. ADAD has biomarkers that serve as diagnostic criteria that are parallel to biomarkers in HD patients that could potentially be used for diagnostic criteria for HD. The measure of hippocampal volume in ADAD corresponds to the decreased striatal and white matter volume measured by MRI in HD and premanifest HD patients. The functional test and imaging tests for ADAD in a 2- year randomized study of 210 ADAD patients in a Colombian population confirmed the diagnostic viability of these two tests. Kieburtz ended his discussion with a suggestion of what the HD community needs to find similar diagnostic criteria to ADAD. He called for a consensus and definition for both premanifest and active HD. He suggested the community needs a test that measures cognition, but also has an imbedded functional component. Finally he said that biomarkers of clinical features such as MRI images need discussion, definition, and universal acceptance.

Motor Assessment Reviewed (Ralph Reilmann, Germany)

Following up Dr. Kieburtz discussion, Dr. Reilmann elaborated on the disadvantages of the standard HD evaluative test, the UHDRS-TMS, and described specific tests that could potentially be useful in the diagnosis of HD. The UHDRS-TMS is useful but does not catch sudden changes in HD progression and ultimately has a profound placebo effect because it focuses primarily on motor symptoms. Still motor symptoms studies are useful because they are common to the phenotype of the disease and are not influenced by a language barrier like cognitive and behavioral tests. The Track-HD study uses the Tapping Force Assessment (TFA), which encompasses two tests, having patients both tap as fast as they can and tapping in a metronomic pattern, meaning they try to keep a specific pace that is first set by a beeping in their ear. The patient then has to keep the same pace of the tap with their index finger after the beeping stops. Dr. Reilmann suggested that TFA was more sensitive to changes of HD progression than the UHDRS-TMS test.

Neuropsychology in Premanifest HD (Julie Stout, Australia)

Dr. Julie Stout discussed the evidence of small but significant cognitive and behavioral deficits in premanifest HD, as well as profound structural effects in the brain. Classical cognitive symptoms of HD include slowed thinking, forgetfulness, apathy, and problems with decision-making.  Stout found that these symptoms existed in patients well before they were diagnosed with HD but only at a minor level. These results are picked up by very specific cognitive tests and Stout claims that an average patient’s life would not be significantly changed by such small decreases in cognition. However, these cognitive impairments accelerate quickly before diagnosis and thereafter, according to the Hopkins Verbal Learning test, visual spatial, transformation, motor, visual working memory, attention, and spoken reading speed tests. These deficits can be detected 10 to 15 years before the onset of HD. Unlike cognitive deficits; Stout says that MRI scans reveal profound structural changes in brain volume which can be detected up to 20 years in premanifest HD patients. However, Stout says that neural activity increases in some areas of the brain in premanifest HD patients, perhaps compensating for neurodegenerative effects that have already taken a toll on white matter and striatal volume. So while decreased brain volume is correlated with decreased cognitive and motor effects, the latter takes a longer time to manifest because of brain elasticity and compensatory activity.

MRI biomarkers in Premanifest HD (Rachael Scahill, United Kingdom)

Dr. Scahill discussed structural MRI as a leading option for biomarkers in HD. The usefulness of MRI is that is a common machine in most hospital and clinic setting. It is relatively inexpensive compared to other imaging options such as PET, fMRI, and diffusion metrics. MRI imaging of decreases in striatal volume is highly correlated with symptom progression. However due to individual variation in initial amount of grey and white matter it is difficult to make MRI a definite clinical feature. Ultimately Rachael suggests that MRI images have to taken into account along with functional and behavioral tests of HD patients. However it is still an essential measure of disease progression. Meanwhile other imaging techniques are getting better, more common, and less expensive.

Overview of pridopidine DRF Study design (Karl Kieburtz, United States and Anna Wickenburg, Sweden)

Kieburtz and Wickenburg end the discussion of premanifest HD by discussing the ongoing study of pridopidine in HD. Pridopidine is a drug that stabilizes dopamine levels in the nervous system. The MermaiHD and HART studies suggest that pridopidine reduces inflammation in the brain in HD patients and improves motor symptoms overall. While the drug is well tolerated in patients and moving on in development, there is a small concern about dangers with anthemia and seizures, so the next study is testing higher doses of pridopidine in the hopes that higher doses will create greater clinical results.

W. St. Amant