The goal of this study is to determine the effects of degeneration of RDoC Negative and Positive Valence Circuit Elements, and how these effects are associated with specific Neuropsychiatric Symptoms (NPS), in persons with Alzheimer?s disease and related dementias (ADRD). Current pharmacological treatments for NPS in ADRD were developed 50 years ago, are often inefficacious, and can have serious adverse effects including increased mortality. Neuroanatomically-based treatments such as TMS, DBS, and tDCS for NPS are promising, but their development has been hampered by our lack of knowledge about the mechanistic and neuroanatomical bases of NPS in ADRD. The proposed project will leverage NIH-supported resources, including the RDoC Project and a project in our laboratory (R01AG062268) to determine the factor structure of NPS in ADRD, to better understand the connections between changes in the Negative (for example fear, pain, and anxiety) and Positive (for example rewarding behaviors) Valence Systems and specific NPS across different neurodegenerative disorders. The same NPS (e.g., apathy) occur across many ADRD diagnoses, necessitating a trans-diagnostic approach to identify common neurobiologically-informed mechanisms of NPS across diagnoses. We will study 40 participants with Alzheimer?s disease (AD), 20 with behavioral-variant Frontotemporal dementia (bvFTD), 20 with Huntington?s disease (HD), and 20 with semantic-variant Primary Progressive Aphasia (svPPA). We have chosen these disorders as they target specific RDoC Negative and Positive Valence Circuit Elements including the prefrontal cortex (PFC), dorsal striatum, and anterior temporal lobes. The first hypothesis is that the ventromedial (vm)PFC plays a central role in Negative Valence and degeneration of the vmPFC will be associated with low Negative Valence on RDoC Paradigms, low Internalizing psychiatric symptoms (including anxiety and depression), and the NPS of apathy. We also hypothesize that degeneration of Negative Valence Circuit Elements that modulate the vmPFC, including the dorsal PFC, dorsal striatum, and anterior temporal lobes, will be associated with high Negative Valence and Internalizing psychiatric NPS. The ventral PFC and dorsal striatum are involved in goal-directed learning and transferring learning from goal-directed to habit systems. We hypothesize that degeneration of the ventral PFC will be associated with deficits in learning from feedback on RDoC Positive Valence Paradigms and with the NPS of repetitive behaviors, and degeneration of the dorsal striatum with deficits in learning from punishment vs. reward and habit learning and the NPS of repetitive thoughts. These investigations could, for the first time, utilize RDoC Paradigms to better understand the development of NPS in humans from neurodegenerative processes, to specific deficits in RDoC Valence Paradigms, to neuroanatomical findings, to NPS. These investigations are clinically relevant as they will improve our knowledge of the mechanistic and neuroana- tomical bases of NPS for use in clinical trials of novel neuroanatomically-based treatments for NPS in ADRD.
Neuropsychiatric symptoms in Alzheimer?s disease and related dementias (ADRD) are a major public health problem as they are common, greatly increase the cost and difficulty of care, and our pharmacological treatments are inadequate. Treatment development has been hampered by our lack of knowledge about the mechanistic and neuroanatomical bases of neuropsychiatric symptoms in ADRD. We will leverage existing NIH resources, including The Research Domain Criteria (RDoC) Project and a project in our laboratory to re- define neuropsychiatric symptoms on the basis of their underlying factor structure (R01AG062268), to explore how degeneration of brain networks involved in Negative (for example fear, pain, and anxiety) and Positive (for example rewarding behaviors) Valence Systems leads to specific neuropsychiatric symptoms in patients with ADRD with a goal of identifying brain networks to target with anatomically-based treatments to reduce neuropsychiatric symptoms in patients with neurodegenerative disorders, including Transcranial Magnetic Stimulation (TMS), Deep Brain Stimulation (DBS), and transcranial Direct Current Stimulation (tDCS).