Piece of Mind: Biomarkers in Alzheimers Disease

	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 have a different cause and evolve at a different stage of the disease compared to that of amyloid accumulation. Studies on this are currently being carried out on living patients using PET imaging.

11C-PiB PET is an excellent research tool to use in PET centers that have cyclotrons on site, but it is not going to be useful as a clinical tool because of its very short half-life of about 20 minutes, explains Mathis. An F18-labelled PiB tracer with a longer half-life could be made in a regional cyclotron and shipped and distributed easily though. Ninety percent of the U.S. population is covered by commercial production of F18-labelled FDG and PET scanner network, Mathis notes. "If we use the same distribution regional centers to make F18-labelled amyloid agents, it would be available to 90 percent of the population in U.S.," he says.

"When we have a drug that can delay or treat Alzheimer's disease, then imaging will have a huge impact," shares Mathis. (Currently, there are more than 80 drugs at various stages of testing, many of which are aimed at reducing amyloid buildup; no new drugs are expected to come to market in the next five years.)

Physicians can treat the symptoms of memory loss with cholinesterase inhibitors, but it doesn't treat the root cause and today there is no cure for Alzheimer's disease. "Drug companies are using amyloid imaging in their clinical trials—to screen for subjects who qualify for the trial and also to follow subjects who are in the trials to see if it lowers amyloid in the brain," Mathis says. A phase 2 study published in Lancet Neurology in April 2010 used 11C-PiB PET imaging to assess the effects of potential Alzheimer's disease drug, bapineuzumab, a humanized anti-amyloid-? monoclonal antibody.

Amyloid imaging moving to the lab

A U.S. FDA advisory committee in late January voted unanimously to recommend approval of the first beta-amyloid imaging agent florbetapir (Amyvid, Eli Lilly)—conditional on a reader training program that demonstrates reader accuracy and consistency through a re-read of previously acquired scans. However, in March, the full panel reversed course, denying approval because of the hefty physician training requirements associated with reading the studies.

The committee noted that for the first time a negative scan would be clinically useful in indicating that Alzheimer's pathology is unlikely to be the cause of a patient's cognitive decline.

There is potential for beta-amyloid imaging to help Alzheimer's disease therapy assessment, in non-invasively assessing plaque burden of amyloid and thus determining if a drug is effective, notes Daniel H. Silverman, MD, PhD, head of the Neuronuclear Imaging section at UCLA Medical Center and associate professor of molecular and medical pharmacology at the David Geffen School of Medicine. It also will likely expand the market for currently underutilized brain PET.

Current drugs on the market "slow the rate of cognitive decline from Alzheimer's. It's proven," Silverman notes. "And, in addition to contributing to quality of life, slowing a patient's neurological decline is a cost-effective solution as well, since each extra month in a nursing home in the U.S. costs $6,000 to $7,000."

With 10 to 20 percent of clinically diagnosed Alzheimer's patients lacking Alzheimer's disease pathology at autopsy, and more than 40 percent of those with early dementia who are proven at autopsy to not have Alzheimer's disease having been actually misdiagnosed with the disease during life, both the diagnosis and determination of risk for Alzheimer's disease remain poor. Extensive research is underway to discover ligands that can visualize beta-amyloid burden in the brain, a signature of Alzheimer's disease.

Framingham Estimated Lifetime Risks for Alzheimer's by Age & Sex

Source: Alzheimer's Association 2011 Alzheimer's Disease Facts and Figures.

Framingham Estimated Lifetime Risks for Alzheimer's by Age & Sex

Source: Alzheimer's Association 2011 Alzheimer's Disease Facts and Figures.

Recently published research in the Journal of the American Medical Association found a strong quantitative correlation between florbetapir F18's signal on PET scans and the presence of beta-amyloid in the brain at death.

Thirty-five elderly individuals underwent florbetapir-PET scans within 12 months of death. "Florbetapir-PET images were assessed visually using a semiquantitative visual score ranging from 0 [no amyloid] to 4 [high levels of cortical amyloid] by three board-certified nuclear medicine physicians who were not involved in any other aspects of the study," according to Clark and colleagues. These findings were correlated to cortical beta-amyloid pathology at autopsy (measured using immunohistochemistry or by silver strain), with the pathologists blinded to imaging results.

Additionally, florbetapir-PET was used to evaluate 47 young (mean age 26 years) and cognitively healthy individuals, with the hypothesis that the imaging would reveal fewer than 10 percent of these healthy participants presenting with beta-amyloid burden.

Good correlation was observed between whole brain florbetapir-PET scores and the postmortem amyloid pathology measured by both immunohistochemistry and silver stain neuritic plaque score, with values of 0.78 and 0.71, respectively. Of the 29 patients so far, and considered for primary analysis, 15 met pathological criteria for Alzheimer's disease and 14 had low levels of beta-amyloid aggregations, therefore not fulfilling the pathological criteria for Alzheimer's disease.

Within these findings, 14 of 15 individuals were positively identified with Alzheimer's disease using florbetapir-PET (sensitivity 93 percent) and 14 of the 14 patients with pathological confirmation as Alzheimer's disease-negative were evaluated as such using PET (specificity 100 percent).

"In total, the blinded read results for the florbetapir-PET images agreed with the final autopsy with respect to the presence or absence of neuropathological criteria of Alzheimer's disease in 28 of 29 cases," explained Clark and colleagues. They argued that this finding "suggests that a florbetapir-PET image provides an accurate and reliable assessment of beta-amyloid burden."

All 74 of the younger individuals imaged presented with florbetapir-PET images were negative for beta-amyloid burden. The agreement among the three nuclear medicine readers across the whole ranged from 91 to 99 percent.

Also of interest on an exploratory basis, one false-negative and two false-positive diagnoses of Alzheimer's disease or dementia late in life were found via autopsy, whereas florbetapir-PET agreed with the autopsy results (considered the gold standard) in all three cases.

"[T]he authors convincingly showed that the antemortem imaging signals related to postmortem amyloid pathology," wrote Monique M.B. Breteler, MD, PhD, of the University Medical Center Rotterdam, in the Netherlands, in an accompanying JAMA editorial. "However, the present study falls short in evaluating the sensitivity and specificity of florbetapir imaging."

Breteler called the 97 percent agreement between florbetapir-PET and the postmortem pathology "likely inflated," due to the nonrandom selection of persons who were more likely to have beta-amyloid burdens. Similarly, the findings that none of the younger cohort presented under florbetapir-PET with beta-amyloid burden could equally overestimate the specificity of florbetapir-PET in detecting beta-amyloid burden.

"[J]ust as the observation of a flock of white swans does little to support the notion that no black swans exist, so the observation of amyloid-negative scans in young persons does little to establish the specificity of this imaging mode in persons aged in their 70s and 80s, who may or may not have varying amounts of coexisting brain atrophy and other pathologic changes," Breteler argued.

Still, Clark and colleagues affirmed the importance of their findings in adding to a body of evidence indicating that biomarkers might signal beta-amyloid burden and help diagnose, predict and even treat Alzheimer's disease.

Also in the pipeline are two additional F18 amyloid imaging agents in phase 3 FDA clinical trials in the U.S.—Bayer Schering Pharma AG's florbetaben and GE Healthcare's flutemetamol.

FDG-PET imaging

FDG-PET is clinically approved in the U.S. for differential diagnosis of frontal temporal dementia from Alzheimer's disease. However, FDG-PET scans may look normal in cognitively normal subjects with significant beta amyloid deposits in the brain, Mathis says.  

Researchers are looking to see how  biomarkers tie together. Combined classifiers, algorithms that would take data from several biomarkers, and demographic variables such as age or gender to compute the individual risk of Alzheimer's disease, are being developed by Liana Apostolova, MD, MS, assistant professor in neurology at the Mary S. Easton Center for Alzheimer's disease research, University of California, Los Angeles and colleagues. Apostolova's group focuses on combining imaging and genetic information in predictive classifier models using data from the ImaGene study—a project that follows cognitively normal and mild cognitive impairment (MCI) subjects longitudinally with detailed cognitive and clinical assessments, MRI scans, gene expression and proteomics measurements.

The Alzheimer's disease Neuroimaging Initiative (ADNI)

National Institutes of Health (NIH)'s Alzheimer's disease Neuroimaging Initiative (ADNI), the largest public-private partnership in Alzheimer's disease research began in October 2004, as a six-year research project to study changes of cognition, brain structure and function, and biomarkers in elderly controls, subjects with MCI, and subjects with Alzheimer's disease. A major goal of ADNI is to determine and validate MRI, PET images, and CSF/blood markers as predictors and outcomes for use in clinical trials of Alzheimer's disease treatments.

"ADNI-1, the first Alzheimer's disease neuroimaging initiative is not a clinical trial but a study of the disease process using different imaging and biomarker techniques—it is a database of reference values for elderly control, MCI and Alzheimer's disease patients," shares Mathis. A total of 800 subjects including 200 normal controls, 400 individuals with MCI and 200 subjects with mild Alzheimer's disease were recruited at approximately 50 sites in the U.S. and Canada for longitudinal follow up in ADNI-1.

What does all this mean? "Within a couple years, we will likely be able to give patients and their families statistically reliable estimates as to how quickly (or slowly) their cognition will decline over the next several years," Silverman says. "We also see potential for brain imaging with PET to begin to overcome the current problem of it being grossly under-used, with respect to both the available evidence pointing to its diagnostic and prognostic utility from even the earliest stages of progressive cognitive decline, as well as under the specified conditions in which Medicare has already deemed its use to be 'reasonable and necessary' in patients with early dementia."