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- 2009 Annual meeting - Conference and discussion


General Assembly of CADASIL France
March 28, 2009
Scientific and Medical Conferences
Discussion with the medical team
Many members of the medical team attended the "Cadasil France Remembrance Day":
·        Professor Marie-Germaine Bousser, member of the National Council on Ethics and Scientific Board President of Cadasil France
·        Professor CHABRIAT representing CERVCO
·        Dr. JOUVENT, responsible for the research project of high definition MRI
·        Dr. Anne JOUTEL, Director of Research at INSERM, which conducts research on CADASIL in the team of Professor Tournier-Lasserve
·        Mrs. Annie KURTZ, Neurology Department’s psychologist at Lariboisière Hospital and Board member of Cadasil France
·        Mrs. REYES, Mrs. DUBOIS, psychologists
·        Mrs.  Jocelyne RUFFIE, Professor Bousser’s Assistant
·        Mrs. LEDER-MOREL, social worker working part-time for CERVCO
·        Mrs. HELLO, Secretary of CERVCO.
DNA Learning Center:  Mrs. ROCHETTE
Mrs. ROCHETTE is responsible for scientific media relations at Genethon.  She participated the entire afternoon to medical discussions to present a proposal for initiation and also benefit from the medical debate and get to know us.
AFM (French Association against Myopathies), which organized the telethon, financed workshops conducted by the DNA Learning Center. The center offers training and information workshops on advances in Biology and Genetics for all audiences, particularly directed to associations in different cities. These courses are taught by top scientists, with an aim for popularization of science. The objective is to understand researchers, to be able to discuss with them, to have a better understanding of scientists' work, to have knowledge base in molecular biology and genetics, to better explain the disease CADASIL, to comprehend its transmission rules,  genetic testing, and to understand time scale of Research.
A three-day training is proposed for members of Cadasil France. It will be held in the Paris region, at Genethon's premises of Evry. A group of twelve to fourteen people must be assembled. This workshop is open to all persons over the age of fifteen, interested in the subject, does not require any prior knowledge, medical or on Cadasil. The dates for this course are from Wednesday 23 to Friday, September 25, 2009.
Each training day lasts six hours, with observations, experiments, practical work, discussions, tour visit of Genethon, presentation by a Cadasil expert, etc.
Yves DE SARS, Administrative Board member, is responsible for taking care of enrollments and providing information to those interested ( such. 02 43 81 21 10).
This training is free of charge. Meal expenses will be covered by Cadasil France. The association may also provide financial assistance for transportation and housing, subject to resources in accordance with the rules of the association.
Presentation on Genetic Research: Dr. Anne JOUTEL
Since the identification of the Notch3 gene in 1996, knowledge has advanced in stages.
Again this year, progress has been made in understanding the mechanisms of the disease.
1) A new transgenic mouse model developing brain lesions was generated
A first mouse model developing vascular lesions similar to those observed in patients was produced in 2003. However, further analysis revealed that these mice did not develop brain lesions.
In collaboration with a German laboratory headed by Professor Norbert Hübner in Berlin, a new transgenic mouse model was designed.
These mice are the result of sophisticated genetic engineering designed to make the mouse carrying a greater amount of Notch3 protein (about 4 times) in the same areas, especially in both large brain arteries as well as smaller vessels called capillaries, and in addition with a CADASIL mutation. Control- mice presenting also a large dose of Notch3 protein, but normal, without mutation, were also produced.
Vessels and the brain of these new transgenic mice were analyzed in detail from the age of one month until the age of 20 months. In perspective, a normal mouse lives an average of 24 months. These new transgenic mice with the Cadasil mutation present, at the age of 1 month, on the extracellular area of cerebral vessels, characteristic accumulation of the Notch3 receptor and at the age of 5 months, characteristic deposits called "GOM" that can be seen under electron microscopy. Interestingly, we detected in these mice, from the age of 12 months, the first signs of damage in the brain's white matter and at 20 months, lesions in the white matter but not the cortex (brain surface) as well as a reduced blood flow throughout the brain.
By obtaining mice which develop same lesions as humans, we are able to study them throughout their lives and analyze the chronology of events. In particular, it was observed in these mice that the cerebral arteries’ walls were not thickened, that cerebral arteries were not stenotic (narrowed), the cells of arteries’ walls were not altered and that cerebral vessels were sealed. On the contrary, it was observed that all small vessels (capillaries) were affected and became rare in the white matter area. Moreover, it was revealed at a very early stage (before the onset of brain damage) abnormal contractility of the arteries. These results suggest that two initial abnormalities in CADASIL disease are first, a mal-functioning of the arteries which do not dilate well and second, an attack on all small vessels, leading to a reduction of cerebral perfusion (decrease of blood flow to the brain) in particular in the deep areas of the brain. On the contrary, it seems that the degeneration (destruction) of the arteries (which is not observed in this model) is a fairly late event in the disease.
This new model is however not perfect since these mice do not develop all symptoms of CADASIL disease, such as strokes. Thus, work remains in researching factors that cause these strokes. In contrary, these mice will be valuable to begin assessing treatment strategies, such as testing whether a decrease in blood pressure can delay the onset of brain damage. These mice will also be very useful to further study the mechanisms of the disease, in particular causes of dysfunction of arteries and reduction of capillaries. .
2) Identification of the proteins that make up the GOM (Granular Osmiophilic Material)
The GOM deposits are characteristic and specific of the CADASIL disease. These deposits are observed under electron microscopy on the surface of smooth muscle cells near the Notch3 protein, which also accumulates. The GOM were discovered over 15 years ago today, but we still do not know their composition. Laboratory study suggests that the GOM may contain proteins that cling in an abnormal fashion to the Notch3 protein when it is mutated and that sequestration of these proteins could play a causal role in the disease.
Our laboratory has undertaken efforts in characterization of these GOM by sophisticated techniques of biochemistry i.e. mass spectrometry, using arteries from Notch3 transgenic mice, which are dissected under microscope.
Promising results were obtained. An important track of study, representing the beginning of a lengthy research program, is to understand what happens when the Notch3 protein builds up, becomes a ”glue" which other proteins are stuck to.
It is also worth noting that mice are different from humans and therefore all knowledge of these animals will require further study and replication on humans.
Presentation by Professor Hugues CHABRIAT
Professor CHABRIAT introduced Mr. Alexia BOURGEOIS, psychologist, working part-time at CERVCO from the month of May, especially on attention and memory disorders.
Hospital Clinical Research Program (PHRC)
The follow-up study of patients over a period of three years with a budget of 400,000 Euros until 2007 was extended with funding of 290 000 Euros to continue the monitoring program.
The initial goal in 2003 was to monitor 200 patients for three years. In fact, the cap of 200 participants was reached in late 2007, and a program extension is necessary so that the last patients included in this study were followed for 3 years and to extend the monitoring of initial participants, over a total period of 54 months (4 years).
The goal is that 250 patients were monitored in 2010 with the same tests over a long period, using the same methods (MRI, tests of memory and concentration, biological samples, clinical follow-up) and with the same data analysis. Currently, there are 214 people that are part of this program.
MRI: a lot of results must be analyzed. 472 MRI examinations were performed by the Paris team (for each participant in the study: at first, then after 18, 36 and 54 months) and 226 by the German team in Munich. The MRI done in Paris were being worked in Lyon (via automatic means: measuring lesions, small infarcts and micro bleeding). A team from Lariboisière Hospital arrived there to complete the review of each MRI and validate the results. The analysis is complicated, time consuming and the results will be refined gradually. The objective is to better measure the progression, which will also help assessing the effectiveness of future treatment trials.
Cognitive Exams: memory, concentration, attention. Between two assessments, separated by 18 months, it was determined that the progression of results varies depending on the initial cognitive status at the beginning. The global cognitive score depends neither on age and sex, nor initial handicap. Evolution is usually slow and shows little difference between two assessments spaced at a year and a half apart.
Overall, in an 18 months’ period, there is little change at the clinical level. Hence it is important to extend the follow-up over a longer period. We found that the change of the  disability scale score  evolves over a period of 18 months if the patient develops already numerous cerebral lacunas (small cavities of nervous tissue which are the result of minor strokes) and extensive lesions in the white matter (Rankin score: 0 if no symptoms, 1 if small symptoms and no disability, 2 if small disability,3 if  moderate disability and needing a third party for certain acts, 4 if the person is not autonomous, needing help in everyday’ s activities, 5 if the person requires necessary support i.e. "nursing").
The disease does not progress in a linear fashion. Those with few symptoms progress with little change. Those whose situation worsens the most are those who already show serious signs of the disease.
It is necessary to better identify what changes at the MRI level, to better understand what happens in the brain when the lesions are developing. Initial results from the monitoring program show that we can measure quantitatively the evolution of lesions.
It is difficult to identify changes in the number of strokes, which depends on the evaluation criteria of the observers. So far, MRI images of participants were analyzed in each stage of study separately. It is in fact necessary that this work be performed in the presence of all data obtained at Month 0, Month 18, Month 36, etc. to determine the evolution of these lesions.
On average, all these results will help define useful criteria in assessing the impact of a future drug.
New Study
A new study will begin in the coming months. Indeed, even within the same family, the white matter lesions can vary considerably. Professor DICHGANS, from Munich, focuses on this variability feature between individuals. An initial study of 151 patients showed that age, blood pressure, and family affiliation have an impact on the extent of lesions. This has no connection with the severity of the disease. Several teams in Europe will work on this subject. All participants of the monitoring program will probably be asked to consent to this new study.
Use of genetic testing for Research
Patients with a blood DNA sample for genetic diagnosis of CADASIL will be contacted for an amendment to the consent form they signed. Indeed, these swabs for diagnostic purposes cannot be used for research, including whether other genetic factors are present to explain the variability of white spots (see above).
A letter will be sent to these patients asking them for consent so that their DNA can be used for studies of the disease.
Presentation by Dr. Eric JOUVENT: MRI study of very high resolution
MRI scans are usual done with devices whose power is 1.5 Tesla, which is 30,000 times the earth's magnetic field (unit of measure that characterizes the magnetic field, the strength of the magnet). The purpose of this study is to use the Neurospin Technology at Saclay near Paris where a new imager with a 7 Tesla power will increase the image of the brain surface with higher resolution, to better understand the effects of lesions on the morphology of the furrow cortex (which is modified when there are white spots), to have a finer view of the neuron cell bodies, and small vessels, to measure brain atrophy (natural phenomenon from 40 years of age, but it is more noticeable in patients who are the most affected, suffering the most strokes).
There are only 20 devices units of this capacity in the world and no clinical study has yet been made with this technology.
CADASIL is a micro-cerebrovascular disorder that represents a clinical model for studying the impact of subcortical tissue damage in general on the structure, morphology and function of the cerebral cortex. The results of the study will have an interest beyond Cadasil.
The use of magnetic resonance imaging at high field (7 Tesla) and very high resolution (about 100 microns) in this model of cognitive impairment of “pure” vascular origin may lead to better understanding of the mechanisms linking subcortical lesions caused by strokes and degenerative phenomena triggered by CADASIL. It should also allow better understanding of the changes occurring in the brain’s subcortical area in the course of cerebral microangiopathy and its clinical impact, especially at the cognitive level.
On the other hand, these data will provide precise information on the mechanisms involved in the dementia of vascular or mixed origin and better understanding the role of degenerative brain tissue occurring as a result of the accumulation of lesions of vascular origin.
This new imager will allow better viewing the small vessels that nourish the deeper areas of the brain that are rarely visible, to better characterize the nature of the cerebral cortex (surface) and to observe brain lesions outside the white spots. This more precise information will lead to better understanding of the disease.
Thirty patients and thirty volunteers who are not suffering from Cadasil (control subjects with similar ages and sexes as 30 patients) will undergo two visits, spaced every 18 months. The study will be launched in a few weeks, after obtaining the approval of the National Ethics Committee.
Patients who will be contacted with offer to participate in the study are those already in the Hospital Clinical Program which was discussed previously.
The examination will last approximately one hour, in a larger room than for normal MRI, with more security and monitoring. There is no injection of contrast medium. The magnetic field is stronger, it is noisier, but proper protection is being put in place. The examination usually takes place without any difficulty; some patients experience some temporary nausea. The team in charge of the project is looking for volunteers among patients and unaffected members who wish to participate in this study.
Questions and Answers
Question: Is it possible to improve information on Cadasil for physicians of all specialties?
Answer by Professors BOUSSER and CHABRIAT: Educating all physicians on rare diseases overall is difficult. With the implementation of reference means as the Orphanet website and referral centers such as CERVCO, it is now easier for professionals to obtain information if a CADASIL patient consults with them. We would wish however that major health organizations have a website which carries official information.
CERVCO puts in place a network of experts in all areas. They will have access to a protected area of ​​common information on the website of the reference center.
Question: Is it safe to assume that a person placed in an institution such as a retirement home, receives appropriate care and medications while the staff does not know the disease?
Beyond this, what relationships are possible and desirable between the institutions that receive patients and CERVCO ?
And: How do hospitals have a minimum of equipment (floor lifts, adapted beds, etc.)?
Answer by Professors BOUSSER and CHABRIAT: if necessary, please write to the Director of the institution to request for necessary support equipment and ask the medical team to contact CERVCO as well as regional experts while a reference network is being established.
Addition of Dr. HERVE (CERVCO) after the meeting: "The loss of autonomy that characterizes the progression of the disease in some patients with CADASIL is related to the occurrence of cerebral infarction. Most medical and paramedical staff in nursing homes have experience in treating patients with infarction or cerebral hemorrhage because it is a common disease among the elderly. CADASIL presents characteristics related in particular to the accumulation of these strokes and the progressive development of motor and intellectual functions disorders. Knowledge of these characteristics and main features of the disease may help to better care. One of the missions of our referral center (CERVCO) is to disseminate information regarding the characteristics of the disease and the care of patients with CADASIL. This information is available on the CERVCO website, and we must encourage all involved parties to consult it in the care of a CADASIL patient. "
Question: Is it a coincidence that in a family affected by CADASIL, there are many cases of neurological diseases, notably Lou Gehrig's disease?
Response from Dr. HERVE obtained after the general meeting: "There is no association (other than the one linked by chance) between CADASIL and Lou Gehrig's disease."
Question: A person being treated at Lariboisière told the story of her case that was difficult to diagnose. She had no known family ancestors with symptoms of CADASIL. It was eventually discovered a mutated gene in exon 24, confirming the diagnosis of CADASIL. How is this possible? What are the implications for transmission to children? Are there other cases of this type in France or in the world?
Answer of Dr. JOUTEL (after the general; meeting): "The patient reported that none of her parents had symptoms of CADASIL disease. This is not the most common situation, but is quite possible for several reasons:
1) A parent carrier of the mutation could die prematurely of another disease before symptoms of CADASIL appear.
2) We now know that symptoms of CADASIL disease can be extremely minor and may not develop until an advanced age (after age 80).
3) In addition, there exists in CADASIL disease what are called de novo mutations. It is referred to an individual with a mutation that has not been transmitted by one of his/her parents, but has appeared spontaneously.
In the case of CADASIL disease, mutations are usually detected in exons 3 and 4 of the Notch3 gene but in theory, they can present in any other exon between No. 2 and No. 24. To my knowledge, actually no mutation has been reported so far in exon 24, but there is no official catalog of all mutations detected in CADASIL disease. The risk to an offspring being a carrier of this mutation is the same as for other CADASIL mutations, i.e. 1 in 2 chances. It is of course a statistical risk. "
Question: May CADASIL be the cause or at least exacerbate heart problems, kidney and urinary tract, eye, ear and gastrointestinal origin?
Response from Dr. HERVE obtained after the general meeting: "CADASIL may be responsible for ENT (Ear-Nose-Throat) symptoms (Tinnitus and hearing loss). Comprehensive exams can be administered at Lariboisière for patients who complain of these symptoms. Functional urinary disorders (leakage or retention exposing risk of urinary tract infection) may occur in the later stages of the disease. Symptoms of cardiac, ophthalmologic or gastrointestinal origins are not directly related to CADASIL. Prolonged bed confinements in severe forms can of course decrease intestinal transit, but dedicated treatments are available and usually at least partially effective. "
Question: How many medical staff in the world are working on CADASIL and do you have any information on the International Research?
Response of Professors BOUSSER, CHABRIAT and Dr. JOUTEL: there are few laboratories in the world working on Cadasil. Two main reasons: the disease was discovered in France, the Americans have long considered that they were not concerned and that the profitability of such research was low with a high risk of a negative result. Currently:
• Two laboratories in Boston (United States) have an activity on Cadasil: generation of mouse model, research on the mechanism of migraine
• A laboratory in Sweden studying molecular aspect
• Another laboratory in Finland is researching Cadasil and has exchanges with the French Team
• The German team who work closely with France
 • Italy has a small activity. .
In France, the Alzheimer Plan 2008-2012 is a national priority. In fact, this plan is entitled "Alzheimer's and related diseases." It should also focus on vascular diseases such as Cadasil.

Creation date : 24/07/2009 @ 17:02
Last update : 21/03/2012 @ 09:51
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