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Category Archives: biomarkers

Are you Genetically Predisposed to Alzheimer’s Disease?

I meet many people that worry they might be genetically predisposed to Alzheimer’s by birth. Some of them tell me they would like to know, others say they don’t want to know. As the number of people suffering from Alzheimer’s grows this is certain to become a major medical issue nationally.

Myriad Genetics has a genetic test for breast cancer. Their BRACAnalysis® assesses a woman’s risk of developing breast or ovarian cancer. BRACAnalysis is a genetic test that requires only a blood sample to determine whether a patient has a BRCA1 or BRCA2 gene mutation, indicating a predisposition to hereditary breast and ovarian cancer. The test is expensive but might be covered by insurance. Author note: I worked on the start-up financing for Myriad Genetics.

In a just released research study, researchers are looking at specific blood markers and may be able to detect a person’s predisposition to Alzheimer’s. This is exciting news. I know from personal experience with my mother that early detection is important and does effect outcomes. I am also aware of cases where families waited to take action and the result usually means a quicker onset of the debilitating disease. If you suspect Alzheimer’s or dementia you must take immediate action. If you had a severe chest pain you would call 9-1-1 wouldn’t you?


Related post Alzheimer’s Disease Genetics Study

Researchers Seeking to Identify Alzheimer’s Risk with New Biomarkers Make Significant Progress by Focusing on a Specific Blood Marker

Blood Test Could Give People Advance Warning of Disease, Allowing for Earlier Intervention

A simple blood test to detect whether a person might develop Alzheimer’s disease is within sight and could eventually help scientists in their quest toward reversing the disease’s onset in those likely to develop the debilitating neurological condition, Columbia University Medical Center researchers announced today.

Building on a study that started 20 years ago with an elderly population in Northern Manhattan at risk or in various stages of developing Alzheimer’s disease, the Columbia research group has yielded ground-breaking findings that could change the way the disease is treated or someday prevent it. These findings suggest that by looking at the blood doctors may be able to detect a person’s predisposition to developing the dementia-inducing disease that robs a person of their memory and ability carry out tasks essential to life.

Results presented online in the Proceedings of the National Academy of Sciences during the week of Sept. 8, 2008 suggest that individuals with elevated levels of a certain peptide in the blood plasma, Amyloid Beta 42 (Aß42), are at increased risk of developing Alzheimer’s disease and that the decline of Aß42 in the bloodstream may reflect the compartmentalization or “traffic jam” of Aß42 in the brain, which occurs in people with Alzheimer’s.

“To date, Aß42 levels have measured most reliably in the cerebrospinal fluid, which is more difficult to collect than blood,” said Nicole Schupf, Ph.D., Dr.P.H., associate professor of clinical epidemiology at Columbia University Medical Center and lead author of the paper. “Blood draws can be done with relative ease and greater frequency than spinal taps, which is typically the way cerebrospinal fluid is collected.”

In this study, researchers found that plasma levels of Aß42 appear to increase before the onset of Alzheimer’s disease and decline shortly after the onset of dementia. Researchers surmise that Aß42 may become trapped in the brain, which could account for the decrease in levels post-dementia.

The principal investigator on the Northern Manhattan study, Richard Mayeux, M.D., M.S., professor of neurology, psychiatry, and epidemiology, and co-director of the Taub Institute of Research on Alzheimer’s Disease and the Aging Brain at CUMC, likens the finding to something similar that is seen in heart attack patients, who typically have elevated lipid levels in their bloodstream prior to a heart attack, but post-heart attack lipid levels may decrease.

Using more specific antibodies developed by the Ravetch Laboratory at Rockefeller University, the researchers were able to hone in on the most detrimental form of amyloid compound, the protofibrillar form of Aß, according to Dr. Mayeux, who is the senior author of this paper.

While the cognitive impairments of Alzheimer’s can be monitored throughout the disease course, clinicians have had no reliable way to monitor the pathologic progression of the disease. Being able to reliably measure Aß levels in the blood could provide clinicians with a tool that forecasts the onset of Alzheimer’s much earlier. Earlier detection would of course be an important step in combating the disease, researchers said.

This research is supported by a Program Project Grant by the National Institutes’ of Health National Institute of Aging. Other authors on the paper from Columbia University Medical Center include Ming X. Tang, Ph.D., Jennifer Manly, Ph.D., and Howard Andrews, Ph.D. The Department of Immunology at the New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York, also contributed to this research. An image of a brain tissue coated with amyloid plaque is available upon request, as is a copy of the PNAS paper.

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The Taub Institute for Research on Alzheimer’s Disease and the Aging Brain at Columbia University Medical Center is a multidisciplinary group that has forged links between researchers and clinicians to uncover the causes of Alzheimer’s, Parkinson’s and other age-related brain diseases and discover ways to prevent and cure these diseases. Taub neuroscientists partner with researchers at the Gertrude H. Sergievsky Center at Columbia University Medical Center, which was established by an endowment in 1977 to focus on diseases of the nervous system. The Sergievsky Center integrates traditional epidemiology with genetic analysis and clinical investigation to explore all phases of diseases of the nervous system. For more information about these CUMC centers visit: http://www.cumc.columbia.edu/dept/taub/ or
http://www.cumc.columbia.edu/dept/sergievsky/.

Columbia University Medical Center provides international leadership in basic, pre-clinical and clinical research, in medical and health sciences education, and in patient care. The medical center trains future leaders and includes the dedicated work of many physicians, scientists, public health professionals, dentists, and nurses at the College of Physicians & Surgeons, the Mailman School of Public Health, the College of Dental Medicine, the School of Nursing, the biomedical departments of the Graduate School of Arts and Sciences, and allied research centers and institutions. Established in 1767, Columbia’s College of Physicians & Surgeons was the first institution in the country to grant the M.D. degree and is among the most selective medical schools in the country. Columbia University Medical Center is home to the largest medical research enterprise in New York City and state and one of the largest in the United States. For more information, please visit www.cumc.columbia.edu.

Original Content The Alzheimer’s Reading Room

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Markers in Blood and Spinal Fluid, and a New Imaging Agent, Show Promise for Early Detection of Alzheimer’s

Alzheimer’s Association International Conference on Alzheimer’s Disease 2008

With the continued aging of the population and the growing epidemic of Alzheimer’s, early detection of the disease is crucial for risk assessment, testing new therapies, and eventual early intervention with better drugs, once they are developed. Four studies reported today at the Alzheimer’s Association’s 2008 International Conference on Alzheimer’s Disease (ICAD 2008) in Chicago bring us closer to that goal of early detection by describing advances in biomarkers.


Markers in Blood and Spinal Fluid, and a New Imaging Agent, Show Promise for Early Detection of Alzheimer’s

A biomarker is a substance or characteristic that can be objectively measured and evaluated as an indicator of normal body processes, disease processes, or the body’s response(s) to a therapeutic intervention.

It is widely believed that Alzheimer’s disease brain changes, including amyloid plaques and neurofibrillary tangles, begin many years before symptoms are evident or there is significant death of brain cells. It is critical to identify affected individuals while they are still cognitively normal so that future disease modifying therapies can preserve normal function. The testing and eventual use of such therapies requires identification of affected and “at risk” individuals in order to steer them to clinical trials, and to direct and monitor therapy.

“Discovery of measurable markers that track with the presence of Alzheimer’s pathology and that predict the development of cognitive decline in people who are still cognitively normal, known as ‘antecedent biomarkers,’ are especially needed,” said William Thies, PhD, vice president of Medical and Scientific Relations at the Alzheimer’s Association. “It is greatly preferable that these markers be easy to obtain, such as in samples of blood or urine, or through readily available imaging technologies, such as MRI and PET.”

Blood Test on White Blood Cells May Be Useful for Early Detection of Alzheimer’s

Healthy brain cells do not go through the process of division and replication (known as the “cell cycle”) that is common in other cells in the body. However, in Alzheimer’s disease, brain cells have demonstrated an abnormal tendency to prepare to re-enter this cell cycle, which may increase their likelihood of dying or directly cause their death.

The equivalent cell cycle defect is found in lymphocytes of people with Alzheimer’s. Lymphocytes are white blood cells in the immune system that can easily be collected for testing by a simple blood draw. Professor Thomas Arendt, Director of the Paul Flechsig Institute, University of Leipzig, Germany, thought that this suggested a vehicle for detecting Alzheimer’s.

In a study performed in the U.S. by GW Medical, the licensor of Arendt’s technology, Arendt and colleagues measured the expression of CD-69 (a protein involved in white blood cell growth and production) on multiple cell lines in people with probable Alzheimer’s (n=32), healthy controls (n=30) and other dementias, chiefly Parkinson’s disease dementia, (n=26).

Variations in levels of CD-69 enabled the researcher to clearly differentiate between Alzheimer’s subjects and demented Parkinson’s subjects. It was accurate 91 percent of the time when the diagnosis was Alzheimer’s and 92 percent of the time when it was Parkinson’s dementia. The assay correctly differentiated people with Alzheimer’s from cognitively normal subjects 88 percent of the time when the diagnosis was Alzheimer’s and 82 percent of the time when the person was cognitively normal.

In addition, Arendt found that the test results did not vary with dementia severity as measured by the Mini Mental State Exam.

“The lack of variation suggests that this test may be useful in the early stages of Alzheimer’s,” Arendt said. “A larger trial is underway with results expected by late summer 2008. If confirmed, it will give primary care physicians a better, more accurate and non-invasive test for Alzheimer’s disease.”

Spinal Fluid Marker Tracks Brain Amyloid, May Identify Alzheimer’s Before Symptoms

Some researchers believe that flaws in processes governing production, accumulation, or disposal of amyloid protein in the brain are the primary cause of Alzheimer’s. Aβ42 is a particularly “sticky” variety of amyloid protein fragment that is more likely to aggregate into small clusters and eventually into the plaques that are considered one hallmark of the Alzheimer brain.

Anne M. Fagan, PhD, of the Washington University School of Medicine, St. Louis, MO, and colleagues previously demonstrated in a small group (n=24) that a low level of Aβ42 in cerebrospinal fluid (CSF) is an effective marker for determining the presence of amyloid in the brain as assessed by PET scans using a marker called Pittsburgh Compound B (PIB).

In a new study presented at ICAD 2008, Fagan reported on a much larger cohort (n=132; age 45-88 years, mean 65.7). This group included individuals who were non-demented plus those with very mild or mild dementia. Consistent with the prior study, the researchers observed a striking inverse relation between presence of amyloid in the brain and levels of Aβ42 in CSF.

Overall, those people with high amounts of brain amyloid (as indicated by PET scan images showing positive PIB-binding) had low CSF Aβ42 (36/37, 97%). Those with low levels of brain amyloid (negative PIB-binding) had high CSF Aβ42 (80/95, 84%). This was true regardless of cognitive status, indicating excellent sensitivity of CSF Aβ42 for identifying the presence of brain amyloid, according to the researchers.

In addition, they observed that three non-demented, low CSF Aβ42, PIB-positive study participants have subsequently received an Alzheimer’s diagnosis suggesting that positive PIB and low CSF Aβ42 may be useful as markers of “preclinical Alzheimer’s” (that is, Alzheimer’s prior to visible symptoms).

“We found that CSF Aβ42 is an excellent marker for identifying the presence of amyloid in the brain, regardless of the person’s cognitive status,” Fagan said. “Our analyses also suggest that a decline in CSF Aβ42 may effectively identify non-demented individuals who are in the preclinical stage of Alzheimer’s, even before they are PIB positive.”


Brain Enzyme May Improve Alzheimer’s Risk Assessment and Early Detection

Researchers have previously found elevated β-secretase (BACE1) activity in the brains of patients with Alzheimer’s compared to healthy individuals. BACE1 is one of two enzymes involved in the pathological processing of amyloid precursor protein (APP) and the production of toxic Aβ (beta amyloid, the main constituent of amyloid plaques in the brains of people with Alzheimer’s).

Professor Harald Hampel, of Trinity College Dublin, Ireland and the University of Munich, Germany, Professor Yong Shen, of Sun Health Research Institute, USA, and colleagues investigated whether BACE1 assessed in cerebrospinal fluid (CSF) may be a feasible biomarker candidate for predicting Alzheimer’s in people with mild cognitive impairment (MCI). MCI is a transition stage between the cognitive changes of normal aging and the more serious problems caused by Alzheimer’s.

The research had two parts. In the first part, the scientists measured BACE1 levels in CSF in 80 people with Alzheimer’s, 59 people with MCI, and 69 healthy elderly controls (HC) at two independent, international research centers. MCI subjects showed highly increased levels of BACE1 activity when compared to HC and people with Alzheimer’s. BACE1 activity was significantly correlated with Aβ level. A subsequent validation study replicated these initial findings in a new and independent set of 41 people with Alzheimer’s, 46 with amnestic MCI and elderly HC.

In the second part, 47 MCI subjects were clinically followed up over two years to assess the predictive value of BACE1 in combination with other biomarker candidates for predicting the conversion from MCI to Alzheimer’s. The additional candidates were abnormal brain proteins total tau and phosphorylated tau measured in CSF, and baseline performance on a large neuropsychological testing battery. Fifteen (15) MCI subjects converted to Alzheimer’s after a mean follow-up interval of 2.3 years. Analysis showed that BACE1 protein levels and ApoE genotype (a genetic risk factor for Alzheimer’s) were the strongest predictors of conversion to Alzheimer’s, after controlling for age and gender. The classification accuracy was 78%, the sensitivity was 80%, and the specificity was 77% for the combined model.

“These important findings pave the way for further rigorous assessment of BACE1 as an effective and accurate clinical diagnostic tool, which could significantly improve risk assessment and early detection of Alzheimer’s,” Hampel said. “We believe that BACE1 will be an excellent outcome biomarker to look at in ongoing clinical trials of anti-amyloid, disease modifying therapies. Furthermore, we are working on a blood-based diagnostic test for BACE1 as well.”

Improved Amyloid Imaging Agents for PET in Development

A major recent advance in Alzheimer’s is the ability to create images of amyloid in the brains of living people using positron emission tomography (PET) scanners. With PET, a radioactive compound, or tracer, is injected into the person to be scanned. The tracer attaches to a target substance in the body, in this case amyloid, which then “lights up” on the image captured by the scanner.

In research reported at ICAD 2008, Michael J. Pontecorvo, PhD, of Avid Radiopharmaceuticals, Philadelphia, PA, and colleagues reported the development of a novel 18F-labeled PET amyloid imaging agent, 18F-AV-45, that may eventually provide a practical approach for routine brain imaging for Alzheimer’s

PET scanners are relatively common – they are available in most hospitals – yet one of the challenges to more widespread use of PET imaging in Alzheimer’s is that the radioactivity of the first amyloid-imaging tracer, called 11C-PIB or Pittsburgh Compound B, is relatively short-lived. With this agent, based on radioactive carbon, half of the radioactivity is lost every 20 minutes. This means that it must be manufactured onsite, a process that requires a cyclotron (a type of particle accelerator), which is rarely found in community hospitals. This limitation has prompted a search for longer-lived tracers, such as 18F-labeled agents, based on radioactive fluorine, which would be suitable for regional production and wider community use.

In the study, three 18F-labeled compounds were evaluated in 42 cognitively healthy elderly volunteers and 39 individuals with Alzheimer’s. Each participant received a single intravenous injection of one of the compounds followed by PET imaging.

People with Alzheimer’s showed retention of all three tracers in brain areas expected to be high in amyloid. In contrast, cognitively healthy volunteers showed rapid removal of the tracers, with minimal retention in the brain. Two individuals diagnosed with Alzheimer’s had a pattern of tracer uptake similar to healthy volunteers. Chart notes for both suggested unusual presentations – prominent Parkinsonism in one case and slowly progressive dementia in the other.

While the three compounds were similar in pattern and amount of tracer retention, they differed in how they were processed by the body in ways that favored one compound, 18F-AV-45. For example, 18F-AV-45 showed rapid uptake and steady levels were maintained in the brain between 50 and 90 minutes post injection. This allowed high quality images to be obtained from PET imaging beginning 50 minutes after 18F-AV-45 administration, with minimal inconvenience or delay for the patient or the imaging center, according to the researchers.

“18F-AV-45 is being used as a research tool today, but it has the potential to aid in the diagnosis and early detection of Alzheimer’s in a community setting and may be a useful biomarker for the development and monitoring of novel amyloid reducing therapies,” Pontecorvo said. “On the basis of the findings we reported today, Phase II trials with 18F-AV-45 have been initiated.”

About the Alzheimer’s Association
The Alzheimer’s Association is the leading voluntary health organization in Alzheimer’s research, care and support. Our mission is to eliminate Alzheimer’s disease through the advancement of research, provide and enhance care and support for all affected, and reduce the risk of dementia through the promotion of brain health. Our vision is a world without Alzheimer’s. For more information, visit http://www.alz.org.

About ICAD
The Alzheimer’s Association 2008 International Conference on Alzheimer’s Disease (ICAD 2008) is the largest gathering of Alzheimer researchers in history. At ICAD 2008, more than 5,000 researchers will share groundbreaking information and resources on the cause, diagnosis, treatment and prevention of Alzheimer’s and related disorders. As a part of the Association’s research program, ICAD serves as a catalyst for generating new knowledge about dementia and fostering a vital, collegial research community.

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* Thomas Arendt. “Diagnosis Of Alzheimer’s Disease Using Peripheral Blood Lymphocyte Expression Of CD-69 Following A Mitogenic Stimulus.” (Funders: National Institutes of Health, GW Medical, Provista Life Sciences)
* Anne M. Fagan. “Update on the relationship between in vivo amyloid imaging with 11C-PIB and CSF Aβ42.” (Funders: : National Institute on Aging, Dana Foundation, Anonymous Foundation, Charles and Joanne Knight Alzheimer’s Initiative)
* Harald Hampel. “Alteration of beta secretase (BACE1) functional candidate biomarkers in subjects with mild cognitive impairment and Alzheimer’s disease.” (Funders: Science Foundation Ireland, Federal Ministry of Education and Research (Germany), Alzheimer’s Association)
* Michael J. Pontecorvo. “Development of 18F-AV-45, a novel 18F-labeled Aβ amyloid imaging agent.” (Funders: Avid Radiopharmaceuticals)

Contact:
Alzheimer’s Association
Media line: 312.335.4078
E-mail: media@alz.org
ICAD 2008 press room, July 27-31: 312.949.3253

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