Biomarker Update: Alzheimers Detection
The worldwide costs of dementia are $604 billion (U.S.) in 2010, according to the World Alzheimer Report 2010 by Alzheimer's Disease International. Biomarkers, which are reliable indicators of disease processes or the body's response to therapy, hold promise in early Alzheimer's disease (AD) detection. Recent updates in AD detection using amyloid PET radiotracer 18F-flutemetamol, as well as proteins in the cerebrospinal fluid and blood are currently being assessed.
The World Alzheimer Report 2010 estimated that there are 35.6 million people living with dementia worldwide, which is expected to increase to 65.7 million by 2030 and 115.4 million by 2050. Early diagnosis of AD is very important as treatments could then target the disease in its earliest stages, before irreversible brain damage or mental decline has occurred.
Currently, three 18F-labeled amyloid ligands are in Phase 3 clinical development: Florbetapir (Amyvid, Eli Lilly), Flutemetamol (GE Healthcare) and Florbetaben (Bayer Schering Pharma). "Florbetapir has the potential to reach the clinics within six to nine months," according to Carrillo. Eli Lilly has received a complete response letter from the U.S. FDA, establishing the need to establish a reader training program for market implementation, which the company is developing. A negative Florbetapir PET scan would be clinically useful in indicating that Alzheimer's pathology is unlikely to be the cause of a patient's cognitive decline. Both consumers and physicians who use Florbetapir should understand that it rules out Alzheimer's—it doesn't confirm that you have it, says Carrillo.
18F-Flutemetamol, currently in Phase 3 trials, is expected to become available for clinical use for amyloid imaging in AD and mild cognitive impairment within the next one to two years, according to Rik Vandenberghe, MD, PhD, professor in neurology, AD Centre K.U.Leuven, University Hospitals Leuven, Belgium. 18F-Flutemetamol highlights beta-amyloid in a PET scan and is structurally identical to 11C-Pittsburgh Compound B (PiB) except for one fluorine atom in place of a carbon atom, making it more stable than PiB.
The Phase 2 study results of 18F-Flutemetamol, published by Vandenberghe et al, showed that 25 of the 27 scans from AD patients were assigned to the "raised uptake" category, nine of the 20 scans from the mild cognitive impairment (MCI) group, and one of the 25 scans from the controls (Ann Neurol 2010;68(3):319-329). This means a sensitivity of 93 percent and a specificity of 96 percent with the clinical diagnosis as comparator (AD vs. controls), according to Vandenberghe.
"As a secondary outcome measure, we also found that cortical 18F-Flutemetamol uptake correlated very closely with uptake of PiB and that repeatability within the same subject scanned on two separate occasions also was high," he adds. "One important advantage is that the findings are highly repeatable between centers, while cerebrospinal fluid [CSF] measures have until now had to deal with a relatively high between center variability," says Vandenberghe. An ongoing Phase 3 study is investigating the predictive value of 18F-Flutemetamol uptake in MCI for subsequent conversion to AD.
However, there are large variations in biomarker measurements between studies, as well as between and within laboratories. The U.S. Alzheimer's Association has initiated a global quality control program to estimate and monitor variability of measurements, quantify batch-to-batch assay variations, and identify sources of variability. The program is open for laboratories using commercially available kits for amyloid beta-42, T-tau or P-tau.
"The most important thing now is to standardize the biomarker measurements around the world," says Zetterberg. He says that in Sweden it has been easy to implement the new AD diagnostic criteria because most CSF samples in Sweden are analyzed in their laboratory at University of Gothenburg.
It also is possible to correlate blood measurements with the amount of amyloid plaque seen in the brain. Samantha Burnham, PhD, a post-doctoral research fellow at Commonwealth Scientific Industrial Research Organisation (CSIRO) in Perth, Australia, and colleagues have generated a model using nine blood-based markers (including amyloid beta-42, ApoE and cortisol) to estimate the amount of deposited amyloid in the brain. "We achieved 83 percent sensitivity and 85 percent specificity for identifying individuals with high amyloid loading vs. those with low amyloid loading," she says.
Burnham believes that the addition of other biomarkers may improve the efficacy of the test and their team currently is obtaining further blood measurements to explore this. "Once we are satisfied with the biomarkers, we will need to further validate them including looking at other disease cohorts for specificity and in population screening. It also will be necessary to format tests onto a platform suitable for widespread screening," she adds.
What challenges lie ahead? "First, we need to more clearly understand through longitudinal studies what biomarkers actually represent or indicate as a person develops dementia over time. Second, we do not have enough information to standardize any of these biomarkers, including the amyloid imaging biomarkers," says Carrillo.
"It is likely that due to the late detection of the disease, drug candidates for AD have been largely ineffective. Drug candidates need to be tested at the early stages of disease before irreversible damage occurs," says Burnham. Thus, there is a real need to validate biomarkers for early detection as well as a means to measure the rate of progression of AD.
The World Alzheimer Report 2010 estimated that there are 35.6 million people living with dementia worldwide, which is expected to increase to 65.7 million by 2030 and 115.4 million by 2050. Early diagnosis of AD is very important as treatments could then target the disease in its earliest stages, before irreversible brain damage or mental decline has occurred.
Amyloid PET imaging
An accurate measurement or indicator of increased amyloid deposits in the brain could possibly provide an earlier diagnosis of AD prior to cognitive decline. The Alzheimer's Association and the National Institute on Aging published new criteria and guidelines in April for the diagnosis of AD. The groups called for extensive research, especially in the use of biomarkers for early Alzheimer's detection to better understand what amyloid deposits mean in the brain, what changes happen over time and how they come to actually determine whether the patient has dementia or not, says Maria Carrillo, PhD, senior director, medical and scientific relations of the U.S. Alzheimer's Association in Chicago.Currently, three 18F-labeled amyloid ligands are in Phase 3 clinical development: Florbetapir (Amyvid, Eli Lilly), Flutemetamol (GE Healthcare) and Florbetaben (Bayer Schering Pharma). "Florbetapir has the potential to reach the clinics within six to nine months," according to Carrillo. Eli Lilly has received a complete response letter from the U.S. FDA, establishing the need to establish a reader training program for market implementation, which the company is developing. A negative Florbetapir PET scan would be clinically useful in indicating that Alzheimer's pathology is unlikely to be the cause of a patient's cognitive decline. Both consumers and physicians who use Florbetapir should understand that it rules out Alzheimer's—it doesn't confirm that you have it, says Carrillo.
Entering clinics: 18F-flutemetamol
 |
| Transverse sections through representative 18F-flutemetamol images from a case with Alzheimer’s disease in an early stage (A) and an age-matched healthy control (B). Source: Rik Vandenberghe, MD, PhD, professor of neurology, AD Centre K.U. Leuven University Hospitals Leuven, Belgium. |
The Phase 2 study results of 18F-Flutemetamol, published by Vandenberghe et al, showed that 25 of the 27 scans from AD patients were assigned to the "raised uptake" category, nine of the 20 scans from the mild cognitive impairment (MCI) group, and one of the 25 scans from the controls (Ann Neurol 2010;68(3):319-329). This means a sensitivity of 93 percent and a specificity of 96 percent with the clinical diagnosis as comparator (AD vs. controls), according to Vandenberghe.
"As a secondary outcome measure, we also found that cortical 18F-Flutemetamol uptake correlated very closely with uptake of PiB and that repeatability within the same subject scanned on two separate occasions also was high," he adds. "One important advantage is that the findings are highly repeatable between centers, while cerebrospinal fluid [CSF] measures have until now had to deal with a relatively high between center variability," says Vandenberghe. An ongoing Phase 3 study is investigating the predictive value of 18F-Flutemetamol uptake in MCI for subsequent conversion to AD.
Fluid biomarkers
Of the fluid biomarkers, CSF is the furthest along the road toward acceptance, according to Carrillo. Studies have shown that approximately 90 percent of MCI patients with pathological CSF biomarkers at baseline will develop AD within nine to 10 years, according to Henrik Zetterberg, MD, PhD, professor of neurochemistry at the Sahlgrenska Academy in Gothenburg, Sweden, and colleagues. The CSF biomarkers amyloid beta-42 levels already are fully decreased at least five to 10 years before conversion to AD dementia, while total-tau (T-tau), and phosphorylated-tau (P-tau) seem to be later markers.However, there are large variations in biomarker measurements between studies, as well as between and within laboratories. The U.S. Alzheimer's Association has initiated a global quality control program to estimate and monitor variability of measurements, quantify batch-to-batch assay variations, and identify sources of variability. The program is open for laboratories using commercially available kits for amyloid beta-42, T-tau or P-tau.
"The most important thing now is to standardize the biomarker measurements around the world," says Zetterberg. He says that in Sweden it has been easy to implement the new AD diagnostic criteria because most CSF samples in Sweden are analyzed in their laboratory at University of Gothenburg.
It also is possible to correlate blood measurements with the amount of amyloid plaque seen in the brain. Samantha Burnham, PhD, a post-doctoral research fellow at Commonwealth Scientific Industrial Research Organisation (CSIRO) in Perth, Australia, and colleagues have generated a model using nine blood-based markers (including amyloid beta-42, ApoE and cortisol) to estimate the amount of deposited amyloid in the brain. "We achieved 83 percent sensitivity and 85 percent specificity for identifying individuals with high amyloid loading vs. those with low amyloid loading," she says.
Burnham believes that the addition of other biomarkers may improve the efficacy of the test and their team currently is obtaining further blood measurements to explore this. "Once we are satisfied with the biomarkers, we will need to further validate them including looking at other disease cohorts for specificity and in population screening. It also will be necessary to format tests onto a platform suitable for widespread screening," she adds.
What challenges lie ahead? "First, we need to more clearly understand through longitudinal studies what biomarkers actually represent or indicate as a person develops dementia over time. Second, we do not have enough information to standardize any of these biomarkers, including the amyloid imaging biomarkers," says Carrillo.
"It is likely that due to the late detection of the disease, drug candidates for AD have been largely ineffective. Drug candidates need to be tested at the early stages of disease before irreversible damage occurs," says Burnham. Thus, there is a real need to validate biomarkers for early detection as well as a means to measure the rate of progression of AD.
| Matching Patients & Researchers: Alzheimer's Association TrialMatch | ||
"Through Alzheimer's Association's TrialMatch, patients and family members can look up the Alzheimer's trials online and find a trial that is actually recruiting and matches the patient's medical history so that he or she doesn't waste time in trials that he or she is not qualified for," says Maria Carrillio, PhD, senior director, medical and scientific relations of the U.S. Alzheimer's Association in Chicago. Physicians can use TrialMatch to find local trials that their patients can participate in, she adds. |
