Unveiling the Role of Neuroinflammation in Neuropsychiatric Symptoms of Dementia

Atlantic Fellow Cristiano Schaffer Aguzzoli discusses new research that reveals the crucial role of neuroinflammation in the development of neuropsychiatric symptoms in dementia patients.

A Curious Case

As a neurology resident in Brazil, I had the opportunity of evaluating and assisting a young patient with very early-onset behavioral variant frontotemporal dementia. At just 24 years of age, he presented intense neuropsychiatric symptoms—agitation, irritability, nighttime disturbances, and motor issues—initially thought to be linked to a primary psychiatric disorder. Neuropsychiatric symptoms are common in individuals with a neurodegenerative disease, significantly impacting the lives of both patients and caregivers beyond cognitive symptoms.

Published during my time as Atlantic Fellow for Equity in Brain Health at UCSF, in collaboration with Atlantic Fellows Rafi Hadad and Petronilla Battista under the supervision of GBHI Co-Founding Director Bruce Miller, this case fueled my passion to delve into the root causes of neuropsychiatric symptoms in patients with dementia. I wanted to understand the main culprits of these symptoms in Alzheimer’s disease and other neurodegenerative disorders.

The Influence of Neuroinflammation

In a new study, published in JAMA Network Open and conducted at the University of Pittsburgh under the mentorship of Tharick Pascoal along with Victor Valcour, and Bruce Miller of UCSF, we discovered that neuroinflammation significantly contributes to the development of neuropsychiatric symptoms, surpassing the effects of classical hallmarks of Alzheimer’s disease pathology—amyloid and tau.

We further illustrate that neuroinflammation specifically drives symptoms like irritability, agitation, and nighttime disturbances. Interestingly, our research suggests that it does not influence the development of other symptoms such as delusions and hallucinations. These findings suggest a pivotal role of neuroinflammation in distinct neuropsychiatric symptoms, while amyloid and tau may be responsible for others.

Implications for Clinical Practice and Drug Development

Our study carries significant implications for clinical practice, showcasing the potential of biomarkers to identify neuroinflammation in the brain, aiding in predicting the development of neuropsychiatric symptoms in dementia patients. In the era of precision medicine, these biomarkers help identify individuals at higher risk of developing specific symptoms like irritability, agitation, and nighttime disturbances.

Conversely, our results propose that novel therapeutic drugs targeting neuroinflammation may alleviate these symptoms in individuals with Alzheimer's disease. Moreover, our study influences the design of randomized clinical trials, suggesting the use of distinct neuropsychiatric symptoms as clinical outcomes when evaluating anti-inflammatory drugs.

We are currently collaborating with other centers to explore whether our recent findings on inflammation and neuropsychiatric symptoms extend to other neurodegenerative disorders, such as frontotemporal dementia and dementia with Lewy bodies.