APATHY AND NEGATIVE SYMPTOMS IN ALZHEIMER'S DISEASE: INVESTIGATION OF THE PROLINE*COMT INTERACTION FOR SYMPTOM TARGETING TO POSITIVELY IMPACT QUALITY OF LIFE

Background: Neuropsychiatric symptoms such as apathy are frequently described in patients with Alzheimer's disease (AD), as well as those who have sustained a traumatic brain injury (TBI). In fact, reports have suggested that close to one half of all AD and TBI patients exhibit apathy, which is characterized by the loss of motivation to participate in activities, social withdrawal, and emotional indifference, and these symptoms often present in incipient AD (including mild cognitive impairment [MCI]) or within the first year after brain injury. Apathy and related symptoms contribute substantially to the huge personal and economic costs for individuals living with AD and TBI: Apathy can disrupt patients' participation in family life and social integration, and can lead to more intensive utilization of health care services. Furthermore, apathy in AD is associated with a rapid course of functional and cognitive decline, and in TBI patients, negatively impacts rehabilitation. Of relevance, substantial caregiver burden and distress have been significantly associated with the presence and severity of apathy. Apathy is a 'negative' neuropsychiatric symptom. Although commonly considered a major symptom domain of psychiatric illness, the full spectrum of negative symptoms can also present in patients with dementia and constitutes an independent behavioral dimension that is not an outcome of depression and/or cognitive status. Intriguingly, it has been suggested that targeting of these symptoms in AD may extend the time to conversion from MCI and possibly positively alter the trajectory of the disease process. However, there are no approved treatments for negative symptoms in AD or TBI, and thus there is clearly a need for new research into interventions that target neuropsychiatric symptoms of AD and TBI, in particular negative symptoms, to improve the quality of life for individuals living with TBI and AD, and also to alleviate the burden on their caregivers. Of relevance, our preliminary studies of the amino acid proline and the catechol-O-methyltransferase (COMT) gene, offer a molecular pathway for intervention to target negative symptoms. Proline is a precursor of the neurotransmitter glutamate and may function as a central nervous system (CNS) neuromodulator. COMT encodes the enzyme that catalyzes deactivation of catecholamines, including dopamine (DA). Proline is catabolized by the proline dehydrogenase enzyme (encoded by the PRODH gene). In the Prodh null mouse, elevated proline stimulates glutamatergic synaptic transmission and increases prefrontal cortical (PFC) DA transmission. We recently found that fasting plasma proline levels (which reflect CNS levels) and the functional COMT Val[158]Met polymorphism significantly interact, predicting negative symptom outcomes in patients with psychiatric illnesses. Specifically, in COMT Val/Val patients (high enzyme activity, thus less prefrontal DA) high proline is protective, with low negative symptom severity or a greater symptom reduction over time. Patients who are carriers of the low COMT activity Met allele (Val/Met or Met/Met) demonstrated the opposite, exhibiting significantly more negative symptoms or less symptom improvement as proline levels rise. COMT and proline may interact to modify negative symptoms by impacting neurotransmitter systems in a manner similar to that observed in the Prodh null mouse. Of importance, this interaction effect, which is consistent across two different psychiatric illnesses, has implications for genotype-targeted treatment of negative symptoms because proline-modulating medications that can either up-, or down-regulate proline already exist. Hypothesis: We hypothesize that the proline x COMT interaction and its impact on negative symptoms, either beneficial or detrimental, as previously observed in psychiatric disorders, is generalizable across neuropsychiatric diseases. For this first study we will test our hypothesis in patients with AD. Follow-on studies would target TBI. The specific aim of this application is to test for a statistical interaction between fasting plasma proline and COMT Val[158]Met genotype on negative symptoms in 112 female AD patients.Research Strategy. Aim 1a. To collect fasting blood from 112 probable AD patients with negative symptoms and measure plasma proline levels plus perform COMT Val[158]Met genotyping. Patients with AD were chosen for this initial project because (a) they exhibit significant levels of negative symptoms; (b) COMT genotype can impact behavioral symptom presentation including apathy in AD; and (c) there is evidence of increased CNS and peripheral proline in AD patients which may result in DA-neuromodulatory responses resembling those in the Prodh null mouse, with effect modification by COMT. A gender stratified approach was chosen because (a) of the over 5 million AD sufferers in the United States, nearly two-thirds are women; and (b) proline gender differences have been reported and thus, we seek to avoid potential gender confounds. Plasma proline will be measured from fasting blood and genotyping. Aim 1b. Evaluate negative symptoms using the Scale for Assessment of Negative Symptoms-AD (SANS-AD). Studies of negative symptoms in AD have guided our instrument choice to use this modified version of the SANS. Aim 1c. Explore the relationship between COMT and proline on negative symptoms in AD. Using linear regression we will test for a cross-sectional interaction between proline and COMT: Dependent variable=total SANS-AD score. Secondary outcomes will be individual SANS-AD items.