DIAN Dispatch From Hawaii: After Slow Start, Network Is Humming
After more than a year of rumbling to life, the Dominantly Inherited Alzheimer’s Network (DIAN) has kicked into gear and is now enrolling research participants at a healthy clip. Here’s an update on how things are going, brought to you fresh from the lectern and hallway conversations in Honolulu. That’s where DIAN scientists and some family representatives met on 9 July 2010 for an all-day meeting in advance of the International Conference on Alzheimer’s Disease. DIAN leaders capped this internal meeting with an evening presentation of initial DIAN results to industry leaders, which formed part of their preparations for adding drug trials to the study as early as possible. “DIAN proved to be even more challenging to get underway than we anticipated,” said its principal investigator John Morris of Washington University, St. Louis, Missouri. “For example, it took a long time to get regulatory and cyclotron issues ironed out across the 10 DIAN performance sites, and because of these issues we had to add staff to help with the tremendous administrative efforts. But in the past few months, all sites have become operational and our enrollment rate is exceeding expectations.”
DIAN is a U.S./UK/Australian network of initially 10 research sites, whose investigators have banded together to offer the families with autosomal-dominant AD a two-pronged study tailor-made for them (DIAN-info.org). Primarily, the study aims to monitor the preclinical development of the disease biology 20 years earlier than a person’s estimated age of symptom onset by way of comprehensively tracking, side-by-side, all major biomarker candidates research has produced to date. It is a demanding study for participants, who have said time and again that what they really are hoping for are treatment studies. Therefore, DIAN has started a process of essentially wooing drug company researchers, who are themselves looking for a way forward amid a three-way tug of sensing a new opportunity, wanting to do the right thing, but being loathe to shoulder additional risk for a candidate drug into which they have invested many millions.
So what’s new? First, enrollment. Almost one-third into its funding period, DIAN has enrolled 90 participants as of 7 July 2010, currently adding about 15 per month for an expected 250 by next summer. Because only 32 people had joined by March 2010, the overall pace of enrollment is slower than originally anticipated. Why the sluggish start? For one, DIAN is highly complex. Not only does each site change its own local procedures to adhere to a centralized, uniform and intensive protocol, but also, IRB approval needs to be granted at each site. Every change and every important communication require coordination across three continents. “It’s an honor to be part of DIAN,” said Paul Aisen, who heads the ADCS in San Diego, a DIAN subcontractor. “But it involves lots of PIs in different time zones and a lot of data exchange, so the coordination effort is significant.”
For another, technical problems outside DIAN’s control have cropped up. Because the cyclotron (an expensive instrument that makes the radiochemical needed for amyloid imaging in DIAN) servicing the Boston and Providence sites is being replaced, no PET scans have been done there since last October, and the New York City site cyclotron went offline for repairs after an audit. This has slowed these sites down, and in response, DIAN participants may now undergo PET scanning at the Washington University site.
On the upside, however, enrollment has picked up speed since the spring. Moreover, the network is considering expansion from 10 sites to 11 by adding the University of Pittsburgh Medical School led by William Klunk. The Pittsburgh group has been studying approximately 20 carriers of autosomal-dominant AD mutations for up to seven years already through their Alzheimer’s Disease Research Center. Discussions are underway to determine how at least some of them can join the more extensive DIAN protocol if they wish to do so. Newly recruited volunteers from Pittsburgh would also be offered the option to join DIAN. For example, a previously unknown family with autosomal-dominant AD approached Klunk following a local screening of the 2008 HBO special series on AD (for a segment with Klunk and Chet Mathis, see movie 8 in ARF Video Gallery). Sequencing confirmed a previously identified presenilin 1 mutation. This family, too, is interested in DIAN, Klunk said.
New families are joining at other sites as well. For example, Ralph Martins, who leads DIAN’s Perth site in Western Australia, is expecting a one-month visit from a Libyan family this September. The father and four of his six children will spend the month to complete all of DIAN’s baseline assessments, Martins said. One daughter is pregnant and one is a minor, otherwise they would all come, he said, adding, “They are highly motivated.” The extended family has about 50 at-risk relatives. Martins has been working with this family for about 12 years, when the proactive husband of an affected mother of six contacted him. Because shipping blood from Libya is tricky, Martins requested it be dripped on filter paper and mailed as a letter. Martins’s group found a previously known PS1 mutation with onset in the early forties when they sequenced the blood of the mother, her sisters, and all her children. To date, he has not disclosed the children’s genotype. “I have worked with this family since the children were young but have never met them in person. It’s very exciting to have them come,” Martins said. Martins developed the early research on this Libyan family, as well as on other families in Western Australia that enabled Perth to become a DIAN site, with support from the Australian McCusker Alzheimer’s Research Foundation, a private philanthropy.
The Libyan family is noteworthy not only for its size and willingness to travel the globe for a full month of scientific research participation, but also because it illustrates that families from across the globe can, in principle, join DIAN. The Libyan family speaks English fluently. This is a requirement at present, as results from cognitive tests need to be gathered in a standardized manner and entered into a common DIAN database. To help DIAN expand, both John Ringman’s and Richard Mayeux’s groups at the Los Angeles and New York sites, respectively, are working on translating the tests into Spanish to open the doors to known families from Mexico, Spain, the Dominican Republic, and other Spanish-speaking nations.
But enrollment remains hard work. Stephen Salloway, who heads the Butler Hospital DIAN site in Rhode Island, mentioned an extended family of 50 people, most of whom are reluctant to join, Salloway said. In discussion, Alison Goate of WashU noted how going to family reunions has enabled her to build rapport and to explain the purpose of research in a friendly setting outside the exam room. In discussion, Denise Heinrichs, a family representative, noted that while families are deeply scared, they do want help. “The key is to educate them. They don’t want this to go on from generation to generation. If they know enough, they will want to do it for their children.” DIAN family members, with help from WashU’s Randy Bateman, Wendy Sigurdson, and the DIAN administration, have begun organizing a support group that, once up and running, will operate independently from the scientists to facilitate open communication between otherwise isolated families who find themselves in a similar situation. Likewise, Martin Rossor and colleagues at the UK site have done the same. Efforts to allow these groups to connect are in planning. In particular, study participants within three years of their expected age of onset need added outreach, said Natalie Ryan of London’s DIAN site at University College. Not only does anxiety intensify at that time, but people at this stage may already be finding it more daunting to organize the logistics of traveling long distances, taking off from work and arranging child care.
The support needs for this type of study are great, and yet, when asked what is the single biggest factor that would attract more family members to research participation, DIAN scientists and family representatives replied unanimously: a therapeutic trial. See Part 2 of this story.—Gabrielle Strobel.
This is Part 1 of a two-part series. See also Part 2. Download PDF of the entire series.
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