Background and Objective: One in five older adults has Mild Cognitive Impairment (MCI), a precursor of dementia. Apathy, a profound loss of initiative and motivation, is seen in as high as 60% of patients with MCI. Patients with apathy often neglect activities they are fully capable of, related to self-care and physical activity, which leads to long term impairment and disability. Apathy is associated with impaired executive function, increased caregiver burden, and higher rates of conversion to dementia. Treatment of apathy in MCI has the potential to improve the psychological and cognitive health status of Veterans enabling them to function more fully in society. Apathy treatment may also fundamentally alter the trajectory of neurodegeneration. However, apathy research sorely lacks: non-pharmacological treatments, objective measurements, biomarkers, and knowledge whether treatment of apathy improves function, reduces caregiver burden, and decreases conversion from MCI to dementia. Repetitive transcranial magnetic stimulation (rTMS) applied to the dorsolateral prefrontal cortex (DLPFC) has yielded promising results in apathy treatment. The study will examine the efficacy of rTMS treatment on apathy and related measures such as cognition, functional status, quality of life, and caregiver burden. Lasting effects of these changes during long-term follow-up will also be examined. An innovation of the proposal is to use a cognitive response from a single session of rTMS to predict a behavioral response to the longer course of treatment. The study also proposes to test two promising candidates for validity as biomarkers for apathy research. Finally, the study will explore if rTMS treatment influences the rates of conversion of MCI to dementia. Research Plan: A three phase study has been designed. Phase I will consist of comprehensive assessment and a single session of stimulation in participants eligible for rTMS (N = 75). Phase II will be a double-blind sham controlled randomized trial of rTMS for apathy (N = 50). Phase III will be a series of assessments annually till the end of the study to ascertain rates of conversion to dementia (N = 125).
Aim 1 will determine the efficacy and lasting effects of rTMS in treating apathy in MCI compared to sham treatment.
Aim 2 will determine the efficacy and lasting effects of rTMS on cognition, functional status, quality of life, and caregiver burden compared to sham treatment.
Aim 3 will determine the predictive validity of changes in executive function (Conner's Continuous Performance Test) and biomarker (Brain Derived Neurotrophic Factor (BDNF)) correlates of apathy after a single session of active rTMS to the overall change in apathy after 4-weeks of treatment.
Aim 4 will compare the rates of conversion of MCI to dementia in those that received rTMS to sham treatment. This exploratory aim will enable determination of the effect size for preventing/delaying dementia and serve as the foundation for a larger, more definitive study. Methods: Older Veterans (N = 125) meeting the modified Mayo Clinic criteria for MCI will be enrolled. Their behavioral profile (Neuropsychiatric Inventory), apathy, physical function, memory, executive function, and caregiver burden will be assessed at regular intervals. Blood will be drawn three times to estimate ApoE4 carrier status and BDNF levels. Actigraphs will be used to measure physical activity correlates of apathy. Fifty participants will undergo 20 treatments with either active rTMS coil or sham coil. Yearly assessments for incident dementia will be done. Hypotheses related to the primary outcome measures will be tested with 80% power to detect at least 0.7 standard deviations difference in means between the active and sham groups. Clinical Relevance: Knowledge gained from the successful completion of this project will help improve the management of apathy, decrease caregiver burden, and improve the quality of life of veterans with MCI. Results from this study can be readily translated to clinical practice as rTMS is currently available for depression treatment in many VA medical centers.
Apathy, a profound loss of initiative and motivation, is often seen in older Veterans with memory problems. Apathy leads to serious health problems, increases dependency, and caregiver burden. If untreated, apathy hastens the progression to frank dementia. In a pilot study, we found that apathy, working memory, and function can be restored using magnetic stimulation in some but not all older Veterans. The reason for this variation is unknown. We propose a three-phase study in 125 older Veterans with mild memory problems. Their motivation, memory, and function will be measured periodically. Veterans with apathy that are eligible for treatment will receive either real or sham magnetic stimulation to the front part of their brain over 20 sessions. Genetic testing and biomarkers will be used to differentiate those who respond to magnetic stimulation from those who do not. Impact on function, quality of life, and rates of progression to dementia will also be studied.
