Tracking an Elusive Thiefby Diana Smith


December 7, 2012 | A new era is dawning in the evaluation of Alzheimer’s disease, thanks to a hallmark imaging solution pioneered with the help of Siemens and a slate of dedicated researchers.

Alzheimer’s disease is truly one of the cruelest diseases that strikes the elderly, at the height of years that are supposed to be “golden.” Instead, the neuro-degenerative disorder snarls the body’s command center, slowly eroding brain function. It robs victims of their memory, steals the most basic of bodily functions and finally life, over a course that can last a decade or more.
There is no known cure. Further, today’s most effective drug therapies for Alzheimer’s only assuage symptoms, doing very little to slow progression of the disease.
Progressive mental decline and aging have been noted in history for hundreds of years. But it wasn’t until 1906 that a German physician, Alois Alzheimer, put together pieces of the puzzle, identifying a collection of brain cell abnormalities as a specific disease. When Alzheimer performed an autopsy on one of his patients who died after suffering for years with severe memory problems and confusion, he discovered dense deposits surrounding the nerve cells, and inside the cells, he observed twisted bands of fibers.
Today, this degenerative brain disorder is named after him, and when found during an autopsy, these plaques and tangles mean a definitive diagnosis of Alzheimer’s disease.
The brain lesions between cells are abnormal, insoluble protein deposits called amyloid plaques. Amyloid plaque is widely believed to be a precursor to another kind of abnormal protein, the neurofibrillary tangles (NFTs), or hairlike threads that exist within nerve cells of Alzheimer’s patients. Over time, amyloid plaque and neurofibrillary tangles clump into a convoluted mess of blockages in the brain, halting normal nerve cell transmission.


Amyloid plaques are of great interest to researchers, including Kirk A. Frey, MD, PhD, of the University of Michigan Alzheimer’s Disease Center in Ann Arbor, Michigan, USA, and Adam S. Fleisher, MD, of the Banner Alzheimer’s Institute in Phoenix, Arizona, USA. “The interplay of what goes wrong in the brain in the processing of proteins is very important,” says Frey.
For researchers and clinicians, the challenge was that amyloids in the brain could previously only be detected during an autopsy. Clinicians do not have reliable tools to accurately assess the cause of cognitive decline, but rather make “probable” diagnoses based on mental and cognitive examinations.
“In research clinics, such as the one here at the University of Michigan and other universities and academic centers worldwide, the accuracy of that clinical designation has probably been no better than 80 percent,” explains Frey. “We could not be completely confident until the pathologist told us. Despite our best efforts, we would be wrong in evaluating one in five patients.“
He adds, “You can imagine what kind of problem this poses. For clinical trials, a pharmaceutical firm has an idea about possible pathological processes and wants to target that as being specific to Alzheimer’s disease. You mount a trial where, at best, one in five patients does not have the problem that you’re targeting, and therefore, of the patients in treatment, one in five will not benefit.”


That scenario now has changed, thanks to an innovative imaging solution unveiled earlier this year by Siemens: The first-ofits-kind comprehensive amyloid imaging solution designed to detect beta-amyloid in the living brain. The new imaging solution is multi-pronged, encompassing four unique elements – the manufacturing and distribution of a PET imaging biomarker, the Biograph® mCT PET•CT scanner, syngo®.PET Amyloid Plaque1 neurology quantification software, and the support network an imaging institution needs to plan, implement, and successfully operate amyloid imaging services.
According to Fleisher, the new solution may play a critical role in future Alzheimer’s research. “It’s a game-changer,” he says. The PET scan utilizes imaging biomarkers – small molecular tracers that monitor biological processes – to detect amyloid in the brain. “If amyloid is not present, even with dementia, it is not Alzheimer’s.”
Dementia is a late stage of Alzheimer’s disease, explains Fleisher. ”Amyloid plaque starts in the brain 10 to 20 years before symptoms are exhibited. Research is being done to see if, through the detection of amyloid plaque, it may be possible to predict the onset of Alzheimer’s disease years before symptoms appear,” he says. “This would not only allow earlier treatment, but also, hopefully, enable the development of better drugs that effectively block, or even reverse, the progression of the disease.”
A key component of the Siemens imaging solution is the software, syngo.PET Amyloid Plaque, which takes a patient’s PET amyloid exam and automatically registers it against a reference model of a PET amyloid brain. When combined with visual assessment, these capabilities assist physicians in making an interpretation of the PET image. The new software’s algorithm strongly correlates with the reference model (Fleisher method) developed by Dr. Fleisher and his research colleagues. Fleisher utilized six empirically derived regions of amyloid plaque formation for the analysis of the data and established a threshold value to dis tinguish between a healthy brain and one afflicted with Alzheimer’s.
During a scan, some amyloid tracer is naturally retained in the normal brain, so it is important to differentiate between white matter tracer uptake and gray matter amyloid plaque deposits. Amyloid within the brain’s white matter is considered normal in most cases, but tracer uptake in the gray matter may indicate abnormal activity. However, white and gray matter are integrally interlaced in a compact manner, making differentiation a challenge. Siemens new Biograph mCT offers the highest image quality2 at the industry’s finest volumetric resolution of 87 cubic-millimeter and accurate, quantifiable results.
After imaging the brain, the syngo.PET Amyloid Plaque software automatically compares a patient’s scan with a reference model PET scan, which identifies six zones to evaluate pathological levels of amyloid plaque burden. “This information gives radiologists an additional tool when they conduct visual assessments and make evaluations,” says Fleisher. “The images support other clinical findings, giving clinicians added confidence for their evaluation.”
The third element of the solution is the PET imaging biomarker manufacturing and distribution expertise of PETNET Solutions, a Siemens company. Siemens’ PETNET Solutions employs a dedicated staff and a fully integrated operational support infrastructure for the production of amyloid imaging biomarkers, which enables it to offer imaging centers and hospitals a high level of delivery reliability of up to 96 percent.
“For clinical use, as well as for research use, reliability in obtaining radiotracers is critically important,” says Fleisher. “For patients, it has to do with scheduling and fitting into busy scanner schedules, and when you have tracers that can be produced and delivered reliably, it translates into time, it translates into convenience for patients, and ultimately, it translates into cost savings for our center.”

For imaging centers and departments, implementing and expanding these amyloid imaging services can be challenging. In the planning stage, if customers create a flawed business plan it could lead to revenue loss. An incomplete implementation plan can cause delays in starting up this new clinical service. In the growth stage, a limited referral base and unawareness of offerings can restrict patient access and business growth. Finally, during the operational stage, inconclusive or wrong interpretation of amyloid imaging cases can lead to unsatisfied referring physicians, which can limit demand for amyloid imaging services. Siemens’ PETNET Solutions leverages the expertise of its field staff who average over 10 years of experience in PET imaging to help customers ensure successful implementation of amyloid imaging services. There are two key areas where they help customers: The first is with a personalized plan that involves a walk-through to identify site requirements to help ensure no step is missed to enable customers’ success when they go live with offering amyloid imaging. The second is the large network of expertise ranging from workflow and marketing support, to scanner protocols, clinical training, and business plan support, which enables customers to have access to resources essential for a successful implementation of amyloid imaging.

Adam S. Fleisher, MD, Banner Alzheimer’s Institute in Phoenix, Arizona, USA

In North America, Alzheimer’s disease holds 5.4 million people hostage – most of them over age 65. Every 68 seconds, a person in the United States develops Alzheimer’s. Also in the USA, deaths from Alzheimer’s disease have increased 66 percent between 2000 and 2008, while deaths from other major diseases, including the nation’s number-one killer, heart disease, have all decreased during the same period.3 And, Alzheimer’s is the only disease in the top ten with no cure.
Worldwide, there are an estimated 36 million people who are victims of the devastating illness.4 This number is expected to nearly double every 20 years to an estimated 65.7 million in 2030 and 115.4 million in 2050.4 Many experts predict that with the rise in the aging population, Alzheimer’s disease may well be the next global health epidemic. “Alzheimer’s disease is a very significant global healthcare problem,” concurs Frey. “It’s an exceedingly common medical problem, and it’s also exceedingly expensive, not only in terms of family and caregivers, but also in terms of healthcare resources. Medications that are regularly prescribed and used for symptomatic treatment of Alzheimer’s have some effectiveness, but they are not as effective as we would want or need, and they are relatively expensive,” Frey reports. “In the United States, expenditures of US$2,000 to US$3,000 per year just for prescription medications are not uncommon.”
Yet, that expense is miniscule compared to someone who requires 24/7 supervision for their care. According to Frey, the family almost always bears the burden of care at first, but eventually, virtually all demented patients require an institutional setting to medically manage their safety as well as to supervise their daily care and daily activities. Those expenses are very substantial.
Currently, Alzheimer’s is one of the most expensive illnesses society must bear, with global costs reaching US$604 billion in 2010.4 And, that number is expected to skyrocket as the population around the globe ages. Siemens is working to help provide solutions. The first step is Siemens’ comprehensive imaging solution to detect amyloid plaques, one of the key pathological features of Alzheimer’s disease, in a living person. With this new solution, the only one currently available, researchers now have a new way to evaluate Alzheimer’s and other causes of cognitive decline. Most importantly, the solution provides clues to help track down this elusive and silent thief – and killer.