Among the many members from the medical team who attended "Cadasil France Remembrance Day":

·                   Professor Marie-Germaine Bousser, Scientific Board President of Cadasil France

·                   Professor Tournier-Lasserve

·                   Professor Chabriat, Head of Neurology Department, Northern Hospital Group (Lariboisière and Fernand Widal Hospitals) and CERVCO coordinator

·                   Doctor Jouvent, Head of High Definition MRI Research Project

·                   Doctor Anne Joutel, Director of Research at INSERM in charge of CADASIL Project

·                   Mrs. Annie Kurtz, psychologist of Neurology Department at Lariboisière Hospital  and Administrative Board member of Cadasil France

·                   Doctor Hervé, neurologist in charge at CERVCO

·                   Mrs. Reyes, Dubois and Jabouley, psychologists

·                   Mrs. Jocelyne Ruffié, Professor Bousser’s  Assistant

·                   Mrs. Leder-Morel, part-time social worker at CERVCO

·                   Mrs. Hello, Secretary of CERVCO

·                   The Chinese neurologist in a one-year mission at Lariboisière Hospital’s Neurology Department.

 

Before the questions/answers session, the following five topics were discussed:

1.         Genetic Research

2.         Hospital Clinical Research Program

3.         Grant of Cadasil France to CERVCO

4.         Study of MRI in High Definition

5.         Request for genetic testing by "asymptomatic concerned subjects"

 

 

 

Since the identification of Notch3 gene in 1996, knowledge gain has advanced in stages. Yet in 2009, progress has been made in understanding the disease’s mechanisms. Last year, a new transgenic mouse model was presented. It was obtained thanks to close collaboration with a laboratory in Berlin. This model emphasized the mutated Notch3 protein.

 

These mice developed arterial lesions characteristic of the disease: abnormal accumulation of the Notch3 protein and GOM (Granular Osmiophilic Material, balls visible under electronic microscope) as well as lesions of the white cerebral matter. It was the first mouse model with brain lesions obtained in the world.

Throughout 2009, study of this new mouse model has been pursued to better understand the mechanism that triggered appearance of brain lesions. In particular, the structure of vessels was analyzed in brain sections from these mice using techniques of histology and immunohistochemistry. Under microscope, segments of cerebral arteries were dissected to study directly their contractile properties via arteriography. This research allowed quantifying among these mice the cerebral blood flow in different parts of the brain, at different ages. Moreover, analysis was performed in these mice concerning their ability to adapt properly blood flow in the brain either when the arterial pressure dropped or when the mice were stimulated.

 

Two main conclusions we can derive from these analyses are that white matter lesions which result likely from a perfusion defect of the brain are caused by a combination of two types of anomaly:  on the one hand, altered contractility and resistance of the arteries and on the other hand, progressive disappearance of tiny vessels in the white matter area.

 

But these mice do not develop strokes and exhibit white matter lesions only until an advanced age (18-20 months). Therefore, we must "improve" this model so that the mutant mice would develop lesions much sooner, in greater numbers, so that they present a complete picture of the disease before treatment testing strategies may be assessed. Several avenues of study are being explored.

 

At this moment, we must understand what leads to the dysfunction of vessels and their scarcity. Over the years, results indicated that it is unlikely that a malfunction of the Notch3 protein is responsible for these alterations. The track currently being pursued is that the Notch3 mutated protein while building up, triggers the accumulation of other proteins which disrupts their operation.

 

Work has been conducted on brain tissues of deceased patients and arteries of mice with mutated Notch3 protein to identify proteins that accumulate in the vessels. Using sophisticated technology such as mass spectrometry, several proteins that accumulated in the vessels were identified. The work focuses specifically on one of these proteins that we will call “X”, which has been shown that it interacts with the Notch3 protein. The involvement of this protein X in the mechanism of CADASIL lesions is being actually explored using other mice which no longer carry this protein X. These mice were obtained from our collaboration partners in Germany.

 

Meanwhile, work is being performed on the normal function of Notch3. It shows that this gene has a fundamental role in the operation of small arteries. Two other genes have been identified as having an important role in this function. It is important to note that basic fundamental research on Cadasil is also very crucial for other diseases of small arteries. The current tracks are very serious, but much more time is yet to be required.

 

 

 

The team of Professor Chabriat in the past year has the backing support of a Chinese neurologist, whose mission will be concluded soon. A Hungarian doctor will soon join his team to work on imaging.

 

The follow-up study of patients started in 2003 with the aim of following 200 patients for a period of three years. In fact, the cap of 200 participants was reached in late 2007. Therefore, a program extension was required so that the last patients included in this study were followed for three years and to extend monitoring of initial participants, over a total period of 54 months (4 years and 1/2). The objective has been adapted so that 250 patients were followed 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.

 

We thank for their participation in this program: patients and their families; numerous doctors, neurologists, psychologists, nurses, and of course the organizers, Jocelyne Ruffié and Solange Hello who played a central role.

 

Analysis of these results is now possible. It is performed by the Neuro-Epidemiology Department at Pitié-Salpêtrière Hospital. The same study was conducted in Germany, with data assessments being released every 18 months (overall assessment and of memory, MRI, etc.) covering a total of 313 participants, French and German, among which 54.9% are women. Preliminary results were presented by Professor Chabriat. However, they require further study before being published in a few months. They will then be circulated to members of Cadasil France.

 

Conclusions of this study will allow evaluating the number of participants who are needed to implement a drug test, to define criteria to measure its effectiveness, and assess the cost. It is worth noting that a drug test does not necessarily have a dramatic effect on the first trial. It requires numerous participants and a significant time period to show proof of its effectiveness. If a molecule is tested on 100 people for a year, it may have perhaps no effect, while the same study could give good results over a period of five years.

 

Moreover, Cadasil is considered to be a rare disease, for which it is difficult to finance a treatment protocol, but it could be a model for other diseases. There may be different tracks : neuro-protective drugs or medication for regulating blood pressure, having a moderating effect on the "flexibility", contractility of vessels, etc.

 

But initially, it is essential to have an animal model which develops the disease as closely to reality as possible in order to assess different kind of treatment.

 

 

 

Dr. Hervé indicates that the PHRC Program has shown that gradual walking and balance disorder is a significant symptom of the disease progression. So far, we only observed the presence of these disorders in individuals, without either quantifying them or measuring their progression. As a result, Dr. Hervé has submitted a request to the association for financial assistance to purchase a device with photoelectric cells to measure walking speed. This grant of €2000, approved by Cadasil France, will enable the implementation of this study.

 

An Italian student is currently responsible for assessing maximum walking speed and balance tests of patients monitored by CERVCO.

 

 

4. CADA7 Study of MRI in very high resolution by Doctor Eric Jouvent

 

Conventional MRI scans are usually conducted with devices whose power is 1.5 Tesla, which is about 30,000 times the earth's magnetic field. The aim of the study called CADA7 is to use technology of NeuroSpin [1], which has a new imaging device whose power is 7 Tesla. This device allows observing small arteries which are not visible in conventional imaging and lesions outside the white spots. This more accurate information will improve our knowledge of the disease.

 

Moreover, results of the CADA7 study will have interest beyond Cadasil since there are only 30 devices of this capacity in the world, four located in Europe, and no clinical study has yet been conducted in France with this technology. The use of magnetic resonance imaging at high magnetic field (7 Tesla) and very high resolution (about 100 microns) in this model of cognitive impairments of “pure” vascular origin could lead to better understanding of mechanisms linking sub-cortical lesions caused by strokes and degenerative effects they trigger in Cadasil, particularly at the cognitive level.

 

30 patients and 30 volunteers who are not suffering from Cadasil (control subjects with similar age and sex as the 30 Cadasil patients) will undergo two visits, spaced every 18 months. The test lasts about an hour and 15 minutes and takes place after a normal MRI exam, in a larger room, surrounded by more security and surveillance. There is no injection of contrast agent. The magnetic field is stronger, there is more noise, but proper protection is used. The "tunnel" being narrower, the exam may be more impressive than for a "classic" MRI, however it usually takes place without any difficulty for participants.

 

This study began in September 2009, was delayed due to technical difficulties, thus only seven people have had this exam up to now. After various technical adjustments and modifications in planned image sequences, the study has just resumed. The NeuroSpin team is strongly committed to conduct this innovative study.

 

 

Between 2003 and 2009, multidisciplinary consultations of people who were expected to undergo Cadasil genetic testing encompass 31 at-risk individuals. These so called "asymptomatic concerned subjects" need some guidance during their procedures. Recommendations in the past had been developed by the World Neurology Foundation, with representatives from patients’ associations, for predictive testing for Huntington's disease. They were used to establish strict guidelines to assist people in their journey.

 

In effect, it is important to understand and analyze their expectations and motivations. What is the expected benefit of a predictive test? Why one would want to know if he/she has the mutated Cadasil gene while there is effectively no cure? These people without symptoms must make their decision independently, without influence of a relative or a doctor. Thus the person must make an enlightened decision. To this effect, the person must be fully informed in advance in order to choose whether to undergo genetic testing.

 

In addition, confidentiality must be respected. Communication of results must be made by the doctor who prescribed the test, under conditions that respect the individual, if possible in the company of a designated relative. Besides, the person also has the right not to know and to retract at any time. Thus, 61% of applicants did not go through with the test. As the benefits of the test may be up to each individual, it is necessary to take the time to analyze the motivations of each person.

 

It is for these reasons that the protocol takes place in stages and requires a minimum of three consultations. The approach is as follows:

 

1.      A multidisciplinary consultation takes place with a neurologist, a geneticist and a psychologist.

 

2.       After a cooling-off period of reflection of about two months, a personal appointment is made to collect the first sample, if the person still wants to pursue it. A few days later, a second sample, which can be obtained in the local province, is made to avoid errors.

 

3.      If the person maintains his/her desire to know the result, a consultation is scheduled with a neurologist and a psychologist for the announcement of result after about two months. The presence of a relative is recommended during this meeting and a psychological follow-up is thus suggested.

 

Indeed, if the result is positive, the person will have to live with a "sword of Damocles." A whole range of symptoms may appear: one can interpret a headache, forgetfulness, tingling ... as a sign of disease ; anxiety for future disorders to come, without knowing where or when they may arise.

 

But if the person is not a mutated Notch3 Cadasil gene carrier, that person may experience feelings of guilt and must readjust his/her perspective of the future as he/she may already expect with the illness.

 

The motivations of a person with no symptoms but wishes to undergo genetic testing are varied. But regardless of whatever they are, it is always important to know the future to take control of the anxiety. Based on answers to different questions, psychologists have derived the following statistics:

·        Cognitive motivations for 52% of participants : need to know, to remove doubt about genetic status, to obtain information about the disease affecting a family member, while the topic is sometimes a taboo in the family. Not knowing is stressful. But knowing that one is carrier of the mutated gene does not answer all the questions because, within the same family, symptoms are very variable.

 

·        Altruistic motivations for 39% of participants: need to inform one’s descendants, need to think about own wish to have children (96% of consulted women are of childbearing age), risk of transmission of the disease, family solidarity, to participate in medical research.

 

·        Behavioral motivations for 32% or participants: need for action to prepare for outcomes either at professional or personal level,  need to anticipate the future, to take precautions, to avoid certain treatments that would not be advised, to adopt a healthier lifestyle ...

 

1.      Concerning the sex of applicants:

·        19% male, average age of 38 years (between 31 and 60).

·        81% female, average age of 35 years (between 22 and 47 years).

 

2. Concerning the elapsed time during which people know they are "at risk" before undergoing the procedure of genetic research : most frequently, the applicants know about the presence of the disease in the family for about two years. In the extreme case, the elapsed time ranges from 3 months to 19 years.

 

3. Concerning the dropouts along the process:

·        61% of applicants for genetic testing give up after the first consultation.

·        39% did the sample, but only 32% of them proceed all the way to the end.

 

4.   Concerning the test results: among those sampled, 50% do not have the mutation and 50% are carriers.

 

5.   Concerning the anxious interpretations: among those with a complaint about one of the symptoms (headaches, neurological disorders, cognitive disorders), 60% went to the end of the process, but only 16% actually had the mutation of Cadasil.

 

 

 

 

Scientifically, objectively, Cadasil is a genetic autosomal dominant disease. So if a parent has the disease, the risk for their child is 50% ; it is the same for men and women. There is great variability in the manifestation of the disease within the same family.

 

However, those people at risk may be biased. Some believe that the physical or psychological likeness with a sick parent is proof that they are affected. Others believe that the disease can "skip a generation" or affect only women. These beliefs, of course, are wrong.

 

The interpretation varies depending on whether one is a health professional or a requestor of genetic testing.

 

 

 

 

Question 1: "I notice that I did not receive any communications, no contact with the Cadasil delegated team in Picardy." And "Can you explain how the link works between CERVCO and neurologists in the region. How do follow-ups take place? "

 

Answer:  Cadasil France has 140 members, 11 of which make up the Administrative Council. It is not possible to have delegates of the association in each province. But to maintain regional contact, the Alliance for Rare Diseases has representatives in the provinces. For medical monitoring, centralization in Paris is necessary for research and follow-up coordination.  CERVCO is actually establishing a network of neurologists-correspondents in several cities. Their contact information is listed on the CERVCO website. A file of treatment has been established to define their cooperation with the Paris Center. Prof. Tournier-Lasserve stated that multidisciplinary consultations for diagnostic genetic are available in the regions.

 

Question 2: "The MRI study is it always in place and should it continue in the future? The new generation MRI program is still in effect?”  And "MRI should it be conducted with or without contrast agent?"

 

Answer: Dr. Jouvent discussed today the progress of CADA7 Project in which there is no injection of contrast medium. The injection of contrast agent during a MRI classic exam is common. It is used to determine whether cerebral infarcts occurred recently.

 

Question 3: "What should I have to do to give my brain when I die to help research?"

 

Answer: The brain donation can be very useful in clarifying the causes and mechanisms of brain diseases. To inquire about this, you can contact the National Bank of the brain (GIE Neuro-CEB) located in Paris at Pitié-Salpêtrière Hospital. Contact information will be published on the CERVCO website.

You should know that it is not possible to donate both brain and body to Science when one dies.

 

Question 4: "Why would skin biopsies no longer be done to detect Cadasil?"

 

Answer: The genetic test is highly reliable, thus it does not justify to perform skin biopsies, which are more complex.

 

Question 5: "Traveling on airplanes is it the cause of neurological disorders?"

 

Answer: On airplane or in high altitude, the sensations may be more aggravated. These disorders do not affect the disease in any worse manner.

 

Question 6: "Prenatal diagnosis is performed from an amniotic fluid or placenta sample with the risk of causing a miscarriage. A new method would be available from a simple blood test from the 11th week. The mother's blood actually contains fetal cells that could now be isolated. "

 

Answer: Prenatal diagnosis is subject to ethical rules. It is administered in a prenatal diagnosis center approved by the Ministry of Health.  One member of the couple must have diagnosis of mutated gene carrier; prospective parents must accept consultations at multidisciplinary center preferably as soon as pregnancy is contemplated. Subsequently, when pregnancy is in progress, a sampling of placenta is performed (in the tenth week). This medical procedure can cause miscarriage. If the embryo is carrying the mutated gene, an abortion is proposed. The risks of sampling procedures and the decision after an unfavorable result are very difficult steps for a couple.

 

The new test method from blood sample of the pregnant mother is currently performed only to determine the baby's Rh-blood. It is actually being evaluated for cystic fibrosis. It should be possible for Cadasil in the future.

 

Unlike prenatal testing, in-vitro fertilization does not require that one of the parents is certain to carry the mutated Cadasil gene. In this case, one of the grandparents is a Cadasil carrier and therefore one of the parents has a 50% probability of having himself the mutated gene. There are three centers in France that the couple may apply. The process takes on average two years. Fertilization is done in test tubes and only embryos not having the mutation are implanted. On average, 55 pregnancies have taken place within this framework in France, for all diseases.

 

Question 7: "Does the small capillaries located in other organs besides brain can malfunction due to Cadasil? In this case, has it been studied and could their deterioration have impact on these organs? "

 

Answer: The disease does not affect other organs besides the brain.

 

Question 8: "When a person has problems with vision or hearing, is the brain area the only zone being affected? Optic or auditory nerves can they be affected too? "

 

Answer: There may be alterations of the retina, but Cadasil cannot be the cause of visual impairment. At the hearing level, it may affect small vessels of the cochlea (inner ear). If hearing problems appear, one must implement a corrective device as soon as possible.

 

Question 9: "Legally, what are the responses to a medical questionnaire?"

 

Answer: Mrs. Leder-Morel, social worker assistant at CERVCO recommends that these questionnaires be completed with care in the case of loans or insurance (illness or disability or death). Omitted or false information may result in a denial of treatment care by insurance. But patients' rights are also subject to protection by law, including bio-ethics; test results of genetic testing cannot be required. It is recommended to seek advice from Mrs. Leder-Morel or another social worker.

 

Question 10: "What attitude should one have for hygiene in daily lifestyle? How to manage stress caused by the result of diagnosis? "

 

Answer: A healthy lifestyle is recommended, avoid cigarettes and alcohol. Multidisciplinary monitoring under CERVCO can lead to a follow-up with a psychologist. A patient-card is under development which will contain recommendations and information in the case of an emergency.

 

Question 11: "What can one do when the Social Security’s advising physician refuses to take into account Cadasil disease to allow for 100% appropriate care?"

 

Answer: The diagnosis of a genetic disease does not lead automatically to support 100% care.  When disorders require expensive care and/or extended treatment, the primary physician makes a request for protocol of treatment. He/she may appeal to CERVCO to complete the file and inform on the course of necessary care.

 

 

 

 

 

[1] NeuroSpin is a major research infrastructure which was inaugurated in November 2006. Its mission is to implement research programs to understand how the human brain functions.  It is located in Saclay, south of Paris inside the Atomic Energy Commission (CEA- Commissariat à l’Energie Atomique).