This study will test the effects of a medication called tolcapone on cognitive, behavioral, and language problems seen in patients with frontotemporal dementia (FTD). Tolcapone increases the amount of dopamine, a brain chemical that may be lowered in FTD. The study will see if tolcapone can improve thinking, behavior, and language in people with FTD and will look at the effects of the drug on brain activity.

Patients with FTD who are between 40 and 85 years of age and who have participated in NINDS protocols 02-N-0001 (Testing a model of the representational knowledge stored in the human prefrontal cortex) and 81-N-0010 (Regional cerebral utilization of glucose in patients with a diagnosis of frontal lobe dementia, atypical parkinsonian disorder, and other basal ganglia disorders) may be eligible for this study.

Participants are admitted to the NIH Clinical Center for 4 weeks. They take tolcapone or a placebo (a look-alike pill with no active ingredient) during study week 1. During study week 3, those who took placebo during week 1 now take tolcapone for 1 week and those who took tolcapone now take placebo. In addition, patients undergo the following tests and procedures:

• Neurological tests to evaluate attention, problem-solving and memory. These tests are repeated several times during the course of the study.
• Test to look for a gene that affects the amount of dopamine in the brain, using blood samples collected in a previous study.
• Blood draws four times during the study.
• Functional MRI (fMRI) to learn about changes in brain regions that are involved in performing tasks. For fMRI, the patient lies on a table that can slide in and out of the scanner, a narrow metal cylinder surrounded by a magnetic field. The procedure takes about 60 minutes and is performed four times over the course of the . FMRI involves taking pictures of the brain during MRI while the subject performs a task so that changes in the brain that occur during these tasks can be studied.

Objective: 1) To test the clinical and cognitive effects on frontotemporal dementia (FTD) patients of a medication that increases the amount of the neurotransmitter dopamine in the brain. In autopsy, cerebrospinal fluid, and imaging studies, patients with frontotemporal dementia demonstrate deficiencies in the dopamine neurotransmitter system. This medication acts by inhibiting an enzyme, catechol O-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 at rest and while the patients read words that decribe animal functions and social attributes and perform a working memory task. 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.

Study population: 30 patients with FTD will participate in the medication trial. These patients will be included with a larger group of FTD patients (for a totoal of approximately 100 patients) who have participated in NINDS protocols 81-N-0010 and 02-N-0001 for the analyses of the effect of COMT genotype on symptom presentation and progression.

Research Design: A 24-day double-blind, placebo-controlled crossover trial and an analysis of COMT genotype on symptom presentation and progression.

Outcome measures: 1) 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. 2) A comparison between COMT genotypes of the ratio of verbal fluency to overall score on the RBANS cognitive battery and loss in points on the Mattis DRS-2 divided by symptom duration.

• Adler CH, Singer C, O'Brien C, Hauser RA, Lew MF, Marek KL, Dorflinger E, Pedder S, Deptula D, Yoo K. Randomized, placebo-controlled study of tolcapone in patients with fluctuating Parkinson disease treated with levodopa-carbidopa. Tolcapone Fluctuator Study Group III. Arch Neurol. 1998 Aug;55(8):1089-95.
• Apud JA, Mattay V, Chen J, Kolachana BS, Callicott JH, Rasetti R, Alce G, Iudicello JE, Akbar N, Egan MF, Goldberg TE, Weinberger DR. Tolcapone improves cognition and cortical information processing in normal human subjects. Neuropsychopharmacology. 2007 May;32(5):1011-20. Epub 2006 Oct 25.
• Baker M, Mackenzie IR, Pickering-Brown SM, Gass J, Rademakers R, Lindholm C, Snowden J, Adamson J, Sadovnick AD, Rollinson S, Cannon A, Dwosh E, Neary D, Melquist S, Richardson A, Dickson D, Berger Z, Eriksen J, Robinson T, Zehr C, Dickey CA, Crook R, McGowan E, Mann D, Boeve B, Feldman H, Hutton M. Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature. 2006 Aug 24;442(7105):916-9. Epub 2006 Jul 16.

• INCLUSION CRITERIA:
• Diagnosis of FTD.
• Already participated in NINDS protocols 02-N-0001 and 81-N-0010. This is to ensure the patients are reliably diagnosed and to allow us to compare the data gathered in the proposed study with data from these other protocols.
• Age 40 to 85. The majority of FTD patients are between the ages of 45-65.
• Assigned durable power of attorney. To allow us to perform research on cognitively impaired subjects ethically.
• Caregiver willing and able to accept the responsibilities involved in the study.
• MDRS2 score less than 132. This is to ensure that the patients have measurable cognitive deficits to attempt to improve in the medication trial.

EXCLUSION CRITERIA:

• The diagnosis of any other type of dementia besides FTD including Alzheimer's disease, Lewy body dementia, vascular dementia, dementia associated with Parkinson's disease, corticobasal syndrome, and progressive supranuclear palsy.
• Known allergy or serious adverse reaction to tolcapone.
• Active liver disease. This is because of the association between tolcapone and hepatotoxicity. This includes hepatitis, with the exception of a past hepatitis A infection from which the subject has completely recovered.
• Current alcohol abuse. This is because of the association between tolcapone and hepatotoxicity.
• Active substance abuse.
• Elevated liver function tests. This is because of the association between tolcapone and hepatotoxicity.
• Patient is taking tolcapone or any other COMT inhibitor, benserazide, alpha-methyldopa, dobutamine, apomorphine, isoproterenol, an MAO-I, or clozapine. This is because these medications can have interactions with tolcapone that could result in adverse effects for the patient.
• Symptomatic cardiovascular disease (i.e., angina, TIAs, syncope). This is to help ensure that patients are medically stable during the study.
• Uncontrolled hyper- or hypotension. This is to help ensure that patients are medically stable during the proposed project.
• Any other contraindication to tolcapone.
• Any medication that significantly affects the dopamine system, including stimulants and antipsychotic medications. This is because these medications could interfere with the testing of our research hypothesis. We will accept patients washed out of these medications. The washout period will be at least two weeks, but may be longer depending on the medication. If a patient cannot tolerate the washout, they will not participate in the study.
• Pregnant women. Women of childbearing potential will be screened by history for the possibility of pregnancy and undergo a urine pregnancy test on the first day of the study.