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Etiology |
Tau:
 Tau is a protein that is coded on chromosome 17. It is present in all neurons and its function is to maintain the integrity and the function of the cell. In brain cells of FTD patients, pathologists are finding excessive deposits of tau, abnormal versions of tau, or a lack of tau. This is a very important discovery because we can now move forward in the development of a treatment for the tau.
Ubiquitin & TDP-43:
Ubiquitin is another protein that can accumulate in FTD and ALS Dementia. Ubiquitin surrounds TDP-43, which is another recently discovered protein that may be a cause of FTD. |
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For the majority of patients with FTD, genetics is not an immediate concern. Approximately 60% of FTD cases are “sporadic,” which means that the disease is not inherited. In a sporadic case, there are no other family members with FTD or a similar condition, and relatives do not have an increased risk of developing the disease.
About 10% of FTD is considered hereditary and is inherited in an autosomal dominant fashion. Genes come in pairs. In an autosomal dominant condition, only one gene in a pair needs to have a change (mutation) for the disease to occur. Autosomal dominant conditions affect men and women equally, and each child of a parent with an autosomal dominant condition has a 50% chance of inheriting the mutation. The majority of this 10% can be attributed to inherited mutations in one of two genes: Progranulin or MAPT (commonly referred to as “tau.”) In these families, there are typically several other affected relatives in at least 2 generations.
The remaining 30% of FTD is often referred to as familial. Familial means that there is at least one other relative who has been affected by either FTD or another neurodegenerative disease, but the family history is not strong enough to be classified as hereditary. At this time, it is unknown if these familial cases are possibly due to shared genetic factors, shared environmental factors, or even a combination of both genes and environment.
It is often difficult to clearly define a family history as being sporadic, familial, or hereditary. Patients and their families are encouraged to speak with a genetic counselor to discuss the most current information available regarding the genetics of FTD. |
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Signs and Symptoms of FTD
FTD typically presents with one of two clinical syndromes. The syndromes consist of features that include primary progressive aphasia or a disorder of social comportment.
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Disorder of Personality and Social Comportment: |
Typically, there is personality change. These patients can seem insensitive and many times display socially inappropriate behaviors. Examples include inappropriate conversation, talking with strangers, overeating, hypersexual behavior, neglect of physical appearance, disinhibition, apathy, and lack of empathy.
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This form of difficulty may be present along with a progressive aphasia and/or a social disorder. We use the term “dysexecutive” to describe difficulty with executive function. This is important for planning and organizing, task switching, and maintaining attention. Problems with executive function can be manifested as repeating gestures (echopraxia) or phrases (echolalia), inability to perform complex tasks that involve multiple steps, and selective attention.
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Primary Progressive Aphasia: |
Aphasia is a disorder of speech and language that occurs when atrophy or damage occurs in the parts of the brain responsible for language. Depending on the portion of the brain that is compromised, components of language can be selectively impaired. One form of aphasia is called Progressive Fluent Aphasia. This is also called Semantic Dementia. This is characterized by difficulty in comprehension of single words and the use of words to name objects. There may also be difficulty understanding the objects themselves. Another form of language difficulty commonly seen in FTD is Progressive Nonfluent Aphasia (PNFA). This is characterized by a progressive loss of speech. This usually begins with slow, effortful speech. Comprehension of single words is preserved.
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Related Conditions
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Corticobasal Degeneration: |
Corticobasal degeneration (CBD) is another disease of abnormal tau. It typically affects the parietal lobe and frontal lobe. CBD usually presents as a movement disorder. Features associated with this disorder include impaired gestures, deficit with implement use, rigidity, visual-spatial difficulty, and difficulty with simple calculations. |
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Progressive Supranuclear Palsy: |
Progressive Supranuclear Palsy (PSP) is another neurodegenerative disease that causes slowing of movement, loss of balance, and difficulty with speaking and swallowing. The hallmark of this condition is the weakness of the eye movement, beginning with an impaired downward gaze. Areas of the brain the are affected by PSP include the basal ganglia, the substantia nigra, the subthalamus, and the brainstem. Tau accumulation is also evident in this condition.
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Amyotrophic Lateral Sclerosis, commonly referred to as ALS or Lou Gehrig's Disease is a Motor Neuron Disease (MND). As MNDs progress, patients' motor neurons degenerate, and lose their ability to control muscles. Recently, the focus of some ALS research has shifted to understand the cognitive difficulties of patients with MND. In about 10% of patients, MND is accompanied by FTD. The fact that ubiquitinated TDP-43 is the common biochemical link for both FTD and MND helps to explain this connection. Greater recognition of the cognitive difficulties of people with MND will increase our understanding of the condition.
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Diagnosis
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 It is important to rule out other disorders that may mimic FTD. Your doctor may order blood studies to look at B12 levels, thyroid functioning and other age related disorders of metabolism. Some kinds of neurological infections should also be ruled out by looking at the cerebrospinal fluid. This is obtained through a lumbar puncture.
A structural image of the brain is also necessary to rule out several conditions that mimic FTD. For example, small strokes that may accumulate over time can mimic FTD, and this may only be detected on a MRI. A positron emission tomography (PET) can also useful if the MRI is within normal limits or the atrophy, brain shrinkage is too subtle.
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Treatment
Currently there is no curative treatment available for FTD. The current goal of therapies in treatment of FTD are symptomatic relief. While the medicines listed below may be useful in some individuals, other individuals may worsen with a medication, or may have an adverse effect if the medication is administered at an inappropriate dosage. The utility of any medication for an individual patient should be reviewed with your physician. All medications have side effects that should be discussed with the prescribing physician and allergic responses can occur with these medications. These medications represent only a sampling of available medication regimens, and the inclusion of a medication on this list does not represent an endorsement of its use.
Antidepressants:
There are many medications on the market used to treat depression. Depression, anxiety and obsessive behavior are common in FTD. We treat these symptoms with a specific class of antidepressants called Selective Serotonin Reuptake Inhibitors (SSRI). These drugs work to increase the amount of serotonin in the brain. Low levels of serotonin contribute to anxiety and depression. Trazadone is one of the few medications shown to be beneficial in a small, double blinded, placebo controlled trial in FTD.
Neuroleptics:
Antipsychotics are very effective in treating symptoms of FTD. Agitation and psychosis are symptoms most often treated with neuroleptic drugs. New antipsychotic drugs, such as quetiapine (Seroquel) and olanzapine (Zyprexa) are usually well tolerated. Some older antipsychotic agents can have significant side effects for motor functioning, and these may not disappear after use of the medication is stopped.
Antiseizure:
Antiseizure medication or “mood stabilizers” may also be used alone or in conjunction with an antipsychotic medication to decrease agitation. Carbamazepine (Tegretol), divalproex sodium (Depakote) and Gabapentin (Neurontin) may be helpful in managing some of the extreme behavior symptoms when neuroleptic medication alone is not effective.
Medroxyprogestrone:
Sexual disinhibition can be a symptom that is particularly distressing. Medroxyprogestrone is a derivative of the hormone progesterone. It can be useful for calming sexual urges that may be seen in those with FTD.
Dopaminergic Agents:
Some reports describe improved speech fluency with the use of medications that supplement the dopamine brain chemical system. These medications are borrowed from Parkinson’s disease.
Cholinesterase Inhibitors:
These drugs have been approved by the FDA to treat mild to moderate Alzheimer’s Disease. The drugs in this class include donepezil (Aricept), approved in 1996; rivastigmine (Exelon), approved in 2000; and galantamine (approved in 2001 under the trade name Reminyl and renamed Razadyne in 2005).
Cholinesterase Inhibitors are designed to increase the level of acetylcholine in the brain. Acetylcholine is a chemical that helps to carry messages to other brain cells. It is important for memory, judgment, and thought. This class of medications may help with naming in primary progressive aphasia, but can worsen the social disorder of patients with FTD.
Other:
Namenda is approved for the use with vascular forms dementia and moderate to severe Alzheimer’s disease. Clinical reports suggest that this medication may be helpful in some FTD patients as well. |
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