Brown, Charles H.

Background: Although inflammation has been implicated in the pathogenesis of Alzheimer’s disease, the effects of systemic inflammation on brain amyloid deposition remain unclear. Objective: We examined the association of midlife and late-life systemic inflammation with late-life brain amyloid levels in a community sample of non-demented older adults from the Atherosclerosis Risk in Communities (ARIC) – PET Study. Methods: 339 non-demented participants (age: 75 [SD 5]) were recruited from the ARIC Study to undergo florbetapir PET (amyloid) imaging. Blood levels of high sensitivity C-reactive protein (CRP), a marker of systemic inflammation, were measured 22 years (Visit 2), 16 years (Visit 4), and up to 2 years before PET imaging (Visit 5). Elevated brain amyloid deposition (standardized uptake value ratio >1.2) was the primary outcome. Results: Our primary analyses found no association of midlife and late-life CRP with late-life brain amyloid levels. However, in secondary stratified analyses, we found that higher midlife (Visit 2) CRP was associated with elevated amyloid among males (OR 1.65, 95% CI: 1.13–2.42), and among white (OR 1.33, 95% CI: 1.02–1.75), but not African American, participants ( p-interactions<0.05). Among male participants, those who maintained high CRP levels (≥3 mg/L) throughout mid- and late-life were most likely to have elevated brain amyloid (OR, 8.81; 95% CI: 1.23, 62.91). Conclusions: Although our primary analysis does not support an association between systemic inflammation and brain amyloid deposition, we found evidence for sex- and race-dependent associations. However, findings from subgroup analyses should be interpreted with caution.

Objectives To examine the association between hospitalization, critical illness, and infection occurring during middle‐ and late‐life and structural brain abnormalities in older adults. Design Prospective cohort study. Setting Atherosclerosis Risk in Communities (ARIC) Study. Participants A community sample of adults who were 44 to 66 years of age at study baseline. Measurements Active surveillance of local hospitals and annual participant contact were used to gather hospitalization information (including International Classification of Diseases, Ninth Revision , codes) on all participants over a 24‐year surveillance period. Subsequently, a subset of participants underwent 3‐Tesla brain magnetic resonance imaging (MRI) to quantify total and regional brain volumes, white matter hyperintensity (WMH) volume, and white matter microstructural integrity (fractional anisotropy (FA) and mean diffusivity (MD) as measured using diffusion tensor imaging (DTI)). Results Of the 1,689 participants included (mean age at MRI 76±5), 72% were hospitalized, 14% had a major infection, and 4% had a critical illness during the surveillance period. Using covariate‐adjusted regression, hospitalization was associated with 0.12–standard deviation (SD) greater WMH volume (95% confidence interval (CI)=0.00–0.24) and poorer white matter microstructural integrity (0.17‐SD lower FA, 95% CI=–0.27 to –0.06; 0.16‐SD greater MD, 95% CI=0.07–0.25) than no hospitalization. There was a dose‐dependent relationship between number of hospitalizations, smaller brain volumes, and lower white matter integrity ( p ‐trends ≤.048). In hospitalized participants, critical illness was associated with smaller Alzheimer's disease (AD) signature region (–1.64 cm 3 , 95% CI=–3.16 to –0.12); major infection was associated with smaller AD signature region (–1.28 cm 3 , 95% CI=–2.21 to –0.35) and larger ventricular volume (3.79 cm 3 , 95% CI= 0.81–6.77). Conclusions Whereas all‐cause hospitalization was primarily associated with lower white matter integrity, critical illness and major infection were associated with smaller brain volume, particularly within regions implicated in AD.