Microglial activation, tau and amyloid deposition in TREM2 p.R47H carriers and mild cognitive impairment patients: a multi-modal/multi-tracer PET/MRI imaging study with influenza vaccine immune challenge.

BACKGROUND: Microglia are increasingly understood to play an important role in the pathogenesis of Alzheimer's disease. The rs75932628 (p.R47H) TREM2 variant is a well-established risk factor for Alzheimer's disease. TREM2 is a microglial cell surface receptor. In this multi-modal/multi-tracer PET/MRI study we investigated the effect of TREM2 p.R47H carrier status on microglial activation, tau and amyloid deposition, brain structure and cognitive profile. METHODS: We compared TREM2 p.R47H carriers (n = 8; median age = 62.3) and participants with mild cognitive impairment (n = 8; median age = 70.7). Participants underwent two [18F]DPA-714 PET/MRI scans to assess TSPO signal, indicative of microglial activation, before and after receiving the seasonal influenza vaccination, which was used as an immune stimulant. Participants also underwent [18F]florbetapir and [18F]AV1451 PET scans to assess amyloid and tau burden, respectively. Regional tau and TSPO signal were calculated for regions of interest linked to Braak stage. An additional comparison imaging healthy control group (n = 8; median age = 45.5) had a single [18F]DPA-714 PET/MRI. An expanded group of participants underwent neuropsychological testing, to determine if TREM2 status influenced clinical phenotype. RESULTS: Compared to participants with mild cognitive impairment, TREM2 carriers had lower TSPO signal in Braak II (P = 0.04) and Braak III (P = 0.046) regions, despite having a similar burden of tau and amyloid. There were trends to suggest reduced microglial activation following influenza vaccine in TREM2 carriers. Tau deposition in the Braak VI region was higher in TREM2 carriers (P = 0.04). Furthermore, compared to healthy controls TREM2 carriers had smaller caudate (P = 0.02), total brain (P = 0.049) and white matter volumes (P = 0.02); and neuropsychological assessment revealed worse ADAS-Cog13 (P = 0.03) and Delayed Matching to Sample (P = 0.007) scores. CONCLUSIONS: TREM2 p.R47H carriers had reduced levels of microglial activation in brain regions affected early in the Alzheimer's disease course and differences in brain structure and cognition. Changes in microglial response may underlie the increased Alzheimer's disease risk in TREM2 p.R47H carriers. Future therapeutic agents in Alzheimer's disease should aim to enhance protective microglial actions.

Differential Effect of Demographics, Processing Speed, and Depression on Cognitive Function in 755 Non-demented Community-dwelling Elderly Individuals.

BACKGROUND: Several factors may account for inter- and intra-individual variability in cognitive functions, including age, gender, education level, information processing speed, and mood. OBJECTIVE: To evaluate the combined contribution of demographic factors, information processing speed, and depressive symptoms to scores on several diagnostic cognitive measures that are commonly used in geriatric neuropsychological practice in Greece. METHODS: Using a cross-sectional study, we established a multivariate general linear model and analyzed the predictive role of age, gender, education, information processing speed (Trail Making Test-Part A), and depressive symptoms (Geriatric Depression Scale-15 Items) on measures of general cognitive status (Mini-Mental State Examination), verbal memory (Rey Auditory Verbal Learning Test), language (Confrontation Naming), and executive functions (Category and Phonemic Fluency, Trail Making Test-Part B) for a sample of 755 healthy, community-dwelling Greek individuals aged 50 to 90 years. RESULTS: Participant factors significantly but differentially contributed to cognitive measures. Demographic factors and information processing speed emerged as the significant predictors for the majority of the cognitive measures (Mini-Mental State Examination; Rey Auditory Verbal Learning Test; Confrontation Naming; Category and Phonemic Fluency; Trail Making Test-Part B), whereas depressive symptoms significantly predicted verbal memory and semantic fluency measures (Rey Auditory Verbal Learning Test and Category Fluency). CONCLUSIONS: Clinicians should consider participant demographics, underlying slowing of processing speed, and depressive symptoms as potential confounding factors in cognitive measures. Our findings may explain the observed inter- and intra-individual variability in cognitive functions in the elderly population.