Evaluate the Effects of Tolcapone on Cognitive and Behavioral Dysfunction in Patients With TBI and MCI

Each patient will receive a two-week specified dosing amount of tolcapone (100mg TID on Day
1; 200mg TID on Days 2-14). The patient will be instructed to take the study drug three
times daily. Tolcapone will be tapered after Day 14 to avoid potential withdrawal reactions.

Clinical Instruments for patients:

- Question banks from large patient-reported outcome measure initiatives will be used and
administered and used by computerized-adaptive tests (CATs). These include the TBI-QoL
for patients with TBI and question banks from the patient-reported outcome measure
information systems (PROMIS) and neurology quality of life measurement initiative
(Neuro-QoL). Patients will answer questions related to their mobility, fatigue, pain
interference, positive affect and well-being, depression, anxiety, anger and
irritability, and emotional and behavioral dyscontrol.

- Clinical Global Impressions Scale

- Geriatric Depression Scale-15

- State-Trait Anxiety Inventory

- Hopkins Adult Reading Test

- Frontal Systems Behavior Scale

- Montreal Cognitive Assessment

- Trails A&B

- Modified Wisconsin Card Sorting Test

- NIH Toolbox

- Perceptual Comparison Test

- Brief Test of Attention

- Hopkins Verbal Learning Test

- Brief Visuospatial Memory Test

- Calibrated Ideational Fluency Assessment

- Digit Span

Clinical Instruments for Informants:

- Neuropsychiatry Inventory

- Apathy evaluation scale

- Overt aggression scale

- Frontal Systems Behavior Scale

Laboratory Measures:

- Blood sample for genotyping

- Blood sample for assessing COMT activity.

- Blood sample for a laboratory profile including CBC, CMP, TSH, Hepatitis Panel (B and
C), and RPR

- A urine analysis, urine drug screen, and a urine pregnancy test

- In addition for MCI patients: a blood sample for tests including Serum Calcium, B12,
ESR, and C-reactive protein

TBI Inclusion Criteria:

- Age 18-65

- Diagnosis of mild, moderate, or severe TBI, with classification to be made based on
parameters at the time of the index event or acquired brain injury

- Acquired Head Injury occurred >12 months prior to trial initiation

- Proficient in the English language

- Stable neurological and psychiatric symptomatology for 2 months prior to trial
initiation as determined by the referring Sheppard Pratt physician.

- Stable medication dose and regimen for 2 months

MCI Inclusion Criteria:

- Age 60-75

- Mild Cognitive impairment diagnosed by a physician, defined as a measurable deficit
in cognition in at least one domain (or <1.5SD below age-and education-matched norms
on at least one cognitive domain tested), in the absence of dementia and in the
absence of impairment of activities of daily living

- No abnormalities on other serum tests to rule out other cause of cognitive
impairment: TSH, B12, CBC, Chemistry screen, and RPR.

- Recent structural neuroimaging (within 1 year or since the time of the onset of
cognitive complaint)-noncontrast head CT or MRI-to rule out any gross lesion
inconsistent with the diagnosis of MCI (e.g. subdural hematoma, normal pressure
hydrocephalus, demyelinating lesion, infarct, or mass lesion)

- Proficient in the English language

- Stable neurological and psychiatric symptomatology for 2 months prior to trial
initiation as determined by the impression of the referring Sheppard Pratt physician.

- Stable medication dose and regimen for 2 months

- Montreal Cognitive Assessment (MOCA) score between 18-26

- Clinical Dementia Rating (CDR) Scale Global Score<1

- Lawton ADL/IADL Questionnaire

- Geriatric Depression Rating Scale score < 10

Exclusion Criteria for all patients:

- History of, or active, liver disease or abnormal liver function tests--if the patient
currently has elevated Alanine Transaminase (ALT) or Aspartate Transaminase (AST)
levels that exceed 2 times the upper limit of normal [Normal Reference Ranges ALT
(Male: 4-40 IU/L, Female: 4-40 IU/L), AST (Male: 4-31 IU/L, Female: 4-37 IU/L) or the
ratio of AST:ALT has exceeded 2:1

- Active alcohol use disorder, as defined by DSM-5, of any severity mild, moderate, or
severe

- History of, or active, cardiovascular disease defined as: coronary heart disease,
manifested by myocardial infarction, angina pectoris, or heart failure

- Uncontrolled hypo-or hypertension based on Joint National Committee criteria (JNC7);
Hypotension: Systolic<90mmHg or diastolic<60mmHg; Hypertension: Systolic >140mmHg or
diastolic>90 mmHg)

- History of extra-pyramidal symptoms e.g. tardive dyskinesia, neuroleptic malignant
syndrome, or QT prolongation while on a first-generation anti-psychotic

- Active illicit substance use, resulting in a substance use disorder as defined by
DSM-5, of any severity mild, moderate, or severe

- Patient is currently taking tolcapone or any of the following medications that can
interact with tolcapone resulting in an adverse events: another COMT inhibitor,
benserazide, α-methyldopa, dobutamine, apomorphine, isoproterenol, clozapine, MAO
inhibitor

- Known allergy or serious adverse reaction to tolcapone

- Participated in any investigational drug trial in the past 30 days.

- Pregnant or planning to become pregnant during the study period

- Breastfeeding or planning to breastfeed during the study period.

Other Exclusion Criteria for TBI Patients

- History of repeated/multiple TBI

- Presence of pre-morbid/pre-TBI cognitive impairment or behavioral dysfunction, as per
informant or medical documentation

Other Exclusion Criteria for MCI Patients

- History of mild, moderate, or severe TBI

- Presence of pre-morbid/pre-MCI cognitive impairment as per informant or medical
documentation.