On December 11-13, the 21st International Symposium on ALS/MND took place in Orlando, FL. This event is the largest, international ALS/MND research event of the year. About 800 neurologists, neuroscientists and health professionals attend the event. There are two 'tracks' at the event, one on clinical and one scientific. Each of those meetings take place simultaneously in large meeting rooms across the hall from each other. At the start and end of the symposium a join session is held bringing the two tracks together. The following is a recap of the first day of this year's symposium. Notes are limited to the talks/sessions which I attended. If you have questions/comments, email marketing@als.net. Discussion on these notes and the meeting in general is taking place at the ALS Forum located here: www.als.net/forum. In addition to the narratives provided below, a set of notes collected with the help of Drs. Lincecum, Dhillon and Perrin from ALS TDI is available by clicking here: http://tinyurl.com/2buken3
Session 1: Joint Opening Session
This year's meeting opened with the introduction of Dr. Merle Weinberg, the President of the National Health Council as well as the International Alliance of Health Organizations. Weinberg used her opportunity to open the Symposium by introducing the goals of those two organizations. She encouraged researchers in the room to become involved and described the mission of the Council as striving to get therapeutics "at the right time, to the right patients, in the right place and at the right price." One of the themes from the meeting this year which stood out to me was the inclusion of researchers from other fields of neurodegeneration and disease intervention.
Highlighting this from the beginning was the invitation of a very well-known Alzheimer's researcher, Dr. Virginia Lee of the University of Pennsylvania (Philadelphia, USA), to present the opening remarks on science, specifically on TDP43. Lee was a co-author on a much read report in 2006 which identified the link between TDP-43 mislocalization in both a neurodegenerative disease (ALS) and a form of dementia (FTLD) (Lee et al., 2006). According to Dr. Lee, TDp-43 is an RNA binding protein, but beyond that researchers known little about its specific function in the body. However, she reported the mislocalization or aggregation of TDP-43 in the cytoplasm is a common pathology associated with a spectrum of diseases, including frontaltemporal lobar dementia (FTLD) and amyotrophic lateral sclerosis (ALS). FTLD is the second most common form of dementia among people in the US under the age of 65. In addition, it is known that 30% of FTLD is caused directly through a mutation in the expression of TDP-43 (familial FTLD). Echoing a presenter from the day before, Lee reminded us that TDP43 pathology is thought to be present it at least 90% of all ALS cases – sporadic and familial (see my recap from Dr. Rademarker's Genetics of ALS talk). According to Lee, her work suggests that RNA processing may, in fact, be a primary cause of ALS. Lee closed her plenary by suggesting that FTLD-TDP43 and ALS are syndrome variants of a clinicopathological spectrum of the same neurodegenerative disease.
Providing the opening discussion on clinical research this year was renowned neurologist, Dr. Robert Miller, of the California Pacific Medical Center and the Forbes-Norris MDA/ALS Research and Treatment Center (San Francisco, USA). Dr. Miller began by urging his colleagues not to say that "ALS is untreatable". Dr. Miller introduced the audience to the Cochrane Review of ALS/MND, who was holding a breakout session at this meeting later in the week. The point of that group was to conduct investigations into proposed treatments for ALS, and seek consensus among a group of researchers/neurologists who would then publish it as an educational tool (not unsimilar to the efforts of ALSUntagled mentioned by Drs. Bedlack and Cudkowicz). Miller made a few other points, including recent data that showed 63% of patients take Rilutek, 21% use non-invasive ventilation (NIV) and 9% have a feeding tube. He commented that such studies need to be consistently updated in order to provide clinicians with the confidence needed to provide a standard of care. In the future, he would like to see lager systematic studies of exercise, nutrition and feeding tubes undertaken by the clinical community in order to establish new parameters regarding care. The American Academy of Neurology (AAN) released an updated set of parameters last year (Miller et al., 2009). (A pALS and ALS Forum member recorded this presentation, a transcript of which is available online by clicking here.
Session 2A: RNA Biology of ALS (bullets only version)
The first speaker was a well-known biologist, Dr. Thomas Maniatis, of Massachusetts Institute of Technology in Cambridge, MA (USA). He was invited to provide a detailed look into his ambitious attempt to identify druggable targets by comparing gene transcription changes between samples collected from the ALS mouse model to iPS cell lines derived from ALS patients. To tackle such a large project, his lab took on a computational biologist to specifically design a custom bioinformatics platform to mine and analyze the terabytes of data for targets. One of the outcomes from this effort has been the deep sequencing of samples from spinal cords of both pre- and post-symptomatic mice. That experiment identified 360 genes that were up-regulated and 750 genes that were down-regulated in motor neurons. That paper will be published soon, according to Maniatis. Many of the genes identified were involved in RNA processing. In fact, his lab dug deeper and identified that RNA splicing factors change as well; 14 splicing factors were up-regulated and 35 were down regulated. Turning to the human induced pluripotent stem cell (iPS) side of the project Maniatis reported some early work. His group has developed 4 separate lines; 1 TDP+male, 1 FUS+female and 2 healthy individuals. He made a note of explaining that when they start the iPS process they actually try to create four different lines from each donor sample, and then choose the most stable one for mass production of cells. To date, his lab's technicians have been able to establish stable lines (80% successful differentiation into motor neurons) from each. Early analysis of these samples produced an interesting result; the expression of many genes associated with the expression of mtTDP43 change in the opposite direction of those associated with mtFUS. Maniatis closed by suggesting that the field could benefit from the establishment of a comprehensive RNASeq database for iPS derived cells (motor neurons, glib, spinal cells, macrophage, leucocytes, etc) (Maniatis et al., 2010).
Dr. Laiger-Tourenne of the Ludwig Institute for Cancer Research in La Jolla, CA (USA),was up next, who explained that since there is little understanding regarding the pathogenesis of TDP43 in ALS, her project was designed to answer the question, "Which RNA are bound by TDP43 in the brain?" Using CLIP-Seq technology she and her colleagues identified 6300 genes bound by TDP43; about 30% of the entire murine genome. Laiger-Tourenne presented data from her group's collaboration with pharmaceutical company ISIS, to use antisense technology as a knockdown strategy for TDP43 in the brain of mice. The outcome from that experiment identified another 240 genes that were down-regulated and 360 were up-regulated in TDP43's absence in the brain. In addition, they were able to show that TDP43 plays a broad role in the regulation of splicing of more than 500 RNAs. Interestingly, her lab found there to be no binding of TDP43 identified on SOD1 transcripts; however TDP43 binds the transport of FUS (also other genes involved in neurodegeneration progranulin, Park2, etc). In making that final point, Laiger-Tourenne said that she wanted to highlight that TDP43 is a remarkable RNA binding protein, and that as researchers understand more about what it is normally meant to do, it could be a useful target for drug development (Laiger-Tourenne et al., 2010).
The following discussion was from Dr. Keith Hanson of the University of Wisconsin (Madison, USA), who provide a genetic and biochemical analysis of TDP-43 proteinopathy. He began by showing data that clearly suggested TDP43 toxicity depends primarily upon the nuclear dose of the protein present. His lab specializes in the creation of drosophila (fruit flies) for research, and has developed a line which expresses mtTDP43. Data collected by him and his colleague support the role of the "notch" pathway in TDP-43 proteinopathy. While there are many genes involved in the notch pathway, his group identified three of them, which their data suggested were pivotal in its regulation. They cross-bred flies expressing those genes with the TDP43 line to determine if motor neurons were rescued. TDP43 phenotype was alleviated by knocking out the notch pathway in fruit flies (Hanson et al., 2010).
Dr. Bryan Freidbaum, whose lab at St. Jude Children's Research Hospital in Memphis, TN (USA), focuses on large scale proteomics, and began the next presentation by stating that a TDP43 interactome reveals an association with proteins involved in RNA metabolism. His lab's work suggests that the RNA targets from TDP43 and FUS are likely the same. Friedbaum's group is also using the fruit fly model to test potential targets it has identified because they are an excellent model to understand genetics of TDP43 better (Freibaum et al., 2010).
The fifth speaker of the morning session was Dr. Janice Robertson from the University of Toronto, Canada. She described the limitations of using fly, mouse and other models of disease to identify human RNA targets of TDP-43 because of the huge variation in the intromic sequences among species. Her lab has created a human neuroblastoma cell line in which to conduct research. The Robertson team also conducted CLIP-Seq and indentified that 77% of the binding regions for TDP43 are interons; many at the TGTG repeater and other polyprimidine rich motifs. They also confirmed that TDP43 binds to RNAs involved in multiple biological pathways. Robertson reminded her colleagues that 90% of ALS cases have now been shown to have TDP pathology, irrespective of mutation status of TDP43 itself. Robertson concluded this new information makes TDP-43 a potentially highly-relevant drug target (directly or indirectly) by targeting pathways in which it is associated (Robertson et al., 2010).
I didn't attend the final two talks of this session, but Dr. John Lincecum of the team at ALS TDI did. His notes on the above talks, as well as those two talks from Drs. Paro and Moller are available via PDF by clicking here.
Session 3A: Lessons from Other Diseases (bullets only version)
Session 3B: Care Education and Practice
The first speaker of this section was Virginia Jackson from the USA. She is a nurse who provides care in the clinic and at home for ALS/MND patients. Her presentation focused on asking the question: How are healthcare professionals impacted by working with people with this disease? One of the primary premises throughout her presentation was the need for palliative care professionals to become involved much earlier on in the treatment of a patient and their family, rather than at the end. She commented that too often in the US palliative care discussions only take place when a patient enters a hospice facility or end stage of disease. In summary, her primary goal was to identify triggers and provide solutions to help avoid "burnout" of nurses, neurologists and other allied healthcare professionals in the field which are involved in providing palliative care.
Using both personal anecdotes as well as information gathered from the literature, she proposed that health professionals which work with ALS/MND patients need to identify triggers in their own practice which make them susceptible to "losing control" over a relationship with a patient. Her take home message was twofold. First, health care workers must create barriers and limitations (i.e.: don't give out your home phone number, don't take on too many patients who "remind you of yourself"). And second, that when a person they are caring for passes, they should acknowledge the loss and honor the person by taking an appropriate amount of time to recognize that person's impact on themselves (ie: sharing their thoughts and feelings about the person with colleagues during a group lunch). Many questions followed from the crowd, which contained many allied health professionals, about how best to honor a person under their care. Most in the room acknowledged that the community looses too many skilled and passionate health professionals due to burnout, and thanked Jackson for bringing this topic forward for discussion (Jackson et al., 2010).
The next presentation regarded the results from an educational program piloted in Australia designed to educate various health professionals in that country on palliative care techniques. Interestingly, of the 77 people that participated in the training programs, the organizers found that many of them were not ALS/MND specific although their marketing of the program was targeted at that group of health professionals. They are still finalizing their results and plan to share them with as many people interested afterwards (Mcconigley et al., 2010).
The following speaker was from Italy and provided an interesting talk on whether or not pain is associated with ALS disease progression. Their study included 160 pALS (91 men and 69 women, average age was 62 yo, and on average they had received an ALS diagnosis 42 months prior). Data collected from people living with ALS was compared to 120 controls. All participants completed the "Brief Pain Inventory". More than half of the pALS in the survey reported pain, compared to only a third of those in the control group. The most common pain reported by the Italian pALS in the study was located in the limbs; back pain was where most control group members reported the location of their pain. The presenter, Dr. Calvo of the University of Torino, suggested that his findings provided evidence that pain may be associated with the progression of disease and correlated it to developing joint weakness, cramps, skin pressure and muscle contractions and spasticity. The audience welcomed this report and many of the questions poised showed appreciation for bringing forward to the community of health professionals the need to think about pain in ALS patients differently. A later presentation would provide interesting data that showed that, in fact, the strongest pain medications (opiates) were in fact prescribed more often to non-ALS patients and debate around that took place more in the hallways than in any public forum (Calvo et al., 2010).
The next talk was provided by Ms. Williams of the Carolinas Neuromuscular Center in North Carolina (USA). Her research stood out as the only communication technology presentation during the symposium. Williams' goal was to delineate, if possible, if there was a difference in how pALS and family members of pALS choose to interact with the nursing staff at her center by comparing the number of emails she received to the number of phone conversations that took place. This study followed her communication activities for nine months, during which she categorized them by subject and type. On average she received 101 contacts a week, and interestingly, 90% of them were via the phone and 81% were from patients/family members. Most of the questions she received were regarding appointments. In conclusion, Williams put forth to the community that more of these types of surveys should be undertaken as they can help centers like hers to quantify their individual workloads which can be useful in justifying resources from both internal and external funding sources (Williams et al., 2010).
Dr. Zachery Simmons of the Pennsylvania State University College of Medicine (USA), used his spot at the end of this session's program to report data and conclusions from a survey which he conducted on the use of multidisciplinary clinics (MDC) by pALS, and how that may relate to survival. This was a very interesting survey, and some of its results would contrast with research presented by Dr. Richard Bedlack on Friday regarding clinical trial participation. The survey was completed by 329 pALS, 240 of which reported them as attending an MDC. The survey was "self-reported," meaning that pALS completed the questionnaires themselves. Simmons reported that his research showed that age, gender, and onset location of disease were not predictive variables in determining who was a MDC attendee and who was not. Most interesting, the data suggested that those that attended at MDC had a shorter duration of life with the disease as well as a poorer level of function, while at the same time reported having an overall higher quality of life. There was no surprise in the data in regardsd to the use of Rilutek and pain medication, nursing visits and consultations with a variety of specialist therapists also correlated higher among MDC goers. A review of the survey also suggested those that didn't attend an MDC were more likely to be a participant in a clinical trial, which drew questions from the crowd as to how a patient could be in a trial but not be classified as attending an MDC. Simmons offered a hypothesis that many patients only attended a clinic for the trial itself and not for the MDC's offerings, and therefore may not believe themselves to be involved directly with an MDC (and he reminded people that the survey's were "self reported"). Simmons' efforts, he said, were to try and get to the patients' perspective on the benefits and outcomes from attending an MDC, not the physicians' (Simmons et al., 2010).
Session 4A: Emerging Disease Models (bullets only version)
This session provided an opportunity for several researchers to provide information on their attempts to develop models of neurodegeneration which recapitulate aspects of ALS disease progression. Dr. Jean-Pierre-Julian of the University Laval in Quebec, Canada, was the first to speak. His research, which included utilizing some of the latest technology in imaging as well as molecular investigatory technology, showed that neuroinflamation precedes cognitive and motor defects as well as a progressive reduction in large motor neurons in his mouse model of TDP43. He hopes that this model will one day be a useful tool for drug screening. One of the interesting findings from his teams' work was that ALS disease pathology may be linked to activities specifically taking place in the white matter of the brain; an area of research which has not enjoyed as much attention as other parts of the CNS in relation to ALS over the years. His team hopes to conduct a temporal gene expression experiment, with a focus on brain tissue collected from his model, to determine if there is a gene related "tipping point" that can be correlated to the onset of disease. He hypothesizes that this may exist, as they see inflammation a full two months earlier on average in the brain than in the spinal cord (Julien et al., 2010).
The program then switched back over to another genetic model, the SOD1 mouse. But this time, it wasn't the G93A or G37R, but a new model called the D836. The presenter, Dr. Joyce of the MRC Mammalian Genetics Unit in Harwell, UK, claimed that this model was a better representation of SOD1 caused sporadic ALS. In his experiment he set out to phenotype the animal by measuring its grip strength and gait change over time. In all, females were found to be lighter than males and males were found to be more deficient in behavior over time (Joyce et al., 2010).
The next two presentations were on the use of zebrafish as a model of neurodeneration. The first talk was from Mr. Da Costa of the University of Sheffield, UK, who developed a line of SOD1 zebrafish by mutating the T701 gene. He confirmed their phenotype by conducting motion analysis and swimming tests, during which the flow of water was increased over time and compared between groups (Da Costa et al., 2010). The second talk was from Dr. Sakowski, whose zebrafish were put through similar swimming aptitude tests as the previous presenters' fish were, and showed a similar loss of ability at around 15-20 weeks old. At the same point in time, his team harvested samples of fish and determined that at approximately 20 weeks old the fish have lost nearly 50% of their motor neurons (Sakowski et al., 2010). While the zebrafish is a useful model to study disease pathology, comments from the audience to these two speakers raised the question of whether or not survival was impacted, which data to date show that it is not. Despite the loss of neurons, Sakowski's fish have survived 20 months so far (the average life of a zebrafish in captivity is 2-3 years).
Dr. Liu from the Penn State College of Medicine, USA, gave the next talk which focused on describing an observed association between a mutant protein (HFE H63D) and neuronal viability due to stress being applied to the endoplasmic reticulum (ER). Liu posited that as many as 30% of pALS may carry a mutation in HFE. He also pointed out that his research was using endogenous mutant protein, which when inserted in vitro showed no aggregating into the ER. However, in vivo experiments showed that markers of ER stress were more prevalently in wild-type animals used in experiments, and ER stress has been implicated for many years as a potential role in the onset of ALS, according to Dr. Lui. His work showed that the presence of this mutated protein induces capsase activation, increases early apoptotic cells and activates the unfolded protein response (UPR) which in turn leads to stress being exerted on the ER. This process can take a year, with the UPR being recognized at 6 months and ER stress markers being present at 12 months out. In summary, Lui's work suggests that HFE H63D promotes neuron degeneration through prolonged ER stress (Liu et al., 2010).
The final presentation on models of neurodegeneration came from Dr. Kanekura of the University of Massachusetts Medical School, USA. He also reported on the potential role of ER stress and showed that another protein may aggregate and cause similar outcomes. Kanekura's work used a rate genetic form of ALS, caused by VAPB (ALS8) to investigate ER stress. In his research he found that in that form of disease, P56S-VAPB (a protein), is misfolded and is localized in the ER. While ER chaperons attempted to fix the misfolded proteins, the stress can lead to cell death and eventually, he suggests, cause the onset of clinical ALS (Kanekura et al., 2010).
Works Cited
Calvo et al., A. (2010). Pain in ALS: Frequency and Characteristics in a Population Based Series . Amyotrophic Lateral Sclerosis , 17-18.
Da Costa et al., M. (2010). Development and Characterization of a Zebrafish Model of Mutant SOD1 Mediated Motor Neuron Disease. Amyotrophic Lateral Sclerosis , 21.
Freibaum et al., B. (2010). Characterizing the Role of TDP-43 in ALS. Amyotrophic Lateral Sclerosis , 10.
Hanson et al., K. (2010). Genetic and Biochemical Analysis of TDP-43 Proteinopathy. Amytrophic Lateral Sclerosis , 9-10.
Jackson et al., V. (2010). Palliative Care in Terminal Illness- The Impact on Heathcare Professionals. Amyotrophic Lateral Sclerosis , 17.
Joyce et al., P. (2010). A New Mouse of ALS Carrying a Point Mutation in the Mouse SOD1 Gene. Amyotrophic Lateral Sclerosis , 20-21.
Julien et al., J.-P. (2010). TDP-43 Mutant Transgenic Mice Develop Biochemical and Pathological Features of Amyotrophic Lateral Sclerosis and Frontotemporal Lobar Dementia. Amyotrophic Lateral Sclerosis , 20.
Kanekura et al., K. (2010). Dysregulation if ER Stress Signaling by ALS-Related P56S VAPB Mutant. Amyotrophic Lateral Sclerosis , 22.
Laiger-Tourenne et al., C. (2010). Role of RNA Processing in the Pathogenesis of Amyotrophic Lateral Sclerosis. Amyotrophic Lateral Sclerosis , 9.
Lee et al., V. (2006). Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science , 314, 130-133.
Lee. (2010). New Prespective on Amytrophic Lateral Sclerosis As TDP-43 Proteinopathies. Amyotrophic Lateral Sclerosis , 7.
Liu et al., Y. (2010). Mutant HFE H63D Protein is Associated with Prolonged ER Stress and Decreased Neuronal Viability in ALS. Amyotrophic Lateral Sclerosis , 22.
Maniatis et al., T. (2010). Using Embryonic Stem Cells to Study Motor Neuron/Glia Interactions in ALS. Amyotrophic Lateral Sclerosis , 9.
Mcconigley et al., R. (2010). Development, Implimentation and Testing of an Educational Program to Guide Palliative Care for People with Motor Neuron Disease. Amytrophic Laterial Sclerosis , 17.
Miller et al., R. (2009). Practice Parameter update: The care of the patient with amyotrophic lateral sclerosis: Multidisciplinary care, symptom management, and cognitive/behavioral impairment (an evidence-based review): Report of the Quality Standards Subcommittee of the American. Neurology , 73, 1227-1233.
Robertson et al., J. (2010). RNA Targets of TDP-43 Indentified Using UV-CLIP Are Deregulated in ALS. Amyotrophic Lateral Sclerosis , 10-11.
Sakowski et al., S. (2010). Novel Zebrafish Models to Investigate ALS Disease Pathologies. Amyotrophic Lateral Sclerosis , 21-22.
Simmons et al., Z. (2010). A National Study of Amyotrophic Lateral Sclerosis Multidisciplinary Clinic Utilization. Amyotrophic Lateral Sclerosis , 18-19.
Williams et al., N. (2010). Patient Care Coordination at Carolinas Neurmuscular/ALS-MDA Center: Nursing Management of E-Patients and T-Patients. Amyotrophic Lateral Sclerosis , 18.