Posts tagged disease progression
Articles and news from the latest research reports.
Leading researchers report on the elusive search for biomarkers in Huntington’s disease
While Huntington’s disease (HD) is currently incurable, the HD research community anticipates that new disease-modifying therapies in development may slow or minimize disease progression. The success of HD research depends upon the identification of reliable and sensitive biomarkers to track disease and evaluate therapies, and these biomarkers may eventually be used as outcome measures in clinical trials. Biomarkers could be especially helpful to monitor changes during the time prior to diagnosis and appearance of overt symptomatology. Three reports in the current issue of the Journal of Huntington’s Disease explore the potential of neuroimaging, proteomic analysis of brain tissue, and plasma inflammatory markers as biomarkers for Huntington’s disease.
"Characteristics of an ideal biomarker include quantification which is reliable, reproducible across sites, minimally invasive and widely available. The biomarker should show low variability in the normal population and change linearly with disease progression, ideally over short time intervals. Finally, the biomarker should respond predictably to an intervention which modifies the disease," says Elin Rees, researcher at UCL Institute of Neurology, London.
In the first report, Rees and colleagues explore the use of neuroimaging biomarkers. She says they are strong candidates as outcome measures in future clinical trials because of their clear relevance to the neuropathology of disease and their increased precision and sensitivity compared with some standard functional measures. This review looks at results from longitudinal imaging studies, focusing on the most widely available imaging modalities: structural MRI (volumetric and diffusion), functional MRI, and PET.
"All imaging modalities are logistically complicated and expensive compared with standard clinical or cognitive end-points and their sensitivity is generally reduced in individuals with later stage HD due to movement," says Rees. "Nevertheless, imaging has several advantages including the ability to track progression in the pre-manifest stage before any detectable clinical or cognitive change."
Current evidence suggests that the best neuroimaging biomarkers are structural MRI and PET using [11C] raclopride (RACLO-PET) as the tracer, in order to assess changes in the basal ganglia, especially the caudate.
A study led by Garth J.S. Cooper, PhD, professor of Biochemistry and Clinical Biochemistry at the School of Biological Sciences and the Department of Medicine at the University of Auckland, used comparative proteome analysis to identify how protein expression might correlate with Huntington’s neurodegeneration in two regions of human brain: the middle frontal gyrus (MFG) and the visual cortex (VC). The investigators studied post mortem human brain tissue from seven HD brains and eight matched controls. They found that the MFG of HD brains differentially expressed 22 proteins compared to controls, while only seven were different in the VC. Several of these proteins had not been linked to HD previous. Investigators categorized these proteins into six general functional categories: stress response, apoptosis, glycolysis, vesicular trafficking, and endocytosis. They determined that there is a common thread in the degenerative processes associated with HD, Alzheimer’s disease, and diabetes.
The third report explores the possibility that inflammatory markers in plasma can be used to track HD, noting that immune changes are apparent even during the preclinical stage. “The innate immune system orchestrates an inflammatory response involving complex interactions between cytokines, chemokines and acute phase proteins and is thus a rich source of potential biomarkers,” says Maria Björkqvist, PhD, head of the Brain Disease Biomarker Unit, Department of Experimental Science of Lund University, Sweden.
The authors compare plasma levels of several markers involved in inflammation and innate immunity of healthy controls and HD patients at different stages of disease. Two methods were used to analyze plasma: antibody-based technologies and multiple reaction monitoring (MRM).
None of the measures were significantly altered in both HD cohorts tested and none correlated with HD disease stage. Only one substance, C-reactive protein (CRP), was decreased in early HD – but this was found in only one of the two cohorts, so the finding may not be reliable. The investigators were unable to confirm other studies that had found HD-related changes in other inflammatory markers, including components of the complement system.
Some markers correlated with clinical measures. For instance, ApoE was positively correlated with depression and irritability scores, suggesting an association between ApoE and mood changes.
Even though recent data suggest that the immune system is likely to be a modifier of HD disease, inflammatory proteins do not seem to be likely candidates to be biomarkers for HD. “Many proteomic studies designed to provide potential biomarkers of disease have generated significant findings, however, often these biomarkers fail to replicate during the validation process,” says Björkqvist.
(Source: eurekalert.org)
Scientists Identify Early Predictors of Disease Progression Which Could Speed Huntington’s Disease Drug Trials
Scientists have 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*, published Online First in The Lancet Neurology, 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. 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”, explains lead author Sarah Tabrizi from University College London’s Institute of Neurology.
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.
Here the TRACK-HD investigators extend 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 3 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. Finger tapping was the most sensitive of the motor assessments, while the symbol digit modality test proved to be the most sensitive of the cognitive measures.
According to Tabrizi, “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, Francis O. Walker, M.D., from Wake Forest School of Medicine in the USA says that the TRACK-HD investigators have set the standard for observational studies in other neurodegenerative diseases, adding that, “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 Track-HD study was established to identify differences between people carrying the HD mutation at different stages and healthy controls that could be used to accurately predict the progression of HD using a variety of techniques to assess changes in brain function, motor function, behaviour, and cognition. 366 individuals from Canada, France, the Netherlands and the UK were enrolled: 120 presymptomatic carriers of the HD gene mutation, 123 patients with early symptomatic HD, and 123 healthy controls.
(Source: newswise.com)
When trying to determine the root cause of a person’s dementia, using an MRI can effectively and non-invasively screen patients for Alzheimer’s disease or Frontotemporal Lobar Degeneration (FTLD), according to a new study by researchers from the Perelman School of Medicine at the University of Pennsylvania. Using an MRI-based algorithm effectively differentiated cases 75 percent of the time, according to the study, published in the December 26th, 2012, issue of Neurology, the medical journal of the American Academy of Neurology. The non-invasive approach reported in this study can track disease progression over time more easily and cost-effectively than other tests, particularly in clinical trials testing new therapies.
Researchers used the MRIs to predict the ratio of two biomarkers for the diseases - the proteins total tau and beta-amyloid - in the cerebrospinal fluid. Cerebrospinal fluid analyses remain the most accurate method for predicting the disease cause, but requires a more invasive lumbar puncture. “Using this novel method, we obtain a single biologically meaningful value from analyzing MRI data in this manner and then we can derive a probabilistic estimate of the likelihood of Alzheimer’s or FTLD,” said the study’s lead author, Corey McMillan, PhD, of the Perelman School of Medicine and Frontotemporal Degeneration Center at the University of Pennsylvania.
Using the MRI prediction method was 75 percent accurate at identifying the correct diagnosis in both patients with pre-confirmed disease diagnoses and those with biomarker levels confirmed by lumbar punctures, which shows comparable overlap between accuracy of the MRI and lumbar puncture methods. “For those remaining 25 percent of cases that are borderline, a lumbar puncture testing spinal fluid may provide a more accurate estimate of the pathological diagnosis.”
Accurate tests to measure disease progression are very important in neurodegenerative diseases, especially as clinical trials test new therapies to slow or stop the progression or the disease. Biomarkers for neurodegenerative diseases have been steadily improving, with new developments including spinal fluid tests detecting tau and amyloid-beta protein levels and other neuroimaging techniques developed at Penn Medicine, as part of the Alzheimer’s Disease Neuroimaging Initiative. While a spinal fluid test can be used to accurately pinpoint whether disease-specific proteins are present, the test requires a more invasive lumbar puncture making it more difficult to repeat over time. And for studies using other imaging techniques, such as test measuring whole brain volume, reduced sensitivity of the measurement requires more patients to be enrolled in clinical trials for statistical power to be achieved.
“Since this method yields a single biological value, it is possible to use MRI to screen patients for inclusion in clinical trials in a cost-effective manner and to provide an outcome measure that optimizes power in drug treatment trials,” the authors concluded.