The broad, long-tenn objectives of this proposal are to develop better treatments for frontotemporal dementia (FTD).
The Specific Aims are to: 1) Develop an effective therapeutic intervention for the treatment of FTD. To achieve this aim, the proposed project will test the clinical and cognitive effects on FTD patients of a medication that increases the amount of the neurotransmitter dopamine in the brain. This medication acts by inhibiting an enzyme, catechol 0-methyl-transferase (COMT), that degrades dopamine. The proposed project will also use fMRI to determine the effects of COMT inhibition on prefrontal cortex and temporal lobe efficiency while the patients read words that describe animal functions and social attributes. 2) Determine the effect of COMT genotype on symptom presentation and disease course in FTD patients. The COMT gene has a common polymorphism that affects its function. The Research Design is a 24-day double-blind, placebo-controlled crossover trial of 28 patients with FTD. The Methods to be used are a comparison of measures of behavioral and cognitive symptoms, and fMRI blood oxygenation level-dependent (BOLD) activation in the prefrontal cortex and temporal lobe, when the patients are taking a COMT inhibitor versus when they are taking a placebo. Frontotemporal dementia Is an illness that results in the degeneration of the frontal aspect of the brain. This study will test whether increasing a brain chemical, called dopamine, that is deficient in the brains of patients with frontotemporal dementia patients improves the symptoms of the illness. It will also use brain imaging and genetics to detemnlne the contribution of dopamine deficiency to the symptoms ofthis illness.
FTD is increasingly recognized as an important cause of morbidity and mortality in the United States. Np treatment has been shown to slow the progression, or improve the cognitive symptoms, associated with this devastating illness. In autopsy, cerebrospinal fluid, and imaging studies, patients with FTD demonstrate deficiencies in the dopamine neurotransmitter system. The proposed study is the first to specifically test dopamine augmentation for- the treatment of FTD. The investigations proposed in this project could provide an entire class of medications, previously unutilized, for the treatment of FTD.
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