Neuropsychiatric Symptoms and Microglial Activation in Patients with Alzheimer Disease
Authors: Schaffer Aguzzoli Cristiano , Ferreira Pâmela C. L. , Povala Guilherme , Ferrari-Souza João Pedro , Bellaver Bruna , Soares Katz Carolina , Zalzale Hussein , Lussier Firoza Z. , Rohden Francieli , Abbas Sarah , Leffa Douglas T. , Scop Medeiros Marina , Therriault Joseph , Benedet Andréa L. , Tissot Cécile , Servaes Stijn , Rahmouni Nesrine , Cassa Macedo Arthur , Bezgin Gleb , Kang Min Su , Stevenson Jenna , Pallen Vanessa , Cohen Ann , Lopez Oscar L. , Tudorascu Dana L. , Klunk William E. , Villemagne Victor L. , Soucy Jean Paul , Zimmer Eduardo R. , Schilling Lucas P. , Karikari Thomas K. , Ashton Nicholas J. , Zetterberg Henrik , Blennow Kaj , Gauthier Serge , Valcour Victor , Miller Bruce L. , Rosa-Neto Pedro , Pascoal Tharick A. 
Published: November 2023

ImportanceNeuropsychiatric symptoms are commonly encountered and are highly debilitating in patients with Alzheimer disease. Understanding their underpinnings has implications for identifying biomarkers and treatment for these symptoms.ObjectiveTo evaluate whether glial markers are associated with neuropsychiatric symptoms in individuals across the Alzheimer disease continuum.Design, Setting, and ParticipantsThis cross-sectional study was conducted from January to June 2023, leveraging data from the Translational Biomarkers in Aging and Dementia cohort at McGill University, Canada. Recruitment was based on referrals of individuals from the community or from outpatient clinics. Exclusion criteria included active substance abuse, major surgery, recent head trauma, safety contraindications for positron emission tomography (PET) or magnetic resonance imaging, being currently enrolled in other studies, and having inadequately treated systemic conditions.Main Outcomes and MeasuresAll individuals underwent assessment for neuropsychiatric symptoms (Neuropsychiatry Inventory Questionnaire [NPI-Q]), and imaging for microglial activation ([11C]PBR28 PET), amyloid-β ([18F]AZD4694 PET), and tau tangles ([18F]MK6240 PET).ResultsOf the 109 participants, 72 (66%) were women and 37 (34%) were men; the median age was 71.8 years (range, 38.0-86.5 years). Overall, 70 had no cognitive impairment and 39 had cognitive impairment (25 mild; 14 Alzheimer disease dementia). Amyloid-β PET positivity was present in 21 cognitively unimpaired individuals (30%) and in 31 cognitively impaired individuals (79%). The NPI-Q severity score was associated with microglial activation in the frontal, temporal, and parietal cortices (β = 7.37; 95% CI, 1.34-13.41; P = .01). A leave-one-out approach revealed that irritability was the NPI-Q domain most closely associated with the presence of brain microglial activation (β = 6.86; 95% CI, 1.77-11.95; P = .008). Furthermore, we found that microglia-associated irritability was associated with study partner burden measured by NPI-Q distress score (β = 5.72; 95% CI, 0.33-11.10; P = .03).Conclusions and RelevanceIn this cross-sectional study of 109 individuals across the AD continuum, microglial activation was associated with and a potential biomarker of neuropsychiatric symptoms in Alzheimer disease. Moreover, our findings suggest that the combination of amyloid-β– and microglia-targeted therapies could have an impact on relieving these symptoms.