The 7th Leonard Berg Symposium, part 2.

At the 7th Leonard Berg Symposium, scientists and patient advocates came together to exchange the latest news on detecting disease presymptomatically and to compare what’s known in rare genetic and in common forms of the disease. There was a palpable sense of excitement in the auditorium that, overall, enough lines of evidence are coming together to make preclinical detection possible in practice. Paradoxically, perhaps, this optimism arose alongside a general acknowledgment that autosomal-dominant AD is surprisingly heterogeneous, and that its status as a faithful model for the much larger population of general late-onset AD is far from cut and dried. Here are some highlights. Ira Shoulson is a leading neuro-geneticist and clinician for Huntington disease (HD) at the University of Rochester School of Medicine and Dentistry, New York. He led the conference with a keynote on what the HD experience can teach the AD field. In HD, predictive genetic testing has been possible since 1983; hence, scientists in this community have had more time than their colleagues in AD to study the acceptance and psychological effects of such testing, as well as the characteristics of the presymptomatic period of carriers. Even so, research into preclinical HD is arguably less advanced, partly because fewer large-scale studies exist to observe how the natural history of HD unfolds. In AD, early-stage diagnosis is becoming routine, at least at some academic tertiary care centers. There, clinicians try to implement biomarker-enhanced diagnoses of “prodromal” AD [1] or similarly early stages called by a different name (WashU clinicians would call it incipient or very early AD), and the amnestic subtype of the MCI clinical categorization system appears largely to capture the same group of people. Increasingly, specialized centers will diagnose people who do not meet criteria for dementia if they have a mild memory complaint and a pathological CSF or brain scan. The rallying call in AD now is to move the diagnosis back even further, before the first symptoms appear. In contrast, the diagnosis of HD in the past 20 years has moved back only a year or two as clinicians have become more astute at recognizing early clinical signs, Shoulson said, but it is still an entirely clinical diagnosis made much later than he would wish. In HD, people on average live 40 years of their lives at risk and 20 more years with the illness, though age of onset varies. For each person with HD, five are living at risk for the disease, but no robust biomarker signatures are in place to identify “silent” disease in these people. Scientists do know that certain abnormalities, such as cortical thinning, predate symptomatic HD, as do certain cognitive impairments, but in practice this has not translated into presymptomatic diagnosis and prevention research. To gather more powerful data on the HD preclinical phase, researchers collaborated to launch PHAROS, an observational study that to date has followed nearly 1,000 at-risk, presymptomatic people for five years. One-third of them have the extended glutamine repeat and will develop HD. “We asked people if they would come back every nine months for evaluation. We would not share with them what we found, and we wanted their blood and put it in a database. This was very daunting, particularly securing confidentiality and privacy. It was, in part, what led to the passage of Genetic Information Nondiscrimination Act (GINA),” Shoulson told the audience. PHAROS appears to have been worth the effort. Its initial data show that all motor and cognitive domains