Posted 30 October 2008
2nd U.S.-Israeli-Palestinian Brain Conference
25-28 May, 2008
View Powerpoint Slide Index (Links to presentations also appear in the summary below.)
View photos from the Conference.
Peace Mission: Researchers Unite Under Alzheimer Banner
The setting alone was memorable. For three days this past May, the Mishkenot Sha'ananim, a historic compound of pale gold stone with splendid views of the ancient city walls of Jerusalem, hosted a group of researchers to discuss advances in the early detection of Alzheimer disease. But what made the meeting extraordinary, and historic in its own right, was the mix of participants: scientists, doctors, and students from Israel, the United States, Europe, and the Palestinian territories in the West Bank. The 2nd U.S.-Israeli-Palestinian Brain Conference was an exercise in building scientific bridges across the political divide represented by the security wall that snakes across the hills within sight of the Holy City. Co-organized by Mark Gluck of Rutgers University, Hermona Soreq, Dean of The Hebrew University, and Dina Bitar and Adel Misk of Al-Quds University, the conference built upon the success of a pilot meeting held three years earlier in Jerusalem, which focused on Parkinson disease.
While Israeli and U.S. scientists described cutting-edge research, their Palestinian colleagues spoke of the challenges they face teaching and practicing medicine with few resources. Indeed, the organizers spent three months obtaining special permits so that the Palestinian participants could stay overnight in Israel while attending the conference. Thanks to these efforts, some 20 Palestinians were able to partake of first-rate talks on advances in neuropsychological, imaging and biomarker studies, new therapies, and AD research in developing countries. (The talks included a whirlwind tour of the Alzforum by yours truly.) View Kinoshita Presentation [.ppt] (5 MB)
Marta Weinstock of The Hebrew University Medical Center launched the conference with a plenary lecture describing her work on ladostigil, a drug that targets multiple processes associated with dementia, including oxidative-nitrative stress, reduced cholinergic signaling, microglial activation, and mitochondrial dysfunction. Weinstock described rat models in which these changes are induced by various means including normal aging, injections of streptozotocin (which induces oxidative-nitrative stress and microglial activation), and sodium azide (a mitochondrial toxin). All of these models have impaired spatial memory. In these animals, ladostigil not only reversed the pathogenic processes but also improved performance on the Morris water maze. Teva Pharmaceuticals, which had licensed the compound, conducted human dosing studies and showed low side effects compared with rivastigmine. "When the methods for early detection and quantification of disease progression…become available we would very much like to assess the effect of the low dose on disease progression," said Weinstock. Plans for further clinical studies hit a bump in the road when Teva dropped ladostigil in the wake of a change of management. Weinstock is optimistic that another company will re-license the compound and take it through Phase 2 efficacy trials.
Beka Solomon updated the attendees on her filamentous phage-based approach (see ARF related news story). Intranasal application of the wild-type phage in PDAPP mice resulted in reduced Aβ plaque, reduced astrogliosis, and improved performance on the object-recognition test as well as in a newly developed smell test. Magnetic resonance imaging using gadolinium-labeled phage confirmed that PDAPP mice bind high levels of phage in cortex and hippocampus, correlating with areas with higher plaque burden. Confocal images showed that the phage colocalizes with plaques in 30 minutes. What's more, the phage treatment appears to begin to disaggregate plaques with startling speed. After just 120 minutes, the plaques are tattered around the edge, "like after a tornado," Solomon reported. View Solomon Presentation [.ppt] (3 MB)
Rounding out the talks on AD therapy development, Illana Gozes presented data from a Phase 2 trial of NAP (AL-108), a neuroprotective peptide now being developed by her Canadian biotech company Allon Therapeutics. Results from the trial were reported in detail at a recent Boston meeting (see ARF related news story). View Gozes Presentation [.pdf] (1 MB)
A worry that weighs on any drug developer's mind is whether there will be validated methods to identify individuals at incipient stages of AD, when they are most likely to respond to a treatment. Several talks described neuropsychological tests based on computational models of learning that are highly sensitive to subtle dysfunction of the hippocampus and entorhinal cortex that may precede a diagnosis of mild cognitive impairment and AD. Mark Gluck described his and Catherine Myers's theory of hippocampal-region function in "acquired equivalence learning," the ability to learn associations and then generalize these rules to a new context. In their "face-fish" task, for example, one first learns that a blonde girl likes pink fish and a brunette girl also likes pink fish. In the second phase of this test, the subject is told that the blonde girl likes yellow fish and is then asked which color fish the brunette girl prefers. Cognitively normal people will generalize that the blonde and brunette have similar preferences, and choose the yellow fish. Studies in collaboration with Steve Ferris and Mony de Leon of New York University have shown that individuals with hippocampal atrophy are impaired in this task. In longitudinal studies, people who were impaired in this task and also had hippocampal atrophy were more likely to be diagnosed two years later with MCI or AD (see ARF related news story). View Gluck Presentation [.ppt] (6 MB)
Keri Szabolcs of Semmelweis University in Budapest, Hungary, described how he is applying acquired equivalence learning to study the association of genetics and biomarkers with amnestic MCI (aMCI). While he did not find a clear correlation between acquired equivalence learning and genetic polymorphisms in genes previously implicated in learning, such as BDNF and KIBRA, Szabolcs observed an association with blood levels of TNFα, IL-1α, and IL-3. In a group of healthy elderly, he reported that those with low levels of these proteins committed more errors on the transference phase of the "face-fish" task than did the group with normal levels. View Szabolcs Presentation [.ppt] (2 MB)
Jennifer Bizon of Texas A&M is applying a task called "concurrent discrimination and transfer" to detect cognitive dysfunction in rodents. Bizon said that spatial reference memory, typically assessed using the Morris water maze, is sometimes not sensitive to the initial stages of memory impairment in mouse models of AD, but that an acquired equivalence task might be. She trained mice to dig in a container for a food pellet, and instead of faces and fish, used fragrance and digging material as training cues. She found that normal C57B6 mice learn to transfer a learned rule to new circumstances. In a double-transgenic model expressing the Swedish mutation of APP and a presenilin-1 mutation, however, mice are selectively impaired in the transference phase at age eight to nine months. This is the age at which mice have developed a significant plaque load in hippocampus but did not demonstrate deficits in a spatial reference memory version of the water maze in Bizon's laboratory. She next plans to investigate whether drugs and other interventions can reverse or prevent this deficit in the double transgenic and other models of AD. Bizon shared preliminary data reporting reversal of age-related cognitive decline in a similar task in a rat model of normal aging using drugs targeting cholinergic and GABAergic neural systems. View Bizon Presentation [.ppt] (6 MB)
Computational models of the hippocampus, which led to the acquired equivalence concept, are also suggesting ways to differentiate depression from dementia, according to Martin Meeter of VU University of Amsterdam, The Netherlands. Meeter incorporated serotonin and acetylcholine signaling into a computational model of the hippocampus and predicted that loss of serotonin versus acetylcholine would lead to distinct patterns of performance in word-list recall tests. In this test, subjects are asked to study a list of words and, after a delay, recall as many words as they can, and subsequently recognize the studied words from decoy words. The computational model predicted that both depressed and AD subjects would have reduced recall, but that in the recognition test, the "hit rate" (percent of words correctly recognized) would be stable in depressed subjects and decreased in AD, while the "false alarms" (percentage of decoy words falsely recognized) would increase in depressed subjects and be stable or decreased in AD. Data from actual depressed and AD subjects didn't quite stack up, however, until Meeter and his colleagues noticed that a subpopulation of AD patients had high false alarm rates. These patients turned out to have prefrontal lobe dysfunction, which is associated with an increased propensity to confabulate. View Meeter Presentation [.ppt] (380 KB)
While better early-detection tests are needed, for such tests to be truly useful they need to be taken out of the clinic, asserted Misha Pavel of Oregon Health & Science University. Current approaches for cognitive screening are infrequent and prone to short-term variability due to such factors as mood. They are biased by cultural background, language, and education level, and scores are interpreted based on population statistics rather than in terms of changes within an individual. Such clinical testing is also expensive. To overcome these shortcomings, Pavel and his collaborator Holly Jimison are developing inconspicuous devices to install in elders' homes and appliances to continuously monitor for changes in cognitive function. Pavel's group installed sensors in the homes of 250 elders, where over four years they will monitor such functional indicators as walking speed, aspects of activities of daily living, and taking of medications. These data can be analyzed later for early signs of onset of cognitive impairment in specific individuals. The Oregon team is also examining performance on computerized games, many based on card games, for indicators of subtle cognitive decline. Performance on these games is now being studied in a group of 30 volunteers, with a median age of 80.4 years. People with MCI generally scored lower on these games, but more revealingly, their scores fluctuated more than did the scores of normal individuals. Such fluctuation "seems to be diagnostic," said Pavel (see ARF related news story). While such monitoring has a Big Brotherish aspect that might be a barrier to acceptance, the take-home messages for now, Pavel concluded, are that "elders will participate, continuous monitoring is possible, and that these approaches enable assessment of within-subject trends."
Predicting who will develop AD also seems increasingly feasible using biomarkers combined with neuroimaging, according to Mony de Leon of New York University. De Leon previously reported that shrinkage and reduced glucose metabolism of the hippocampus, seen through MRI and FDG-PET, are about 74 percent accurate in predicting AD seven years before a clinical diagnosis. Of all imaging approaches currently under investigation, FDG-PET appears to correlate best with progression. De Leon's group investigated whether measuring phosopho-tau231 in CSF adds to MRI hippocampal atrophy measures in identifying MCI patients at risk for future AD. These data suggest that combining these approaches can be used for early detection of AD, he said. De Leon also described new data replicating earlier findings (De Leon et al., 2006) that isoprostane is a marker of disease progression, with levels rising over time. View de Leon Presentation [.ppt] (8 MB)
Leyla de Toledo-Morrell of Rush University described her group's progress in developing imaging markers to predict the risk of AD among non-demented elderly. Among 40 people who entered the Rush longitudinal study as normal controls, six developed AD over a 7.4-year follow-up period. She found that in scans taken at baseline, reduced volume of the hippocampus, entorhinal cortex, and parahippocampal white matter were predictors of risk. By comparison, there was no reduction in parahippocampal white matter in people with vascular cognitive impairment and stroke. These data will be published soon, she said. View de Toledo-Morrell Presentation [.ppt] (7 MB)
From cognitive function and brain imaging, the conference dove into molecules with Hebrew University scientists Hermona Soreq and Ephrat Levy-Lahad. Soreq described her pursuit of associations between alternative splicing variations of acetylcholinesterase to stress and aging. Levy-Lahad presented research on the transcriptional regulation of presenilin-2 (PSEN2) in mice. She noted that of the two known promoter regions of PSEN2, one is driven by Egr-1 (early growth response gene), a transcription factor associated with neuronal plasticity. However, an increase in Egr-1 in mice that had undergone fear conditioning was not accompanied by the predicted increase in PSEN2 expression. The take-home message, said Levy-Lahad, is that "if you are developing a PSEN2 mouse model, you will need to pay attention to the fact that it is probably regulated differently than in humans." View Levy-Lahad Presentation [.ppt] (4 MB)
On the third day of the conference, the attendees boarded a bus and journeyed over a twisting, parched road to the campus of Al-Quds Palestinian University in the West Bank. Founded in 1984, Al-Quds launched a medical school in 1997; some of the first graduates are now themselves teaching medical students there. Although travel in and out of the West Bank is severely restricted, the Al-Quds community is Web savvy and, thanks to a World Health Organization program, has online access to medical and scientific journals.
Still, Palestinians face major obstacles in the delivery of medical care for Alzheimer disease sufferers, said Adel Misk, a neurologist who co-organized the conference. Although high birthrates have increased the percentage of young people in Arab societies, the elderly population is also growing, but "there is lack of awareness, lack of nursing homes and day care, lack of funding for care, diagnosis, management, and research," said Misk. The reported cases of dementia are mainly advanced-stage patients, and these numbers are far lower than actual cases, he said. "Our societies consider memory loss as normal aging," he explained. "The factors affecting awareness include illiteracy, a lack of validated psychometric tests for AD, a lack of interdisciplinary teams, and co-morbidity with diseases such as diabetes and hypertension." There is "a burning need for validated psychometric testing in Arabic language," he declared. In addition, he noted that in many Arab countries, patients have no access to the medications that are currently approved in the West for AD treatment.
Misk called on the Palestinian Ministry of Health, Palestinian Medical Council and Association, with Al-Quds Medical School to create a special committee and organize regional meetings to discuss practical issues in dementia care, establish groups to improve the status of AD patients, and develop facilities for genetic testing, lab testing, and neuroimaging. He said such a committee would also need to promote the health care system, develop drug therapy policy, and provide standardization for senior day care and nursing homes. Misk also suggested that environmental exposures are likely to be involved with rates of dementia.
While the challenges in the West Bank are daunting, educational and cultural barriers to AD detection can be surmounted, assured Hakan Gurvit of Istanbul University in Turkey. Gurvit and his colleagues established AD prevalence rates in Turkey using a cross-sectional, population-based study of elders over the age of 70 living in the Kadikov district of Istanbul. The study recruited 1,019 volunteers, including 624 women, and 108 illiterates. The participants were initially screened with the Mini-Mental State Exam and General Depression Scale. This was followed up with a diagnostic workup, which more than 70 percent who screened positive agreed to undergo. The study found a prevalence of 11 percent—"rather high figures for a developing country," noted Gurvit. He suggested that the higher rate resulted from "meticulous efforts to detect very mild cases." View Gurvit Presentation [.ppt] (4 MB)
Rob Friedland of Case Western Reserve University described findings in another Middle East population, Arab Israelis of the Wadi Ara region, who have a high prevalence of AD. ApoE4 is found in only 3-9 percent of the population and cannot account for the high prevalence (Bowirrat et al., 2002). A polymorphism in SORL1 has been reported to be associated with AD risk among the Wadi Ara (Rogaeva et al., 2007; see AlzGene). This population is also characterized by a high fat diet, high rates of smoking and cardiovascular disease, and 40 percent consanguinity, the highest rate in the world "excepting European royal families," Friedland noted. View Friedland Presentation [.ppt] (4 MB)
Friedland has also investigated mechanisms for Aβ clearance, notably auto-antibodies to Aβ. He wondered whether there are common substances that are molecular mimics of Aβ and which could result in auto-antibodies that promote Aβ clearance. In a recent study (Friedland et al., 2008), he and his colleagues found that the amino acid sequence of the potato virus Y (PVY) is highly homologous to the immunogenic N-terminal region of Aβ. NMR data show that the anti-PVY antibody binds to Aβ within the F4-S8 and H13-L17 regions. When mice were inoculated with PVY, they generated antibodies that bind to plaques, neurofibrillary tangles, and neurons in brain tissue from Alzheimer patients. The researchers have inoculated APP overexpressing mice with PVY and hope to learn whether the auto-antibodies will attack the plaques that form in these mice. Friedland hypothesizes that human exposure to PVY through food could be protective. In addition to potatoes, foods that are commonly infected with PVY include tomatoes, peppers, and cucumbers—vegetables, incidentally, that pervade the "Mediterranean diet" said to be protective against a host of age-related ills, including dementia. Picking up on the dietary theme, Amos Korczyn of Tel Aviv University advocated a diet rich in vitamin E (such as the fish- and olive oil-rich Mediterranean cuisine) as part of a preventive lifestyle program to stem the AD epidemic. View Korczyn Presentation [.ppt] (2 MB)
By the close of the historic conference, attendees were already seeing the benefits of reaching out across boundaries. The Palestinians had begun to explore a collaboration to replicate the Turkish study methodology in Palestinian populations. An Arab Israeli woman had connected with care specialists who might be able to help her find care and support for her demented mother. Attendees were excitedly discussing ideas for future meetings and even new types of research centers to promote collaborative neuroscience in the Middle East. Two of the co-organizers, Gluck and Misk, also recruited three young Palestinian medical students from Al Quds who attended the conference to work with them, and their Israeli colleagues from Haifa and Tel Aviv, on a new joint U.S.-Israeli-Palestinian study of Parkinson disease. All in all, the meeting provided much to feed the mind and, at the closing banquet, an abundance of Mediterranean foods to feed the brain.—June Kinoshita.
View photos from the conference.