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Monday, September 30, 2013

Is the Brain Ready for Personalized Medicine? Studies Suggest Not Quite Yet

Guest post by Jason Karlawish, M.D.

"Prescribe the right drug to the right patient at the right time" is not a new medical practice, but when a biomarker—that is, a measure of disease pathophysiology—or a gene makes this decision, that is a radically new medical practice. The promise of personalized medicine is that biomarker and gene driven algorithms will do much of the work of medicine. By predicting patients’ future health and the outcomes of an intervention, they will guide what doctors recommend to their patients. Like the theory of evidence-based medicine, personalized medicine promises a more objective, efficient and precise medical practice.

To date, personalized medicine has largely flourished in the care of patients with common medical diseases, particularly cancer and cardiovascular disease. In the last two decades though, the National Institutes of Health, the pharmaceutical industry, and researchers have invested substantial time and money in research such as the Alzheimer’s Disease Neuroimaging Initiative dedicated to discovering and validating the biomarkers and genes that predict whether a brain will fail. This research is beginning to reshape how we talk about the diagnosis and treatment of the aging brain, an organ that is more and more, like hearts and bones, regarded as an organ "at risk." As a result, clinicians, ethicists, and health care policy-makers are beginning to ask how we should practice personalized medicine for the seemingly healthy brain that is at risk for neurodegenerative dementias such as Alzheimer’s (AD), Parkinson's, Lewy Body Disease and frontotemporal lobar degeneration.

This July, at the Alzheimer’s Association's International Conference in Boston, my colleagues Leo Waterston, Robert Green and I presented research to answer this question. We reported what happens to a person who learns a personalized estimate of lifetime genetic risk of developing AD.

In a 2009 New England Journal of Medicine paper, Dr. Green’s REVEAL study showed that after a person learns she is a carrier of a gene variant that increases one’s risk of developing AD, the APOE e4 variant, she doesn't experience sustained psychological harms. In the study we presented in Boston, we took these analyses one step further. We examined the subgroup of persons who are APOE4 positive and who have not one, but two copies of the e4 allele. This is a small cohort—just 4 percent of the general population—but estimates are that such persons have a lifetime risk of developing AD s as high as 90 percent.

Compared to persons who only have one or no copies of the APOE e4 variant, what happens when you learn you have two copies of this gene, that is, you are “an APOE e4 homozygote?"

The APOE e4 homozygotes were no more likely than persons who carried no copies of the APOE e4 variant to experience clinically significant depression or anxiety. But they did differ in other respects. They were more likely than persons with just one copy of the e4 variant to engage in behaviors that might reduce their risk, such as changes in diet or exercise.

Right now, motivated individuals can purchase the results of their APOE genetic profile from a commercial vendor such as 23andMe. The pressing clinical and public policy question is whether APOE assessments of the risk of brain failure are ready for clinical practice. In short should doctors prescribe, and health care systems reimburse, genetic testing for the risk of Alzheimer's disease? And what about biomarker assessments of neurodegeneration? Last year, the FDA approved PET amyloid imaging as a test to assess whether a person with cognitive complaints does or does not have one of the pathologic signatures of Alzheimer's disease dementia. The number of people who might seek such testing could be in the millions.

The simple answer to the question "Is personalized medicine ready for the brain?" is "no, not yet," especially in the case of costly tests such as PET amyloid imaging. Why? The Centers for Medicare & Medicaid Service’s controversial decision to decline coverage for PET amyloid imaging shows that the Ground Zero of debate is all about demonstrating value. What is the value of learning your brain is at risk of failing?

Answers to this question need to show that gene or biomarker “positive” people do things that improve their health and reduce the costs of health care. The REVEAL Study suggests that some do. The discovery of a medication that would slow cognitive decline in persons who are at heightened genetic or biomarker risk would be of tremendous value, assuming the medication is priced affordable to its value. Presently, there are at least three clinical trials enrolling cognitively normal subjects who have genetic or biomarker positive profiles. These prevention trials are a bold attempt to prove whether we can slow the creep of cognitive decline that ultimately disables many older adults.

Value, though, is not simply a tally of a drug intervention's benefits. It has a flip side: harm. Genes such as APOE are relatively static measures present since birth and therefore perhaps one of the reasons learning one is a double APOE e4 carrier is not harmful. Biomarkers, though, are far more dynamic measures of a failing brain. The shrinkage of the hippocampi seen on MRI imaging or the accumulation of amyloid on PET imaging are the signatures of a failing brain.

This month, in Neurology, my group published the results of a survey of ADNI investigators' views on returning amyloid imaging results to subjects in ADNI. At present, although about half of the cognitively normal subjects are asking to learn their amyloid scan results, few, if any, researchers are telling subjects these results. However, half of those investigators reported that they would like to tell them, but they carefully qualified their willingness. The investigators want evidence-based guidance on how to tell a person his result, and studies of how people react to learning biomarker-based information about their brain being at risk.

We need to prove that people who want to learn this information can live with it and that they will adopt “brain healthy” behaviors. We also need to prove that telling a person her amyloid scan suggests her brain is at risk for decline does not begin to engender a belief that accelerates that decline. Last year’s Alzheimer's meeting in Vancouver, Canada presented a provocative study from David Solomon and colleagues at the UC San Diego. They found that people who learn they are APOE e4 positive perform worse on cognitive tests compared to people who are APOE e4 positive but do not know this information.

This disturbing result evokes the results of years of experimental psychology research showing that when persons who expect to do poorly on achievement tests are given an achievement test, they perform poorly, but when the same test is not called an achievement test, they perform better. Culture and belief may transform a gene or biomarker result from simple data we input into an algorithm, into a stereotyped threat.

Clinicians, researchers and companies are eager to move personalized medicine above the neck, and surveys suggest that some people are eager to learn this information and some doctors want to tell it to them, but research needs to prove that the brain is ready for personalized medicine.

Jason Karlawish, MD, is a professor of medicine, medical ethics and health policy at the University of Pennsylvania and the director of Penn's Neurodegenerative Disease Ethics and Policy Program. He is the recipient of a Robert Wood Johnson Foundation Investigator Award in Health Policy Research.

Author: Jeffree Itrich at 1:46 PM 0 Comments

Thursday, September 26, 2013

A Tau Tracer Comes of Age

Dear Readers,

As many of you are aware, last year the FDA approved the Amyvid PET scan that detects the amyloid plaques seen in Alzheimer’s disease (AD). This ability has revolutionized the field of AD research and clinical trials. Yet amyloid plaques are only one of two key changes observed in the brain of people with AD.

The second change is the presence of tau-containing neurofibrillary tangles inside of neurons. Tau is a critical part of the cellular scaffolding inside of neurons. The tangles are seen at autopsy in brains of patients with AD, as well as other forms of dementia, including frontal-temporal dementia.

A study published in the September 18th issue of the journal Neuron reports a new type of brain scan capable of tracking AD progression through direct imaging of the tau protein in the neurofibrillary tangles. The new tracer was tested in mouse models as well as human participants. Called PBB3, the tracer affixes to tau structures and can be seen with PET scans.

The scans were then used to demonstrate the relationship between the deterioration in Alzheimer sufferers, relative to the presence of tangles of tau. That is, the more tau was observed, the more severe the dementia observed.

This report follows the same observation noted in autopsy studies correlating neurofibrillary tangles with dementia severity. In fact, we know that tangles correlate more closely with severity of dementia than amyloid deposition, so this type of tau imaging is a true breakthrough.

As with many first-generation diagnostic tools, the reported tau tracer comes with some limitations. The tracer is linked to a short acting carbon-11 isotope, which makes it difficult to mass produce for use on a clinical scale. Looking back, this was also the case when the game-changing amyloid PET tracer - PIB – was first introduced to the AD clinical research community in 2004. By 2008, a tracer similar to PIB was linked to fluorine 18 and is known today as Amyvid - the first FDA-approved tracer of brain abnormalities in AD. PBB3 is expected to follow a similar path.

The ultimate impact of a tau tracer could extend well beyond AD. The tracer may offer much needed insight regarding a broader-base of neurodegenerative disease involving tau. From the AD clinical research perspective, the impact is clear. The promise of future intensive investigation into the unique role of AD-related tau is simply priceless.

Thanks for reading.

Michael Rafii, MD, PhD
Director, Memory Disorders Clinic
Associate Medical Core Director
Alzheimer’s Disease Cooperative Study
University of California San Diego
Author: Michael Rafii MD,PhD at 1:31 PM 0 Comments

Wednesday, September 11, 2013

Gender Differences of PTSD Among Service Members and Veterans of the Iraq and Afghanistan Conflicts

Dear Readers,

The recent data emerging from the Veteran's Affairs (VA) Administration notes that women comprise nearly 12% of all soldiers who served in Iraq and Afghanistan. More than 79% are under the age of 40 years, 88% are enlisted, and 12% are Officers. Differences in cognitive (i.e. memory), physical and emotional health-related issues upon returning to the United States, are now being noted in the clinical literature, as troops are trying to re-integrate into civilian life. Some, but not all, reports have suggested that female veterans may seek more outpatient primary care visits than men, in addition to having more mental and "cognitive " health visits compared to men. In addition, other reports note that female veteran VHA users are more likely than their male counterparts to have mild and major depression, adjustment disorders and musculoskeletal and skin disorders.

Some of these health-related findings are thought to be associated with the incidence of physical attacks, harassment, and combat-related exposures experienced by women veterans. Both Traumatic Brain Injury (TBI) and Post-Traumatic Stress Disorder (PTSD) are thought to occur in higher frequency among female military veterans, yet recent data suggest that over 50% of returning female veterans do not realize the signs and symptoms of TBI/PTSD and, many think that they can handle these situations without medical intervention. Further, women often find themselves immediately immersed in family care issues for their own families and relatives without having their own personal care needs met. Whether true gender differences in PTSD or other related cognitive and health conditions exist, amongst female veterans, is a subject that has only recently been examined by researchers. The paper by Crum-Cianflone and Jacobson in the recent issue of Epidemiological Review, summarizes the existing PTSD health data regarding our returning veterans and examines whether true gender differences exist in its prevalence amongst men and women.

The authors noted that in the general US population, the overall prevalence of PTSD is between 5-10% with women having a twofold higher prevalence of PTSD than men. These civilian prevalence rates were similar to that of military women examined prior to the Iraq and Afghanistan wars. Data that used the Millennium Cohort, a cohort of over 75,000 service members (>20,000 women), noted that women had a higher rate of pre-deployment PTSD (3.2% vs. 2.2%, adjusted OR of 1.4) compared to men, measured by the PTSD Checklist Civilian Version (PCL-C). Post deployment data on PTSD however has been scant, yet some reports are noting emerging cognitive issues associated with PTSD in addition to co-morbid medical conditions in our returning veterans.

Existing studies for PTSD are often grouped into service branch areas and active duty veteran status, as differences in the military experiences by branch and methods of data collection (i.e. those seeking VA care versus military samples) occur. Data sets limited to the Army have shown that positive PTSD screening scores were twice as likely to be noted in women compared to men. These studies, conducted 2006-2008, assessed combat experience using a yes/no, four item questionnaire which asked questions regarding being injured or wounded. Higher levels of PTSD with higher levels (i.e. intensity) of combat experience were noted for women, but not for men.

Data from the US Millenium Cohort Study, examined new onset PTSD between men and women. This study, included persons from all service branches, including the active Reserve and National Guard components. Combat exposure was indicated by one positive response to any of the following items that assessed whether or not the veteran was witness to: death due to war, disaster, tragic event; instance of physical abuse; maimed or dead bodies of soldiers, civilians, prisoners of war or refugees. New onset PTSD was noted in 3.8% of women, compared to 2.4% of men, with women showing higher odds of new onset PTSD compared to men, in 3 of the 4 service areas. (Army 1.7, Air Force 2.0, Navy /Coast Guard 1.73)

A study by the National Guard examined members deployed between 2005 and 2007 (n= >25,000) who were surveyed three months post-deployment documenting combat exposures. Positive scores for PTSD three months post-deployment were found in 18% of the women compared to 14.5 % of the males, however at 12 months post deployment, more males reported positive PTSD scores than women (17.9% of the female vs. 24.1 of the males). When adjusted for combat experience/exposures, males had decreased odds of screening positive for PTSD compared to females at three months post deployment and no gender differences were observed at 12 months post deployment.

Lastly, medical data from across multiple VA medical centers have noted that male veterans were more likely to have a health care visit or diagnosis of PTSD(diagnosed by the ICD-9 criteria) compared to women (22% vs. 17%). This finding is supportive of clinical data suggesting that women may not recognize the signs and symptoms of PTSD, or simply choose to manage this issue on their own without medical intervention.

The findings in this review paper are important as they highlight potential gender differences in a highly prevalent condition affecting our veterans. This condition, can be chronic and potentially debilitating, as it is associated with impairment in cognitive, physical and social functioning. Given the expanding roles of women in the military, more sex and gender research in this area is needed. Long term follow up studies should examine all potential modifiable factors that could reduce the risk of PTSD and optimize intervention strategies among female members serving in our military.

Here are three articles you can refer to, to learn about the health issues facing our returning veterans:

Crum-Cianflone NF, Jacobson I. Gender Differences of Post-deployment Post-Traumatic Stress Disorder Among Service Members and Veterans of the Iraq and Afghanistan Conflicts, Epidemiologic Review, Epidemiol Rev. 2013

Riddle JR, Smith TC, Smith B, et al. Millennium Cohort: the 2001-2003 baseline prevalence of mental disorders in the U. S. Military J Clin Epidemiol 2007; 60 (2) : 192-201

Kimmerling R, Street AE, Pavao J, et al. Military related sexual trauma among Veterans Health Administration patients returning from Afghanistan and Iraq. Am J Public Health 2010; 100 (8) ; 1409-1412

Thanks for reading.

Neelum T. Aggarwal, MD
Steering Committee Member, ADCS
Rush Alzheimer’s Disease Center
Rush Institute for Aging
Chicago, IL

Author: Neelum Aggarwal MD at 11:58 AM 0 Comments

Thursday, September 05, 2013

What Can We Learn About Dementia from Parkinson's Research?

Dear Readers,

In a paper published in the August 26th issue of JAMA Neurology, researchers presented data from the Parkinson’s Progression Markers Initiative (PPMI), a five-year observational study modeled after the Alzheimer’s Disease Neuroimaging Initiative (ADNI) being carried out at 24 sites in the U.S., Europe, and Australia. The study has enrolled 400 patients with Parkinson’s disease (PD) and 200 controls.

Many of you may not be aware that Parkinson’s is a rather variable disease, where many patients stay stable for years while others decline rapidly. Some patients seem to have more classic features of the disease, such as a tremor, and shuffling gait, while others have more balance issues, called the postural instability-gait disturbance (PIGD) form. The PPMI has enrolled patients with the various forms of PD to better understand why such differences exist.
More relevant to our discussion, about 75% of people with PD develop dementia about 5-10 years after showing the movement symptoms of the disease. This dementia is distinct from the dementia of AD, but in some cases there is some overlap.

The dementia in patients with PD is thought to arise from the aggregation of a protein called alpha-synuclein (analogous to the beta-amyloid of AD) into Lewy bodies inside of brain cells (analogous to amyloid plaques of AD). Another form of dementia, Lewy body dementia, is where patients develop the dementia first or at least simultaneously with the Parkinson’s type symptoms. The end result in all three diseases is brain cell death (neurodegeneration) leading to onset of cognitive impairment followed by dementia. Of note, the PIGD form of PD progresses more rapidly than other forms of Parkinson’s, and is associated with a greater risk of dementia.

For this study, the researchers looked at baseline cerebrospinal fluid (CSF) from 63 PD patients and 39 age-matched controls. Most patients had received their diagnosis within five months prior to enrolling. The researchers compared CSF levels of a-synuclein, beta-amyloid, the protein tau, and the abnormal form of tau, called phosphorylated tau (p-tau.

The analysis revealed a unique CSF biomarker profile for patients diagnosed with the PIGD form of PD, compared to those with the more common form of PD. The patients with PIGD had significantly lower levels of beta-amyloid (also seen in AD), but also low levels of p-tau (which is increased in AD). In addition, alpha-synuclein was also lower in the PIGD group than in patients with the common form of PD. This finding was expected, as the alpha-synuclein is thought to be accumulating in Lewy bodies, and less of it is circulating in the CSF. The take home message here is that there are unique biochemical changes within two distinct forms of PD, which may explain the observed differences in each variant. By understanding these differences, therapies can be designed that would best treat the underlying cause.

For now, we have a starting point which will allow for follow up of these baseline measures over the next five years as patients progress. The CSF data, as well as brain imaging and cognitive testing will undoubtedly add more information about differences observed across these tests, as well as the symptoms experienced by patients. It is only with this type of careful observation that we can begin rational drug development for the treatment of dementia in PD. And, given the similarities between PD and AD, perhaps also benefit patients with AD and Dementia with Lewy bodies.

Thanks for reading.

Michael Rafii, MD, PhD
Director, Memory Disorders Clinic
Associate Medical Core Director
Alzheimer’s Disease Cooperative Study
University of California San Diego
Author: Michael Rafii MD,PhD at 10:22 AM 0 Comments

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About Us

The Alzheimer's Disease Cooperative Study (ADCS) was formed in 1991 as a cooperative agreement between the National Institute on Aging (NIA) and the University of California, San Diego. The ADCS is a major initiative for Alzheimer's disease (AD) clinical studies in the Federal government, addressing treatments for both cognitive and behavioral symptoms. This is part of the NIA Division of Neuroscience's effort to facilitate the discovery, development and testing of new drugs for the treatment of AD and also is part of the Alzheimer's Disease Prevention Initiative.

The ADCS was developed in response to a perceived need to advance research in the development of drugs that might be useful for treating patients with Alzheimer's disease (AD), particularly drugs that might not be developed by industry.