Abstract/Project Summary
Behavioral and psychological symptoms of dementia (BPSD), also known as neuropsychiatric
symptoms, are highly prevalent in Alzheimer's disease (AD), with increasing frequency and severity as the
disease progresses. Agitation, aggression, aberrant motor behaviors (e.g., wandering, pacing), sleep
disturbances and other BPSD are a significant burden for patients and their caregivers. These behavioral
symptoms are linked to a faster progression of the disease, increased risk of institutionalization, and higher
cost of care. The pathogenesis of BPSD is not well understood, and there are no Food and Drug
Administration (FDA) approved drugs for these disabling symptoms. Antipsychotics are the most used
pharmacological treatment for agitation-related symptoms in older adults with dementia, but their efficacy is low
and there are serious adverse effects, including increased risk of death. Medical societies emphasize that the
management of agitation-related behaviors should begin with an assessment of the underlying medical and
environmental causes. In line with these clinical recommendations, the objective of this proposal is to advance
knowledge on the pathogenesis of BPSD, with the long-term goal of identifying new treatments for these
disabling behavioral symptoms. The primary aim of this proposal is to test the hypothesis that uric acid is
associated with BPSD. The hypothesis is based on evidence that mice genetically modified to accumulate uric
acid displayed more hyperactive and impulsive-like behaviors, and in humans, higher uric acid was associated
with impulsivity-related traits. In clinical samples with neuropsychiatric disorders, such as bipolar disorder and
the rare Lesch-Nyhan syndrome, elevated uric acid levels have been associated with behavioral symptoms
akin to BPSD. Moreover, clinical trials indicate that allopurinol (a xanthine oxidase inhibitor used to reduce uric
acid levels) is effective in reducing manic symptoms in bipolar patients. Support for our hypothesis that uric
acid plays a role in the pathogenesis of agitation-related BPSD has translational implications. Dietary changes
and medications (e.g., allopurinol) are effective in reducing levels of uric acid and could be a safer and possibly
more effective treatment for BPSD than antipsychotic medications. The proposal also test the hypothesis that
personality is associated with risk of BPSD, which is based on evidence that neuroticism and related traits are
strong risk factors for mental health disorders. Even with the onset of dementia, individuals retain some of their
personality characteristics, which are likely to shape behaviors and psychological functioning. The proposed
study will advance knowledge on the role of specific personality traits related to each BPSD, and will inform
interventions by fostering a person-centered approach to BPSD. The long-term goal of this research is to
improve the quality of life and reduce cost of care for individuals with dementia and their caregivers.