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William Klunk: imaging Alzheimer's disease in vivo

2015; Elsevier BV; Volume: 14; Issue: 8 Linguagem: Inglês

10.1016/s1474-4422(15)00159-3

1474-4465

Tony Kirby,

Alzheimer's disease research and treatments

In 2001, when William Klunk and his long-time collaborator Chet Mathis created a molecule that could be used to image Alzheimer's disease in vivo by tagging amyloid β (Aβ), it was one of few eureka moments so far in Alzheimer's disease research. Years of trying different variations of promising compounds had eventually culminated in the creation of Pittsburgh compound B (PiB). “It was a wonderful moment”, Klunk tells The Lancet Neurology, although he and his team remain modest about the discovery. “With PiB, Bill Klunk and Chet Mathis introduced the game changer in the neuroimaging of Alzheimer's disease, allowing for the first time the non-invasive quantitative assessment of brain pathology in vivo”, says Victor Villemagne (Department of Nuclear Medicine and Centre for PET, Austin Health, and University of Melbourne, Parkville, VIC, Australia). Clifford Jack (Mayo Clinic, Rochester, MN, USA) backs these sentiments, describing PiB as the “single most important advance in the history of dementia imaging”. For Klunk, it was a landmark discovery in a career that encompassed chemistry, neurology, and psychiatry before his current focus on Alzheimer's disease. Distinguished Professor of Psychiatry and Neurology and co-director of the Alzheimer's Disease Research Center at the University of Pittsburgh (Pittsburgh, PA, USA), he is helping to take PiB into clinical studies that are testing the efficacy of new drugs for Alzheimer's disease that target Aβ. Originally planning to be an accountant, he was advised to switch to chemistry after winning a chemistry competition at Shippensburg University (Shippensburg, PA, USA). At Washington University (St Louis, MO, USA) he completed his MD and his PhD in neuropharmacology. Having a cousin with epilepsy drove him to research this condition and, with colleagues James Ferrendelli and Doug Covey, he published his first research paper—on the anticonvulsant properties of alpha-substituted gamma-butyrolactones—in Science. However, during his neurology rotation there was not enough contact with patients with epilepsy or application of neuropharmacology to sustain his interest. So he opted for a residency in psychiatry at the University of Pittsburgh. Although Klunk seriously considered a career as a clinician, he realised he loved research too much and in 1988 he completed a fellowship in geriatric neuropharmacology, working with Donald Abraham, who was synthesising new drugs for Alzheimer's disease. They wanted to create a small molecule to bind to Aβ to stop it from aggregating and also planned to tag Aβ so that it could be imaged in vivo. After joining forces with Mathis in 1993, their team worked for more than a decade, trying and testing hundreds of variations of imaging dyes related to congo red and thioflavin T. Mathis, a radiochemistry expert, would label compounds that showed potential for PET scanning in Klunk's binding assays and enter them into preclinical studies. PiB, a variation on thioflavin T, was synthesised in 2001 and 11C-PiB was first tested in people in 2002 by Agneta Nordberg, Bengt Långström, and colleagues (Uppsala University, Uppsala, Sweden), who are long-term collaborators of the Pittsburgh team. The first patient to receive 11C-PiB had early-onset Alzheimer's disease, and the deposition of Aβ was clearly seen. Although patient confidentiality regulations meant Klunk and Mathis could not know her identity, they sent her a letter through their Swedish collaborators, saying “it is only through selfless individuals such as you that medical scientists can push ahead the frontiers of research and make discoveries that will improve the future care of patients like yourself”. 11C-PiB was rapidly used in many centres worldwide and other tracers that use the longer-lived 18F instead of 11C were subsequently developed. Although the US Food and Drug Administration approved the technology in 2013, in the same year the publicly funded Medicare and Medicaid Services announced they would only pay for a PET scan (about $US 5000 each) if real clinical benefit could be proven. The Imaging Dementia Evidence for Amyloid Scanning (IDEAS; NCT02420756) study is about to address this issue in an expected cohort of 18 500 patients. One of the most exciting applications of these amyloid PET tracers is in conjunction with new Alzheimer's disease therapies that target the removal of Aβ deposits in the brain. Several anti-amyloid trials in progress are using PET imaging (NCT01760005, NCT01998841, and NCT02008357). Just as important are the prevention trials being done in people at high risk of Alzheimer's disease. “By giving preventive therapies long before any symptoms have emerged, monitoring the level of Aβ in subsequent years using the tracers, and finally comparing this to clinical outcome, we can determine the real effect of these therapies on disease course”, explains Klunk. Elsewhere, Klunk and Mathis are working with the Michael J Fox Foundation to develop a similar imaging agent for Parkinson's disease that binds to α-synuclein. Klunk is also working on tracers that more selectively show the accumulation of Aβ around blood vessels, which could help to identify those at risk of side-effects of immunotherapy. He is also mentoring the next generation of investigators, including Wendy Yau (the first author of the Article in this issue). Outside work, Klunk and Mathis enjoy fishing trips together, aiming to catch the steelhead fish that flourish in the Great Lakes. Paying tribute to Mathis, Klunk says that they have “had the longest and best partnership”. Longitudinal assessment of neuroimaging and clinical markers in autosomal dominant Alzheimer's disease: a prospective cohort studyOur results support amyloidosis as the earliest component of the biomarker model in autosomal dominant Alzheimer's disease. Our within-individual examination suggests three sequential phases in the development of autosomal dominant Alzheimer's disease—active amyloidosis, a stable amyloid-positive period, and progressive neurodegeneration and cognitive decline—indicating that Aβ accumulation is largely complete before progressive neurodegeneration and cognitive decline occur. These findings offer supportive evidence for efforts to target early Aβ deposition for secondary prevention in individuals with autosomal dominant Alzheimer's disease. Full-Text PDF