SIEMENS

Imagine a city with 100 trillion intersections, no stop lights and virtually no accidents. Replace the intersections with synapses and chemical pulses and you have a picture of a healthy human brain. Allow the pavement in an ever-growing number of intersections to crumble and be replaced by potholes and you have a very different picture—one that reflects conditions in Alzheimer's disease (AD), a degenerative neurological ailment that accounts for 60 to 89 % of all dementias.

In the U.S., 5.3 million people, 95 % of whom are 65 and older, are crippled by AD, and every 70 seconds, according to the Alzheimer's Association, a public health organization based in Chicago, Illinois, someone in the U.S. develops it. Meanwhile, in Germany, according to a recent study by the Fritz-Beske Institute for Healthcare System Research, the number of AD patients is set to double from the current figure of 1.1 million to 2.2 million by 2050. Projections for other regions are no brighter. According to findings published in the December, 2005 Lancet, Latin America and Africa will experience an increase of between 235 and 393 % in the incidence of dementias by 2040, while India, China and much of Asia will experience an increase of between 314 and 336 % for the same period. “We estimate that 24 million people have dementia today,” say the authors, “and that this amount will double every 20 years to 42 million by 2020 and 81 million by 2040.”

Considering these dire predictions, efforts to understand, diagnose and treat this treacherous and invariably fatal disease are in high gear. At Siemens' state-of-the-art Molecular Imaging Biomarker Research Center in Culver City, California, for instance, researchers led by Hartmuth Kolb, PhD, Vice President, Siemens Medical Solutions, are focusing on development of molecules that are designed to seek out and “light up” AD indicators when scanned using positron emission tomography (PET).

Specifically, Kolb's team is in hot pursuit of two key brain pathology hallmarks associated with AD: the beta-amyloid plaques that form in the brains of AD patients, and neurofibrillary tangles (NFTs), which are made up of abnormally phosphorylated tau proteins. Derived from amyloid precursor protein (APP), which is essential for the growth and repair of neurons, beta-amyloid oligomers and fibrils (the constituents of plaques) should not exist independently in the brain. Their presence is therefore a powerful indicator of a process that is characteristic of AD in which APP is cleaved into fragments, the beta-amyloid sections of which form plaques. Another change that is closely associated with AD is transformation of the tau protein, which is involved in forming a neuron's cytoskeleton (protein "scaffolding" contained within the cytoplasm) and in assisting cellular transport. In AD, this important protein is abnormally phosphorylated, leading to the formation of aggregated filaments, which make up the NFTs, thus impeding the normal function of tau and leading to neuronal death.

In the course of the last two years, Kolb's team has developed a fluorine-18 probe that attaches to beta-amyloid plaques. When injected into a person with AD, the probe is designed to aggregate in plaque, making it visible during a PET scan, and thus providing objective evidence of this particular pathological hallmark of the disease. Now in early stage clinical trials, “the probe is being tested for safety in humans and compared with other beta-amyloid probes,” says Kolb.

But the AD research community, which is primarily interested in discovering and hopefully treating the disease before it has a chance to cause irreversible damage, has become skeptical that beta-amyloid plaque testing can provide all the answers. “Recent studies have indicated that the quantity of plaque is not correlated to the severity of the illness,” says Kolb. “It might just be a side effect.” With this in mind, Kolb's emphasis has shifted to an investigation of the tau protein that has been linked to the development of tangles. “We suspect that tau may be a more linear diagnostic indicator than beta-amyloid plaque,” says Kolb. “But we will know much more once we have a probe that binds to it, thus making it possible to image it.” Indeed, a radioactive probe is now being tested on slices from human AD brains, and an optimized variant of this probe is expected to become available for clinical trials in the future.

Whether Kolb and his colleagues are attempting to image tau, plaque or any other AD-associated biomarker, pharmaceutical companies are eager to work with Siemens to determine the effects of their newest compounds on disease pathology. The reasons are clear. Not only is Siemens a leader in biomarker discovery; it is also the worldwide leader in PET, CT and MR imaging. Indeed, as these molecular and anatomical imaging technologies are combined, researchers will be able to see AD-related physiology and pinpoint its location in a fused information environment—a capability that is set to accelerate the drug discovery process. “As soon as we can accurately image a marker,” says Kolb, “we can also begin to see whether a medication is affecting it.”

And as researchers investigate new compounds in clinical trials, they are learning more and more about the differences between normal and AD brains. Not only are there well-known anatomical changes in AD, such as dramatic brain shrinkage and cell loss; there are also physiological changes such as reduced glucose metabolism and neurotransmitter activity that, once more deeply understood, may serve as early warning signs for the disease when imaged over time.

Precisely what mechanisms trigger and drive the development of Alzheimer's disease are not yet clear. But until they are understood, doctors will continue to be powerless to provide anything but palliative solutions. “I think Alzheimer's will eventually turn out to be driven by a combination of beta-amyloid plaque, hyperphosphorylated tau and their precursors,” says Kolb. “If so, we will be on track to early detection, and within ten years we may have the knowledge to slow it down or even bring it to a halt.“