Serotonin Modulation of Neural Circuitry in bvFTD: Understanding the Neurobiology of Mood and Cognitive Symptoms

Dementia is a leading cause of disability and death worldwide, with the most significant impact on those with young-onset dementia. Frontotemporal dementia (FTD) is the most common cause of dementia in patients under 60, and the behavioral variant (bvFTD) is the predominant presenting syndrome. Neuropsychiatric

symptoms (NPS) are core features of bvFTD, and patients with bvFTD require family caregivers to dedicate significant time and resources to managing NPS. In contrast to Alzheimer’s disease (AD) in which the negative impact of NPS is well understood, prior research has not focused on the nature of NPS and its association with

functional decline in bvFTD. The applicant has identified a discrete affective symptom (AS) cluster characterized by depression, anxiety, irritability, and agitation that occur in at least 50% of patients and accelerate functional decline in bvFTD. The treatments developed for the major psychiatric disorders are often

ineffective in bvFTD. Given the high prevalence and disability resulting from AS in bvFTD, there is an urgent need for more effective and safe treatments to improve both AS and cognition. The long-term goals of this application for a Mentored Patient-Oriented Research Career Development Award (K23) from a geriatric

psychiatrist are to enhance understanding of the neurobiology of NPS in bvFTD to inform the development of novel, precision-targeted therapies to slow functional decline, alleviate patient suffering, and ease caregiver burden. A Positron Emission Tomography (PET) study to measure glucose metabolism is proposed to

measure changes in neural circuitry with multi-modal antidepressant (Vortioxetine) treatment that targets both serotonin receptors and serotonin transporters in bvFTD. PET measures of cerebral glucose metabolism to evaluate neural circuitry is a method that is sensitive to neurodegeneration and AS and cognitive impairment.

The following aims are proposed: I. To identify the neural circuitry associated with AS and cognitive deficits in bvFTD and II. To identify the changes in neural circuitry following vortioxetine treatment in patients with bvFTD and AS. The overarching hypothesis is that Vortioxetine will improve AS and executive functioning in bvFTD

and increase cerebral glucose metabolism in the salience network (SN) and default mode network (DMN), respectively. The research plan is complemented by a career development plan to advance skills in 1) clinical research methodology; 2) the design, application, image and statistical analysis, and interpretation of PET

neuroimaging studies; 3) clinical and research applications of neuropsychological assessments and 4) grant writing and overall career development. The mentoring team, collaborators and consultants represent senior faculty with considerable expertise in these areas. Completion of the research and training objectives will

advance the career of a junior investigator toward developing an independent research program focused on developing PET biomarkers of neuropsychiatric dysfunction in FTD and related dementias including AD to guide management and treatment selection as the focus of a future RO1 application.