Piece of Mind: Biomarkers in Alzheimers Disease

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Image courtsey of Kelsey Mason, Cheri Geist, research associates, and Daniel Silverman, MD, Neuronuclear Imaging Center at UCLA Medical Center.

FDG-PET is highly accurate in diagnosing progressive neurodegenerative disease such as Alzheimer's disease even if cognitive dysfunction is only mild. Thus, novel brain imaging probes targeting for instance beta-amyloid will likely serve a different purpose. They will play an important role if beta-amyloid is confirmed as a molecular target of effective therapy, and drugs that target beta-amyloid are actually developed.

Earlier this spring, the Alzheimer's Association and the National Institute on Aging (NIA) published new criteria for the diagnosis of Alzheimer's disease, emphasizing the need for further research on biomarkers. "If we can definitively determine the risk of developing Alzheimer's dementia in people who have biomarker evidence of brain changes but are not showing outward symptoms, we will open an important window of opportunity to intervene with disease-modifying therapies, once they are developed," William Thies, PhD, chief medical and scientific officer at the Alzheimer's Association, explained.

The World Health Organization estimates that there are currently 18 million people worldwide living with Alzheimer's disease. This figure is projected to nearly double by 2025 to 34 million. Much of this increase will be in developing countries, largely due to aging populations.

Alzheimer's disease devastates the brains of sufferers as well as healthcare's pocketbook each year. For example, in the U.S., there are 5.4 million Americans living with the disease and every 69 seconds a new patient is afflicted, according to the Alzheimer's Association's "2011 Facts and Figures" report. Last year, 500,000 more Americans were diagnosed with Alzheimer's. Medicare costs are almost three times higher for people with Alzheimer's and other dementias than for other older people, and Medicaid costs are almost nine times higher. A study by researchers at Johns Hopkins University in Baltimore, published in the American Journal of Public Health, estimated that delaying the onset of symptoms by one year in every Alzheimer's patient would save the United States $10 billion annually.

Alzheimer's pathological biomarker cascade

Neuroimaging biomarkers can improve on our ability to diagnose and treat Alzheimer's disease early. A hypothetical model that relates disease stage to Alzheimer's disease biomarkers was published in January 2010 issue of Lancet Neurology by Clifford Jack Jr. et al. According to the model, biomarkers of beta-amyloid deposition become abnormal early, before neurodegeneration and clinical symptoms occur. 

Amyloid PET imaging

The 11C-PiB tracer—[N-methyl-11C]2-(4'-methylaminophenyl)-6-hydroxybenzothiazole, Pittsburgh compound B (PiB)—invented by Chester Mathis, PhD, and William E. Klunk, MD, PhD, visualizes fibrillar beta-amyloid in the brain. A case study of the first patient with Alzheimer's disease who underwent PET imaging with 11C-PIB PET both during progression of the disease and after death was published online in Brain on Dec. 13, 2010. The patient underwent PET studies with 18F-FDG three times (at ages 53, 56 and 58 years) and twice with PIB (at ages 56 and 58 years), prior to death at 61 years of age, according to Agneta Nordberg, MD, PhD, professor and head of the division of Alzheimer neurobiology, Karolinska Institute in Stockholm. The study showed that the greater accumulation of plaque is accompanied by a reduction in the number of neuronal nicotinic receptors in the brain. There was a negative correlation between regional fibrillar beta-amyloid and levels of 3H-nicotine binding.

Images of both brain FDG-PET (top row) and brain AVID-45 (amyloid imaging agent, bottom row) PET scans, with the FDG-PET coming from two different points in progression of disease...from mild cognitive impairment to full-blown Alzheimer’s disease four years later. It also illustrates the additional diagnostic/prognostic power derived from regional quantification of brain activity and interval changes (upper right image). Source: Kelsey Mason, research associate, Cheri Geist, research associate, and Daniel Silverman, MD, Neuronuclear Imaging Center at University of California, Los Angeles

Further, inflammatory changes were measured in brain regions with low levels of plaques, which suggest that the neuroinflammation related to Alzheimer's disease might