This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Frontotemporal dementia (FTD) is a progressive neurodegenerative disorder with prominent behavioral disturbances and personality changes, as well as early development of language disorder in some patients. Age of onset is typically in the 6th or 7th decade and the duration of the illness is approximately 10 years until death. One third of cases are familial with an autosomal dominant pattern of inheritance, while the other 2/3 of cases are sporadic. Risk factors for FTD are not known at this time. The most disabling symptoms of FTD are often behavioral. Behavioral abnormalities include disinhibited social behaviors such as touching, making rude or sexually explicit comments, and engaging in stereotyped and perseverative speech and behavior. Behavior can be impulsive, and at times aggressive. Hyperorality, with overeating and subsequent obesity, increased alcohol or cigarette use, and inappropriate placement of objects in the mouth occurs frequently. Patients lose the ability to adhere to social norms; many have problems with breaking the law. Attention to hygiene and grooming is typically diminished, and patients are often severely apathetic. There is an almost uniform lack of insight on the part of the patient as to the presence of these disabilities. Behavioral disturbances exact a heavy toll on families and caregivers, and limit the patient's participation in family and community activities, thereby diminishing quality-of-life. Current treatment for FTD is symptomatic and supportive (of the family and caregivers). There is one clinical trial and one case-series demonstrating that selective serotonin re-uptake inhibitors (SSRI's) are effective in some patients with FTD and behavior disturbance. Amantadine is a dopamine-augmenting agent, with a mechanism of both increasing dopamine release at the synaptic cleft and inhibiting its re-uptake. Amantadine's clinical uses are numerous, including treatment of influenza in the elderly, as well as in Parkinson disease. Recently, there has been interest in applying amantadine to the treatment of behavioral disturbances in a variety of brain diseases including traumatic brain injury and FTD. A recent retrospective inpatient review conducted by our group found that amantadine treatment of patients with dementia (FTD and AD) and behavioral disturbance was effective in about 2/3 of patients receiving the drug. We are proposing a randomized, prospective, double-blind, placebo-controlled, 6-week study of amantadine to test the hypothesis that amantadine will be effective in the treatment of behavioral disturbance due to FTD. The primary outcome measure for this study will be the disinhibited behaviors sub-scale of the Frontal Behavioral Inventory (FBI). Secondary outcome measures include other measures of behavioral symptomatology such as the total FBI score and the Neuropsychiatric Inventory (NPI). Other secondary outcomes of interest will be cognitive function, particularly executive function, activity of daily living (ADL) and instrumental ADL (IADL) function, and reduction in apathy.
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