Neuropsychiatric Symptoms and Microglial Activation in Patients with Alzheimer Disease.

Importance: Neuropsychiatric 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. Objective: To evaluate whether glial markers are associated with neuropsychiatric symptoms in individuals across the Alzheimer disease continuum. Design, Setting, and Participants: This 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 Measures: All individuals underwent assessment for neuropsychiatric symptoms (Neuropsychiatry Inventory Questionnaire [NPI-Q]), and imaging for microglial activation ([11C]PBR28 PET), amyloid-ß ([18F]AZD4694 PET), and tau tangles ([18F]MK6240 PET). Results: Of 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-ß 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 (ß = 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 (ß = 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 (ß = 5.72; 95% CI, 0.33-11.10; P = .03). Conclusions and Relevance: In 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-ß- and microglia-targeted therapies could have an impact on relieving these symptoms.

Effects of computerized cognitive training as add-on treatment to stimulants in ADHD: a pilot fMRI study.

The neurofunctional effects of Cognitive training (CT) are poorly understood. Our main objective was to assess fMRI brain activation patterns in children with ADHD who received CT as an add-on treatment to stimulant medication. We included twenty children with ADHD from a clinical trial of stimulant medication and CT (10 in medication + CT and 10 in medication + non-active training). Between-group differences were assessed in performance and in brain activation during 3 fMRI paradigms of working memory (N-back: 0-back, 1-back, 2-back, 3-back), sustained attention (Sustained Attention Task - SAT: 2 s, 5 s and 8 s delays) and inhibitory control (Go/No-Go). We found significant group x time x condition interactions in working memory (WM) and sustained attention on brain activation. In N-back, decreases were observed in the BOLD signal change from baseline to endpoint with increasing WM load in the right insula, right putamen, left thalamus and left pallidum in the CT compared to the non-active group; in SAT - increases in the BOLD signal change from baseline to endpoint with increasing delays were observed in bilateral precuneus, right insula, bilateral associative visual cortex and angular gyrus, right middle temporal, precentral, postcentral, superior frontal and middle frontal gyri in the CT compared to the non-active group. CT in ADHD was associated with changes in activation in task-relevant parietal and striato-limbic regions of sustained attention and working memory. Changes in brain activity may precede behavioral performance modifications in working memory and sustained attention, but not in inhibitory control.