IDL-based KRONOS application also aiding research
in Paget's disease and osteoporosis

Parkinson's Disease is a progressive neurological disorder of the central nervous system, resulting from the degeneration of nerve cells (neurons) in a region of the brain that controls movement. It is estimated that two people in every 1,000 are afflicted with the disease worldwide. Dr. Dale Bailey and his colleagues at several London area hospitals are making inroads in the fight against Parkinson's and other diseases with their IDL-based application called KRONOS.

KRONOS, a nuclear medicine volumetric imaging application, is suitable for both diagnostic and clinical research studies, and is being used in a number of different Nuclear Medicine centres in Europe, Japan and Australia. The study of nuclear medicine looks at physiological processes rather than anatomical structures. In nuclear medicine imaging, short-lived radiopharmaceuticals (radioactive drugs that emit gamma rays and are targeted to the organ of interest) are injected into a patient's bloodstream.

The nuclear camera then takes multiple time-course photographs of the pharmaceutical as it enters and concentrates in these tissues or organs. By tracing this uptake, the resulting nuclear medicine image tells physicians about the biological activity of the organ or the vascular supply that nourishes it.

"Since Nuclear Medicine is a highly interdisciplinary activity, we worked closely with neurologists, computer scientists, radiochemists and mathematicians throughout the world in the development of KRONOS," said Dr. Bailey.

"Our goal in developing KRONOS," he continued, "was to produce a flexible analysis package that could be used in a number of research studies into human diseases. We wanted it to be usable by both research medical staff, such as neurologists, psychiatrists, physiologists, as well as experienced technologists who analyse diagnostic studies on a routine basis."

When a person is afflicted with Parkinson's disease, a particular area of the brain called the basal ganglia, deteriorates, reducing the amount of a brain-signalling chemical, known as dopamine, that is available to the brain. Insufficient dopamine disturbs the balance between dopamine and other transmitters, such as acetylcholine. Without dopamine, the nerve cells cannot properly transmit messages, and this results in the loss of movement control. The disease is typically characterised by a decrease in spontaneous movements, gait difficulty, postural instability, rigidity and tremor.

At several London-area hospitals, including Guy's and St. Thomas' and Hammersmith Hospitals, Dr. Bailey and his colleagues are using IDL to analyse, display and report on the performance of cells in the absorption of radioactive compounds. They hope this data will make it easier to detect the presence of Parkinson's disease at an earlier stage.

"When radioactively labelled DOPA, a drug used in the treatment of Parkinson's disease, is injected into the bloodstream, it is extracted by nerve tissues throughout the body, but primarily by the cells in the basal ganglia," explained Dr. Bailey. "We want to study the rate at which the DOPA is extracted as a measure of the efficacy of the nerve terminals. A decreased rate of extraction of the labelled drug reflects loss of nerve terminal integrity, and indicates that a disease process is present. Positron Emission Tomography (PET) scanning measures the uptake of the radiolabelled DOPA over time in the brain."

"In our research, we record temporal sequences of images, using PET, to measure the uptake of radioactive compounds in the body, over time," explained Dr. Bailey. "From these images, we produce a measurement of the rate at which the different tissues of the body extract the compound from the blood stream and incorporate it into the cells."

KRONOS performs an analysis of this sequence, gathered over 90 to 120 minutes, and determines the rate of extraction by the brain tissue. KRONOS uses three-dimensional reconstructed images acquired every one to five minutes in either of two ways. Regions of interest can be defined over different tissues and the average uptake rate determined. Alternatively, the analysis can be run on each pixel individually (essentially considering each pixel to be a region of interest), producing an image of the uptake rate on a pixel-wise basis. The pixel by pixel analysis produces four parametric images for each section through the three-dimensional volume. These are images of total uptake, rate of uptake, volume of distribution, and the ratio of the integrated uptake divided by the integral of the concentration in a "reference" tissue, which does not have any specific uptake or binding of the drug.

Once chemicals have been introduced into the body by either ingestion or injection, their concentration in the blood stream initially rises. At the same time, tissues of the body start to extract the drug from the blood stream. The blood profile of the drug therefore shows an initial rise, reaching a peak, and then a gradual reduction reflecting extraction of the compound from the blood. Since nuclear medicine uses radioactively labelled pharmaceuticals in imaging studies, Dr. Bailey and his colleagues can measure the uptake of a radioactive labelled compound into the tissues. The rate at which the drug is extracted from the blood is a measure of the function of the cells.

If the concentration of the drug in the blood is maintained at a constant level over time, the amount of drug extracted from the blood into the tissues would be a simple linear relationship. However, this becomes more complicated due to the varying profile in the blood at any time. The KRONOS application implements an accepted method that allows the input to the tissue to be modelled as a constant infusion by a manipulation of the x-axis blood concentration over time. Essentially the integral of the concentration in the blood is divided by the instantaneous value in the blood, and this is plotted on the x-axis. On the y-axis, the instantaneous value of the tracer concentration in the tissue is divided by the instantaneous value of the tracer in the blood. This permits any arbitrary blood profile of the drug's concentration to be converted into a "pseudo-constant" input. Linear regression is then used on the temporal data from the plot to determine the slope of the line and the intercept. The slope is a direct measure, in units of time-1, of the rate of extraction of the drug by the tissues. The intercept is a reflection of the "volume of distribution" of the tracer in the space in which it is being measured, in this case the tissue plus the blood in the tissue.

In Dr. Bailey's model, it is also assumed that over the time of the measurement in the scanner (averaging 1-2 hours), there is little or no significant leakage of the drug from the tissues back into the blood. Therefore, given the input to the tissues and the amount accumulating in the tissues, the rate of uptake can be determined.

"Our analysis is based on a model of uptake, originally developed by Mike Rutland at Cambridge University in the late 1970's, which assumes that once the compound has been extracted from the blood, it does not 'leak' back into the blood stream and out of the cells," Dr. Bailey said.

When Dr. Bailey and his colleagues began looking at software packages to help develop KRONOS, they knew they needed to design a powerful, yet easy-to-use system. "There is a wide range of expertise in KRONOS' users, ranging from computer naive to very sophisticated. The software is written to be flexible enough so that a naive user, who may have sophisticated questions to ask, can perform these analyses without requiring others," he said. "We also wanted to allow users to produce, as output, both parametric images of uptake rate (i.e. pixel by pixel), and mean uptake rate values within a region of interest (ROI), as high quality electronic or hard copy output.

Dr. Bailey built a front-end GUI to KRONOS to "allow users to set many of the variables with the click of a mouse. That really aids the usability and maintains flexibility of KRONOS. The GUI acts as a front end interface to a variety of support programmes," he added.

Prior to developing KRONOS, Dr. Bailey and his colleagues used a number of computer systems to analyse their data. Typically, the data were reconstructed on a dedicated computer, and transferred to a Unix-based analysis station. Regions of interest were defined on the data on the Unix workstation and text files were generated in ordered columns of time, tissue uptake, and tracer concentration in blood or in a reference tissue. These text files were then transferred to a Macintosh for analysis in Excel, using a macro developed by one of the clinicians. There was no facility to generate parametric images of the uptake rate constant. "We had to use a number of different computers, and were limited by the availability of those computers. Obviously the analysis was inflexible and time consuming, and we needed something better."

"Siemens CTI, the manufacturer of the PET scanners which we use, had already chosen IDL as their platform for visualisation and application development. It therefore seemed sensible to develop KRONOS in the same environment. This has proven to be a judicious decision," said Dr. Bailey.

The KRONOS application is written exclusively in IDL, with the exception of a few I/O routines specific to the PET camera, which are written in C and are called from the application's I/O module. "IDL has provided a unified environment for the analysis, display, and reporting of these data, in a tool which is easy to support," said Dr. Bailey. "There was no alternative package available from Siemens at the time to analyse the data or develop the tools to do so, so we had to do it ourselves. We considered developing in C or C++, but knew that it would take much longer than developing in IDL."

"Using IDL has also allowed us to produce 3D images of the parameters described above. This has allowed the data to be analysed in a novel way, by performing a statistical parametric mapping (SPM) of individual scans compared with a normal database. This capability has found wide application in studies of regional cerebral blood flow, but this was the first application of it using a functional image of uptake rate constant or influx. I have also used IDL and the same approach for examining changes in the clearance of radioactive particles from the lungs in patients with cystic fibrosis. IDL has proved to be very useful in that research, as well," he continued.

For Dr. Bailey's research, the data usually come in a manufacturer specific file format from the scanner. At present, five different native formats are supported, and are all specific to Nuclear Medicine gamma cameras and PET scanners. Due to the range of applications, not just in PET but also in SPECT, KRONOS has been designed to allow for different input file formats. Internally, the application stores the data as Interfile, the de facto standard for data representation in Nuclear Medicine, but input can be from a number of different formats native to different manufacturers' scanners.

KRONOS is currently available exclusively on Solaris running on Sparc or Pentium (Linux) workstations. The data vary in size, but are typically 30 to 100 megabytes. The IDL routines KRONOS utilises most are the visualisation routines such as TVSCL, input output functions such as READ and WRITE, WHERE, curve fitting and function minimisation routines. The visualisation tools are used frequently to give the user constant feedback during the study as a technique for better quality control.

"IDL has really been a wonderful tool for us," said Dr. Bailey. "Our productivity has increased significantly, and we now have a very flexible, transportable application. IDL has also been instrumental in giving non-programmers the ability to learn to program with rapid progress. Instantaneous visual feedback during the development cycle greatly reduces the total development time."

"In addition, the support and service we've received in the UK from RSI's direct representatives has been excellent. Telephone and e-mail support has been thorough, and our questions are typically answered quickly," Dr. Bailey added.

KRONOS' influence in Parkinson's disease goes beyond research. At Hammersmith Hospital in West London, KRONOS is being used to evaluate patients suspected of having early signs of Parkinson's Disease. A large, multicentre R&D trial is also using KRONOS for an international evaluation of new drugs for treatment of Parkinsonian disorders.

KRONOS can be applied to other drugs and diseases as well. FDG, a glucose analogue widely used in PET, is amenable to the same analysis. And, at Guy's Hospital, Dr. Bailey and his colleagues are using KRONOS in another research protocol to determine the rate of uptake of radioactively labelled phosphate compounds by the skeleton in metabolic bone diseases such as osteoporosis and Paget's disease.