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National Institute on Aging
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| Genetic Characterization of Dementia |
| This study is currently recruiting. |
| Dementia can be both familial and sporadic (no family history). Three genes have been described for Alzheimer's disease: APP amyloid precursor protein), PS-1, PS-2 presenilin one and two). These gene variants account for 5% of all AD cases and 50% of early onset AD cases. One clearly defined risk factor has been identified for late onset AD, this is termed APOE, apolipoprotein E), on chromosome 19. Several other risk factors for late onset AD are under investigation. |
| For More Information and to be Screened for Eligibility |
| PLEASE CALL: 301-451-6093 |
| Frequently asked questions about our work. |
Focus on Parkinson's Disease: |
| What does studying the genetics of Movement Disorders/Dementia involve? |
| To do the work of solving the genetic causes of movement disorders and dementia, we systematically collect familial, clinical and genetic (blood sample) information on people with a movement disorder or dementia and their relatives. We collect both individuals with a family history and without a family history. |
| Contact with a family often begins in the clinic, by letter or on the telephone. We interview people about their family members; valuable information includes name, date of birth (and death, if deceased), any diagnosis (for example, of Parkinson's disease, dementia, tremor, including essential tremor, and other disorders), and the age of disease onset. We then ask that person to let other family members know we are interested in their family, and if they are willing, ask them to get in touch with us. |
| In our quest to learn why one person in a family might fall ill while others are spared, we also need to interview and examine spouses, children, brothers, sisters, parents, and cousins. |
| What happens to samples once they reach the lab? |
| We purify the DNA, which is in the cells in the blood. This DNA is then screened for known causes of specific movement disorders or dementia. If none are found, then we can perform linkage analysis on large families to learn which gene is causing the disease. The approach used in our laboratory is known as positional cloning. Association studies are also useful, this is where we compare a series of people with a disease (cases) to those without disease (controls) to see if we can find differences between the two groups. |
| How do families participate in our research? |
| Once an individual agrees to participate, the project is explained and we ask for informed consent (permission from the person, or if they have trouble thinking, from a spouse or child). Family history and other medical information is obtained by talking to the person or asking for copies of his/her medical records. If appropriate, a blood sample will be drawn and sent to the Laboratory of Neurogenetics, NIA. Additionally, interested participants may choose to visit the National Institutes of Health for a visit with a movement disorder specialist (this is at no cost to the participant). |
| All information gathered is for research purposes only and will remain completely confidential. There is no profit or financial gain to the researchers from this work, it will simply help us learn more about the causes of movement disorders. |
| Note that unaffected individuals, including adult children and spouses, also need to take part. In fact, collection of a blood sample from spouses is essential if genetic studies are to be successful. We look at how closely family members are related (family genealogy) and whether individuals have inherited a common genetic region. So we need to know the contribution from both sides of the family. We search the entire human genome and calculate the likelihood that regions are "linked" and thus contain the genetic cause of the disease. |
| Why do we do research? |
| By studying the genealogy of familial Movement Disorders or dementia, we can trace the genes responsible. This approach has proven successful for a number of neurological disorders including Alzheimer's disease, Huntington's chorea and now Parkinson's disease. Of course, research in genetics is a dynamic, ever changing process. |
| In addition, we have an "old-fashioned" approach despite the technical sophistication we have at our disposal. One key to research is to keep an open mind. Many breakthroughs in science are due to serendipity. So we are interested in the input of others. What we learn from our study participants (patients and their families) may lead us in new directions. We interview family members, examine affected individuals, draw blood from those individuals, review medical records, and then study the blood, in the laboratory, to find out if there is a difference in the DNA of people with a disorder when compared to the DNA of those who do not have the disease. From a conceptual standpoint, we are concerned about what causes neurodegeneration, that is, the death of the cells of the brain and nervous system that leads to illness. We don't know the causes of these illnesses yet, although we hope that the tools of genetics will add important pieces to the puzzle we are trying to solve. |
| We hope our work makes or will make an important difference in people's lives. We want to find out what the genetic causes of several neurological diseases are. Some of this work has already been done by us and by others, but there is still a great deal to learn. |
| FOCUS ON PARKINSON'S DISEASE SECTION |
| What is DNA and what does Genetics have to do with Parkinson's Disease (PD)? |
| Deoxyribonucleic acid (DNA) encodes the biological blueprint of life in all its diversity. The chemical is composed of four types of nucleotides or bases, A, C, G and T...e.g. GGCGAAACTATCACT. The sequence encodes thousands of proteins that make up the cells, tissues, and organs of every living organism. |
| Less than a decade ago, it was believed that many movement disorders, including Parkinson's disease could not be genetic. Since that time, many have genetic locations (loci) have been found to be associated with various movement disorders. |
| Lewy Bodies and PD, how does our research play a role? |
| Lewy bodies are microscopic deposits, or lesions, of abnormally aggregated proteins found within nerve cells. In most cases of Parkinson's disease, Lewy bodies can be found in the brainstem, including the substantia nigra. More recent studies have suggested that a few Lewy bodies can also be deposited in other brain regions, including the cortex. And finally, a few Lewy bodies may also be found in the brains of elderly people without disease. |
| Our knowledge of what Lewy bodies are, how they form and why they are associated with Parkinson's disease is sparse. Insight can be gained by looking at other diseases with these deposits. In diffuse Lewy body disease (DLBD), a condition far more rare than Parkinson's disease, Lewy bodies are far more numerous and widespread. Memory loss may be a problem. It is currently debated whether DLBD could represent an extremely severe form of Parkinson's disease. |
| In the brain stem, at very high magnification, Lewy bodies appear to have a dense, granular center surrounded by concentric rings of radiating neurofilament protein. Other constituents include ubiquitin and ubiquitin C-terminal hydrolase. However, most recently, by genetic studies on a family from Italy (the Contursi kindred), a new component, alpha-synuclein, was discovered. A mutation in the alpha-synuclein gene leads to early-onset Lewy body parkinsonism in this family. However, in ordinary Parkinson's disease, alpha-synuclein is also present in dramatic amounts in Lewy bodies. We hope that more genetic studies, with the help of other families with Parkinson's disease, will allow us to identify more components. Finding the other pieces in the puzzle will allow us to discover what Lewy bodies are made of and why they form. This knowledge will enable us to make breakthroughs in future treatments for Parkinson's disease. |
| Much is published about Dopamine and Parkinson's disease. Why aren't you studying Dopamine instead of Genetics? |
| Dopamine is the neurotransmitter lost in Parkinson's disease. The main pharmacological (medication) therapies to treat the disorder are based on dopamine replacement, either directly (through levodopa, in the form of SinemetTM) or indirectly by medications which resemble dopamine (dopamine agonists). Dopamine does not pass into the brain from the stomach (does not cross the blood-brain barrier) and is quickly degraded in the blood stream. However, levodopa, a related brain chemical, can cross into the brain from the bloodstream. The brain is able to make dopamine from levodopa. Another way that the level of dopamine can be maintained in the nervous system is to try and prevent its natural breakdown in the body. Major enzymes which metabolize and degrade dopamine are monoamine oxidase (MAO, types A and B) and c-o-methyl transferase (COMT). Medications which inhibit these reactions are selegeline (EldeprylTM) which inhibits MAO-B and tolcapone (TasmarTM) which inhibits COMT. Although all these medications are helpful in treating some of the symptoms of Parkinson's disease, they do not address the cause, the loss of dopaminergic neurons. Why this occurs remains unknown. |
| Why isn't replacing the lost brain dopamine a cure for Parkinson's disease? |
| The answer to this is complicated. However, essentially, other areas in the brain and other neurotransmitters are affected. Abnormal, microscopic, neurofilament-filled deposits, called Lewy bodies may be found in the affected neurons. In Parkinson's disease, Lewy bodies are found in the surviving cells of the substantia nigra, but also, in other brain structures especially later in the illness. Lewy bodies are the hallmark of a group of related disorders with parkinsonism, termed diffuse Lewy body disease (DLBD) where these deposits are more widespread throughout the brain. |
| Giving dopamine replacement is a good strategy, but it does not prevent the underlying cause of the Parkinson's or DLBD. We want to find out more about Lewy bodies, what they are, how and why are they formed and what we can do to prevent their formation? One of the best ways to do this is to study familial Lewy body diseases, including, familial Parkinson's disease, a very important subset of Lewy body disease. |
| Are most cases of PD genetic? If not, then why is studying the genetics of PD important? |
| Most cases of PD are not genetic, although genetic risk may play a role. The families we study, in which there is a large genetic component, are rare. However, studying them is very important. By isolating the gene responsible for PD in those families, we can learn about the biology of the disease in other families and in sporadic cases of PD ("idiopathic PD"). Once a gene is identified, its function can be studied. This is done on the level of biochemistry, in cells grown in culture in the lab, and by using the DNA sequence information. Also, we develop mice which carry the "PD causing" mutation. We study the behavior, movement, and the brains of these mice to see what is abnormal in them. We can also develop treatments using these mice, which could later be used in humans. A similar strategy is currently well under way in the area of Alzheimer's disease, and has been leading to some major breakthroughs using genes discovered in our laboratories. |
| Principal Investigator: John Hardy, Ph.D. NIA Study #: 2003-077 |  |
| NIA - ASTRA Unit Advanced Studies in Translational Research on Aging |
| Laboratory of Neurogenetics Porter Neuroscience Research Center Bldg. 35, Room 1A1000 Bethesda, MD 20892 |
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