29 March 2007. Every other year, Abraham Fisher of the Israel Institute for Biological Research in Ness-Ziona, and Israel Hanin of Loyola University in Maywood, Illinois, team up with two local scientists from a different European country to host an international meeting. This year, the hosts were Werner Poewe, who chairs the neurology department at the Medical University of Innsbruck, and Manfred Windisch, who heads the Austrian contract research organization JSW-Research Ltd. in Graz. The International Conference AD/PD has been growing steadily; this year it drew nearly 2,200 people, up from 1,500 two years ago in Sorrento (see ARF related news story). The flood of registrants—1,800 were expected—led to a last-minute scramble to build a lunch tent outside the conference center and to locate additional hotel rooms. The conference proceeded smoothly, yet its rapid growth prompted some soul-searching among the organizers about how to keep the program sharp and logistics efficient while also preserving the personal flair that has made exchanging ideas and striking up new acquaintances easy at this conference before. At the end of the meeting, the organizers invited ideas from the attendants on how to keep improving. Some mentioned increasing the number of younger and female speakers, as well as offering travel awards to students, but additional suggestions are welcome.
The conference began with a tribute Windisch paid to Leon Thal (see ARF related news story) as a clinician-researcher, friend, and fellow aviator. Then the Austrian Oleh Hornykiewicz, who conducted the first clinical experiments infusing levodopa into PD patients in the 1960s, took history buffs and people too young to remember back to this decade. He told the story of how difficult it had been in those days to convince his fellow brain anatomists that an important projection from the substantia nigra to the striatum existed in the first place.
The conference offered no major news breakthroughs but many tidbits on topics spanning the complex spectrum of age-related dementias and movement disorders, of which Alzheimer's and Parkinson's are merely the best-known ones. One trend apparent at the conference was a vigorous effort to delineate forms of frontotemporal dementia anew in light of the discoveries last year of mutations in the progranulin gene and the identification of the TDP-43 protein as a major component of characteristic intranuclear inclusions. This gives researchers new tools to make sense of the overlapping clinical pictures, genetics, and pathologies of diseases ranging from different dementias all the way to amyotrophic lateral sclerosis. It also spurred a burst of studies to explore how these players fit into the disease pathogenesis and whether they could become therapeutic targets, though this research is only just gearing up and has few results to offer yet. Of several new mouse models introduced at the conference, one in particular illustrated this crossover between diseases, when a tau transgene from a family with the frontotemporal dementia Pick disease, expressed in mouse striatum, gave rise to a rather classic phenotype of parkinsonism and even responded to the PD medicine L-dopa.
In mouse model research more generally, a current trend in the field is to improve them by recreating various sorts of "multiple hit scenarios." Oxidative stress and mitochondrial impairment are typically a general component of this scenario and, combined with disease-specific transgenes, make neurons particularly vulnerable. These experiments either take the form of cross-breeding mouse strains or manipulating neurons cultured from transgenic models. Other translational research in mice strengthened the promise of ACAT inhibition for the future treatment of AD.
Another trend strengthened at the meeting was that efforts to test and validate preclinical biomarkers are beginning to dovetail in that CSF and imaging data are beginning to overlap into signatures that predict who will go on to develop full-blown AD from among a diverse group of people with mild cognitive impairment, and even cognitively normal people in some studies. Scientists are pushing back toward trying to predict AD reliably at a preclinical stage. Many talks throughout the conference echoed what is emerging as a consensus theme, namely that AD, and probably also PD, develop silently during a so-called prodromal phase, and that it is this phase during which therapeutics stand the best chance of working.
In Parkinson disease, efforts to develop antecedent markers are coming to the fore, both in CSF and serum, and even with techniques such as ultrasound. In AD, such work has been going on for a longer period of time. In imaging and biomarker research, efforts at coordinating some of the individual groups' work into national efforts are being discussed in various countries. For example, Japan, Germany, and Australia are starting up projects similar to the U.S./Canadian Alzheimer Disease Neuroimaging Initiative (ADNI), and internal discussions are underway to try to make the databases interoperable so that they support analysis of much larger datasets than any individual center, or even country, can generate.
Talks on immunotherapy offered little hard news, but many speakers converged on the theme that it should ideally become a preventive therapy eventually, given during the prodromal phase before plaques have built up. Alternatively, researchers agreed, it will have to be adjusted carefully so as not to overwhelm the capacity of the AD brain to clear away a wave of antibody-protein complexes washing up against aging blood vessel walls. One point of debate in immunotherapy research revolves around the relative values of N-terminal versus C-terminal antibodies, and active versus passive regimes. But several scientists pointed out that these kinds of categorical distinctions may be less important in determining which antibody is safe than the specific idiosyncratic properties of a given antibody. One open question at this time surrounds the significance of the fluid-attenuated inversion recovery (FLAIR) MRI images that were seen in the phase 1 and the currently ongoing phase 2 trial of Bapineuzumab, aka AAB 001. Such signals generally are seen as indicators of small hemorrhages. As always when there is no definitive data yet, speculation fills the void, and at the conference, opinions on the FLAIR signal ran the gamut from "passive immunization is finished, clinicians won’t risk causing bleeds" to "this is clinically irrelevant; our patients who show FLAIR signals are doing fine." Further research is needed to sort out this issue.
There is much activity on γ-secretase inhibitors and modulators. Companies presented ongoing programs, suggesting that industry has not abandoned γ-secretase as a major target following the discovery of mechanism-based side effects on Notch signaling, but is instead working to circumvent this problem. Scientists from several companies speculated that even if the first suggested γ-secretase modulator already in phase 3 trials, Flurizan (see ARF related news story), obtains FDA approval, its clinical benefit will be small enough to leave room for improvement. BACE secretase inhibitors are inching their way toward early clinical tests. A physiological role for BACE in the myelination of axons has pointed out an area to watch for potential side effects, and a growing number of research laboratories are exploring feverishly what regulates BACE. Other genes, proteins, inhibitory RNAs, environmental influences—all are under the microscope in the search for understanding new BACE-related targets.
On the therapy front, clinical trial results for a few agents were presented, but none surprised with strong effects just yet. The frontrunner of anti-amyloid therapies, Neurochem's Alzhemed, has completed its North American phase 3 trial. Data are being analyzed this month and will be presented in June at the Alzheimer's Association International Conference on Prevention of Dementia (see ARF related conference story) in Washington, D.C., according to Neurochem representatives. The makers of anti-amyloid drugs are vying to persuade the FDA to allow them to claim on their drug's label that it modifies disease rather than just treats its symptoms, and several presentations dealt with how clinical trial design would have to change to make this possible. While companies are wrestling with the difficult scientific problems posed by a new generation of experimental anti-amyloid therapies, a number of more traditional transmitter-based approaches were presented. They include serotonin receptor antagonists, butyryl receptor inhibitors, α7 nicotinic receptor agonists, and even estrogen receptor β agonists.
Approaches that have failed in the past, such as gene therapy and agonists of M1 muscarinic acetylcholine receptors, are making a careful comeback. An M1 agonist originally developed by Abraham Fisher has passed two single-dose phase 1 trials without incident and is about to enter a first multi-dose phase 1 study. Phenserine (see ARF related news story), a cholinesterase inhibitor that is thought to also affect amyloid levels, impressed some colleagues when Swedish scientists reported that it not only improved cognition and clinical symptoms somewhat in people with AD but also lowered their brain amyloid load as measured by PIB PET and shifted their CSF amyloid markers, as well. The reassurance came not so much from the drug’s small effect on cognition, but from its concurrent nudging of two separate biomarkers. Last but not least, the much-dismissed notion of a role for infectious organisms in neurodegenerative diseases is tenaciously hanging on, this time with anecdotal reports that treating Helicobacter pylorus infection in Parkinson patients who also have gastritis rather startlingly improved their PD. On the inflammation front, microglial imaging and experimental uses of the antibiotic minocyline to reduce inflammation drew note. Stay tuned for more detailed stories from the conference.—Gabrielle Strobel.