Dear Friends, We just returned from the 60th annual meeting of the American Academy of Neurology, which took place on the week of April 14th in Chicago. During this 3-day scientific meeting, there were several sessions dedicated to ALS. The highlight was Dr. Petra Kaufmann's report on the results of the CoQ10 clinical trial. In this newsletter, she has a special report, so I will not elaborate. Although I am part of the study and thus any praise I make may considered self-serving, I cannot help but point out that this study had almost no missing data, which is truly remarkable. Many clinical trials are marred by missing data which appears to be an almost inherent problem. I have to congratulate all the investigators. I would say this study was the result of an incredibly strong collaboration between our clinical unit and the Biostatistics Department at the Mailman School of Public Health. The study result was disappointing but showed a non-refutable result. One audience member at the meeting commented that it was a pity to have taken such a long time (3 years) to complete the study and find this negative result. Dr. Kaufmann answered that the CoQ10 study had a dual objective during the 3-year study period: the first was to determine the best dose from two doses, and the second was to find if the best dose selected showed any evidence for futility. If this were a conventional study, that is to study the efficacy of the drug, it would take a longer time period and require 800 patients. It was a big savings for the number of the patients required to complete the study. Another fascinating discovery discussed at this meeting was a protein called TDP- 43, which was discovered only a couple years ago. TDP-43 is a nuclear ribonucleic protein family which is known to control RNA expression in the cells. In ALS and related conditions, this protein is abnormally accumulated, forming an inclusion body inside motor neurons and other cells such as glial cells (supporting motor neurons). Inclusion body is an abnormal cell constituent which should not be present in normal cells. You may have heard that ALS and other neurodegenerative diseases such as Alzheimer's disease or Parkinson's disease are termed as proteinopathy (meaning disease of protein dysfunction). Proteinopathy is characterized by abnormal protein accumulation or aggregates, most likely abnormal in amount and abnormal in quality. Somehow manufactured proteins are abnormal in structure and thus protein moiety becomes abnormally sticky, promoting aggregation of dysfunctional protein molecules. Now, a number of mutations of the gene responsible for TDP-43 protein have been reported as the cause of familial ALS. It is most intriguing that the TDP-43 aggregates are found in many different forms of ALS, including sporadic ALS (which is the most common form of ALS), ALS associated with frontotemporal dementia, frontotemporal dementia without ALS, Guamanian ALS, ALS in Kii Penninsula, and other familial ALS except of SOD1 mutation. It is mind boggling to find that these TDP-43 aggregates are not found in the SOD1 mutations of either patients or mice carrying SOD1 mutation. SOD1 mutations are the most common types of familial ALS, and the animal model called ‘ALS mice’ are all based on transgenic models of this SOD1 mutation. We ask why most ALS has TDP-43 accumulation, but not in the SOD1 mutation. The investigators have been using this SOD1 mutant animal model for the past 12 years, and the majority of basic research papers are derived from studies in SOD1 mice. We start raising the question of whether the investigators have been using the wrong model for most ALS types. It obviously generates a serious concern. It is urgent that we resolve whether the question I raised is valid or whether there is something more to it. Although SOD1 transgenic mice are the best model for ALS to date, we realize that we need to be more cautious about the results coming from therapeutic trials studied in these animal models. We desperately need another and better model than SOD1 transgenic models, and I hope investigators are already working to generate TDP-43 transgenic models. If we can study the cause and cure of ALS in mice and cell models, we will find the solution relatively easily. It is true that mice and humans are very different, and furthermore, it is uncertain if the model one has studied is the right one. You can imagine more primitive animals and cell models may have more limitations in extrapolating their results into humans. We have to study simple, costeffective models, but we may need to come back to the patients with ALS for appropriate investigations. Yet, it is very true that studying human patients poses many insurmountable limitations. Personally, I propose we need to study patients as much as we can in many different settings. Clinical trials are the best example. There are very interesting models that were presented at this annual meeting. There was a report studying a fruit fly with SOD mutations. In fact, there is a zebra fish model and a worm model called C. elegans, all of which carry SOD1 mutations. These models are very useful in studying biological and molecular mechanisms, but I have to express my honest feeling that they would not represent a human disease. At this meeting, there were investigators who have been involved with an NIH-funded multicenter nutritional/respiratory study. The last patient will be completed in June and the data will be analyzed. This is one of the many studies we have been participating in. We will have a slew of new results that will be reported in the next year or two. We very much appreciate the patients and families who participated in the study. Finally, I would like to bring you up to date. Our Center continues to be very busy as usual. The genetic-environmental epidemiology study is in the final stretch and recently we started a prospective oxidative stress study in patients with ALS. Mary Kilty, a coordinator for both studies will give us an update in the next newsletter. We have just enrolled the first patient for pseudobulbar affect (abrupt forced laughter or crying spells in patients with bulbar ALS) and are almost ready to start a new clinical trial with a Knopp neuroprotective drug. Dr. Jinsy Andrews started a small safety study with lithium. You can find her brief study description in this newsletter. Dr. Arbesman, a dermatologist, and Columbia dermatology colleagues are now testing the feasibility of skin as a marker for ALS. This is very innovative and we are all excited about this study. Dr. Arbesman has a section describing his project. Working with the Harvard and Columbia stem cell investigators, we performed skin biopsies from patients with sporadic and familial ALS. We are expecting to hear some exciting news from them. Dr. Amy Chen wrote a brief follow-up note in this newsletter updating oxidative stress and exercise study in patients with ALS. Drs. Basner and Atkeson, Columbia pulmonary specialists, are working with the non-invasive ventilator as to how to improve the effectiveness of this assistive device with intensive monitoring and detailed instruction. Gabriela Harrington, ALS nurse specialist, is working with Dr. Rabkin to improve satisfaction and time-effective allocation of the multidisciplinary team at our ALS Center. Dr. Kaufmann and Kate Bednarz are working to obtain NIH approval for the second phase data entry for DNA banking. Meetings like the American Academy of Neurology are an important opportunity for us to exchange ideas and to see what's happening at other major centers. Many other ALS Centers are busy as well doing a number of the same collaborative investigations together and also their own studies. I would like you to know we are all working very hard to make a big dent on the tough shell of this dreaded disease. Hiroshi Mitsumoto, MD