Neuropsychiatric Symptoms and Microglial Activation in Patients with Alzheimer Disease

Abstract

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.

Microglial Senescence and Activation in Healthy Aging and Alzheimer’s Disease: Systematic Review and Neuropathological Scoring

“…These animal models can only partially clarify what happens in humans due to the fact that AD is a proper human disease which is complex and related to both genetic and environmental factors, with a trajectory of evolution that is different and peculiar for each patient. Just think of the association recently demonstrated between imaging markers of microglial reaction and behavioral symptoms in Alzheimer's disease [220], which is certainly not transferable to mouse models. Thus, the role of microglia in human healthy aging and in AD presents multiple aspects, complex and interconnected.…”

Exploring the Genetic Landscape of Mild Behavioral Impairment as an Early Marker of Cognitive Decline: An Updated Review Focusing on Alzheimer’s Disease

“…Abnormal neuroinflammation has been linked to the longitudinal worsening of cognitive function among patients with AD [ 54 ]. NPS severity has been correlated with increased microglial activation across the AD continuum [ 55 ]. Excessive neuroinflammatory responses have also been related to anxiety and depressive, manic, and psychotic symptoms in several psychiatric disorders [ 56 ].…”

“…In this context, it has been recently demonstrated that among cognitively unimpaired older individuals, astrocytic PRSs for AD are linked to the beta-amyloid burden, while microglial PRSs for AD are linked to both beta-amyloid and tau accumulation. Given the association between neuroinflammation and NPSs across the AD spectrum, future studies should also investigate the relationship between glial PRSs for AD and MBI [ 55 ].…”