This is Part 1 of a seven-part series on presymptomatic detection. See also Parts 2, 3, 4, 5, 6, and 7.
23 October 2009. On 1-2 October 2009, 214 researchers from the U.S., Europe, and Australia, as well as representatives of families with aggressive genetic forms of Alzheimer disease (AD), met at Washington University, St. Louis, Missouri, to devote two intense days of talks and discussion to their goal of presymptomatic detection of this disease. By a growing consensus, defining the “silent” phase of AD has become the field’s central challenge if it is to modernize drug testing and lay the groundwork for AD prevention trials. Presymptomatic carriers of deterministic AD mutations arguably harbor a unique potential to solve this challenge for all of AD. The St. Louis conference pulled together the latest research advances in this area. More than that, it also served as a chance for the far-flung participants in the Dominantly Inherited Alzheimer Network (DIAN) to push their ambitious project forward. In short, initial numbers on enrollment, passionate family input on counseling, community building and data privacy, and budding plans to offer a clinical trial to participating families were the main upshot of these conversations.
In St. Louis, DIAN leaders invited their external advisory committee to review and critique the study’s efforts so far. These scientists will send a detailed assessment directly to the study’s funder, the National Institute on Aging (NIA), but Thomas Bird of the University of Washington, Seattle, told ARF this: “I think the DIAN is a good idea and will provide valuable information. As I see it, the major goal is to identify the earliest signs, symptoms, and biomarker changes in persons known to be at essentially 100 percent risk for developing AD. This data will be important for understanding the biology of the disease and organizing appropriate therapeutic trials. The challenges are several: 1) recruiting and retaining an informative number of subjects, 2) choosing the “right” biomarkers, and 3) demonstrating that the information is relevant to the common forms of AD occurring in the general population.”
Presymptomatic detection in dominantly inherited AD became this year’s topic of the 7th Leonard Berg Symposium, a biennial conference at WashU that began in 1997. The symposium honors the late Leonard Berg, the founder of the WashU Alzheimer Disease Research Center. A clarinetist and saxophone player, Berg finished medical school in his native town of St. Louis at age 22 and built a life of pioneering clinical and advocacy work from there. Berg developed the widely used dementia staging instrument, Clinical Dementia Rating (CDR), which uses informant interviews and intra-individual change as important components. As early as 1979, Berg led the launch of large, decades-long natural history studies in AD and normal aging that are ongoing at WashU. Now led by John Morris of WashU, these studies have spun off longitudinal biomarker studies in the second generation of research participants and in families with autosomal-dominant AD. Berg succumbed to strokes caused by amyloid angiopathy in 2007 (for more on Berg’s life and work, see Morris and Landau, 2007).
The symposium combined a scientific update on catching presymptomatic AD in its genetic and sporadic forms (see Part 3 of this series) with discussion on whether the former models the latter, and a nuts-and-bolts meeting among the leaders of DIAN. This initiative is building an intercontinental, 10-center registry of mutation carriers and their non-carrying relatives, who are adult children of a parent with a known causative mutation in the APP or presenilin genes. It aims to pull these rare and dispersed families together into a longitudinal study that establishes the biological and cognitive course of their preclinical period with standardized data. Importantly, it tries to do so with a degree of statistical power that can support future prevention and treatment trials relevant to the families themselves and also to the much larger population of late-onset AD. The Alzforum has described the rationale and the structure of this complex undertaking before (see DIAN series); hence, this set of stories will focus on what’s new since then.
Chief among the news, DIAN is up and running. Twenty-one participants to date have completed the first round of assessments. As often happens with multicenter studies, enrollment was slow off the blocks, even as prospective participants were impatiently waiting as centers worked to obtain the necessary IRB approvals and local certifications, investigators and some family members said. Like with the Alzheimer's Disease Neuroimaging Initiative (ADNI), for example, each DIAN site needs to be certified on PIB synthesis on best practices, an imaging phantom has to be sent around to ensure standardization of the MRI measurements, etc. This has taken the better part of this year at many sites, but five sites (WashU; BWH; Brown; University of New South Wales in Sydney, Australia; and UCLA) are enrolling already and all others will begin within the month, said Morris, the principal investigator for DIAN. The goal now is to have 100 people enrolled by next July, when the DIAN leaders will gather for their forthcoming face-to-face meeting at the next ICAD conference in Honolulu, Hawaii, and 150 by end of 2010. “This number would put us on track with the original aims of the grant application,” Morris added.
The next ICAD conference also is a goalpost for perhaps the biggest new development at DIAN. At WashU last week, its leaders approved formation of a Clinical Trials Committee, which in plain English means they are putting their thinking caps on for real. Offering drug trials, either for prevention and/or treatment of early symptoms, has always been very much in the investigators’ minds, Morris said. After all, that’s what the families ultimately want and where the potential lies for late-onset AD, as well. But the investigators first needed to focus on getting DIAN going, and felt it unethical to mention future trials as part of what is primarily an observational study when it was not clear yet whether DIAN would happen or whether companies would show sufficient interest. In practice, DIAN does not have enough participants to begin a trial within the next 12 months. However, preparing for such trials requires a lot of work because challenges about design, choice of drug, and genetic privacy need to be overcome (see, e.g., Ringman et al., 2009 and 7 of this series); hence, the time to start planning is now.
Randall Bateman of WashU heads this group. “People at the steering committee meeting were very enthusiastic about starting to explore how clinical trials could be done soon,” said Bateman. At the Leonard Berg symposium, Bateman, Nick Fox of University College, London, UK, John Ringman of the University of California, Los Angeles, Stephen Salloway of Brown University in Providence, Rhode Island, and Reisa Sperling of Boston’s Brigham and Women’s Hospital discussed how best to engage drug company researchers to ensure both scientific rigor in design and execution, and independence in selecting the best drug candidate. “The hope is to have a full group, a charter, and a process in place by next July, so concrete design can go from there,” Bateman said.
During the Leonard Berg Symposium, the spouse of an eFAD patient was asked whether her adult children would want to participate in a treatment or even a prevention trial. Unsurprisingly, perhaps, the answer was: “They would try anything. Their outlook is so bleak. They worry less about side effects from an experimental treatment than about AD.”
A separate goal where DIAN is moving more slowly is expanding the network to include more sites. From the get-go, researchers in Spain, Sweden, Japan, and Italy, who have for years cared for and studied families with autosomal-dominant AD, expressed interest in joining DIAN. “We are open to expanding DIAN but are not ready yet. We first have to focus on getting all 10 sites going full steam on the existing protocol,” Morris said. Taking on more sites and more languages will add complexity and cost. One delicate question is whether sites would be added to the 10 present ones or whether a performance review might swap out underperforming sites for new ones. In St. Louis, the DIAN leaders decided to postpone the issue for one year. That said, some sites have a lot to offer the network if at least a Spanish language version of DIAN could be prepared, Morris noted. Two existing sites, Columbia University and UCLA, are working with Puerto Rican and Mexican families, respectively, and in the scientific session of the symposium, Raquel Sanchez-Valle of the Hospital Clinic Villarroel in Barcelona, Spain, reported that her team is already working with several dozen at-risk relatives from nine eFAD families (see Part 3 of this series).
DIAN itself is in large part about the families in the network. The study will be more successful if it actively integrates them into a shared sense of commitment. To this end, DIAN reserves two seats on its steering committee to family representatives. In St. Louis, an at-risk daughter and a caregiver and mother of six made their mark in two areas. First, they insisted that data sharing has to be devised with the utmost concern for their privacy. “They are steadfast on this issue,” Morris said. The Alzheimer's Disease Neuroimaging Initiative, on which DIAN is modeled, prides itself on making its data available almost instantly to all qualified researchers worldwide as soon as it enters the system. DIAN cannot do that. The investigators have to ensure that the data cannot accidentally identify families or unmask individuals within a given family. For example, study participants who chose not to know their carrier status must be unable to recognize their scan and realize they have amyloid in their brains. Therefore, the goal is to refine de-identification procedures and release that data within at most a year of its deposition in the DIAN database. “That said, we do intend to release all data, not just bits and pieces. But the guiding concerns have to be confidentiality, confidentiality, and confidentiality,” Morris quipped.
Secondly, the family representatives made a case for psychological and emotional support (see Part 2 of this series). This aggressive form of AD can divide extended families as much as it sometimes unites others. Stigma, fear, and the sheer burden of caregiving drive them into isolation. To address these needs, DIAN formed a participant liaison committee. It will work on communicating with participants and supporting them with online services. One idea is to create a forum where they can network and talk about their experiences with AD and DIAN, without the DIAN investigators being privy. “We know we ask a great deal of the study participants. We want to do things not only appropriately but also give them the necessary psychological and social support,” Morris said. Martin Rossor of University College London, UK, who has taken care of families with dominantly inherited AD for 20 years and is now seeing adult children of his original patients, will head this participant liaison group.
When asked whether support services were important, a different, unaffected spouse and mother of three adult children at risk for eFAD wrote to ARF: “Psychologic counseling, above all genetic counseling, are extremely important. The decision to find out one’s fate can be daunting, especially in the case of FAD where there is no cure. I have seen that spouses, siblings, or parents may try to influence participants to be tested or not, but ultimately it should be the decision of the possible carriers, and counseling helps them make that call. Social/emotional support from others going through the same nightmare is as important as counseling. Most families don’t know other families facing similar struggles because the genetic AD mutations are so rare. Most DIAN participants have been caregivers to their own parent or other relatives and know all too well the devastation Alzheimer’s causes to the afflicted individual and the entire family unit. I would hope for call-in support groups, but if that is not possible, then an online forum would be the next best thing.”
In other DIAN news, the scientists decided to add a new sequence to the MRI component, i.e., diffusion tensor imaging. This was not part of the initial protocol but may help the scientists understand if and when the brain’s white matter changes in the run-up to AD. This will not add imaging time or the number of sessions for participants.
Finally, DIAN has a resource allocation review panel headed by David Holtzman, through which scientists interested in studying CSF or plasma samples can request access. Holtzman, like all DIAN investigators, sites, and partnering groups, can be contacted through the Dominantly Inherited Alzheimer Network (DIAN).—Gabrielle Strobel.
This is Part 1 of a seven-part series on presymptomatic detection. See also Parts 2, 3, 4, 5, 6, and 7.