Background The immune response in Alzheimer’s disease (AD) involves activation of microglia which may remove β-amyloid. However, overproduction of inflammatory compounds may exacerbate neural damage in Alzheimer’s disease. AD pathology accumulates years before diagnosis, yet the extent to which neuroinflammation is involved in the earliest disease stages is unknown. Objective To determine whether neuroinflammation exacerbates neural damage in preclinical AD. Methods We utilized cerebrospinal fluid (CSF) and magnetic resonance imaging collected in 192 asymptomatic late-middle-aged adults (mean age=60.98 years). Neuroinflammatory markers chitinase-3-like protein 1 (YKL-40) and monocyte chemoattractant protein-1 (MCP-1) in CSF were utilized as markers of neuroinflammation. Neural cell damage was assessed using CSF neurofilament light chain protein (NFL), CSF total tau (T-Tau), and neural microstructure assessed with diffusion tensor imaging (DTI). With regard to AD pathology, CSF Aβ42 and tau phosphorylated at threonine 181 (P-Tau181) were used as markers of amyloid and tau pathology, respectively. We hypothesized that higher YKL-40 and MCP-1 in the presence of AD pathology would be associated with higher NFL, T-Tau, and altered microstructure on DTI. Results Neuroinflammation was associated with markers of neural damage. Higher CSF YKL-40 was associated with both higher CSF NFL and T-Tau. Inflammation interacted with AD pathology, such that greater MCP-1 and lower Aβ42 was associated with altered microstructure in bilateral frontal and right temporal lobe and that greater MCP-1 and greater P-Tau181 was associated with altered microstructure in precuneus. Conclusion Inflammation may play a role in neural damage in preclinical AD.

IntroductionLittle is still known about the effects of risk factors for Alzheimer's disease (AD) on white matter microstructure in cognitively healthy adults. The purpose of this cross-sectional study was to assess the effect of two well-known risk factors for AD, parental family history and APOE4 genotype.MethodsThis study included 343 participants from the Wisconsin Registry for Alzheimer's Prevention, who underwent diffusion tensor imaging (DTI). A region of interest analysis was performed on fractional anisotropy maps, in addition to mean, radial, and axial diffusivity maps, aligned to a common template space using a diffeomorphic, tensor-based registration method. The analysis focused on brain regions known to be affected in AD including the corpus callosum, superior longitudinal fasciculus, fornix, cingulum, and uncinate fasciculus. Analyses assessed the impact of APOE4, parental family history of AD, age, and sex on white matter microstructure in late middle-aged participants (aged 47–76 years).ResultsBoth APOE4 and parental family history were associated with microstructural white matter differences. Participants with parental family history of AD had higher FA in the genu of the corpus callosum and the superior longitudinal fasciculus. We observed an interaction between family history and APOE4, where participants who were family history positive but APOE4 negative had lower axial diffusivity in the uncinate fasciculus, and participants who were both family history positive and APOE4 positive had higher axial diffusivity in this region. We also observed an interaction between APOE4 and age, whereby older participants (=65 years of age) who were APOE4 carriers, had higher MD in the superior longitudinal fasciculus and in the portion of the cingulum bundle running adjacent to the cingulate cortex, compared to non-carriers. Older participants who were APOE4 carriers also showed higher radial diffusivity in the genu compared to non-carriers. Across all participants, age had an effect on FA, MD, and axial and radial diffusivities. Sex differences were observed in FA and radial diffusivity.ConclusionAPOE4 genotype, parental family history of AD, age, and sex are all associated with microstructural white matter differences in late middle-aged adults. In participants at risk for AD, alterations in diffusion characteristics—both expected and unexpected—may represent cellular changes occurring at the earliest disease stages, but further work is needed. Higher mean, radial, and axial diffusivities were observed in participants who are more likely to be experiencing later stage preclinical pathology, including participants who were both older and carried APOE4, or who were positive for both APOE4 and parental family history of AD.

Background and purposeSleep‐disordered breathing is common in individuals with heart failure and may contribute to changes in the brain and decreased cognition. However, limited research has explored how the apnea‐hypopnea index contributes to brain structure and cognition in this population. The aims of this study were to explore how the apnea‐hypopnea index is associated with brain volume and cognition in heart failure patients.MethodsData of 28 heart failure patients (mean age = 67.93; SD = 5.78) were analyzed for this cross‐sectional observational study. We evaluated the apnea‐hypopnea index using a portable multichannel sleep‐monitoring device. All participants were scanned using 3.0 Tesla magnetic resonance imaging and neuropsychological tests. Brain volume was evaluated using a voxel‐based morphometry method with T1‐weighted images. We used multiple regressions to analyze how the apnea‐hypopnea index is associated with brain volume and cognition.ResultsWe found an inverse association between apnea‐hypopnea index scores and white matter volume (β = −0.002, p = 0.026), but not in gray matter volume (β = −0.001, p = 0.237). Higher apnea‐hypopnea index was associated with reduced regional gray and white matter volume (p < 0.001, uncorrected). Cognitive scores were not associated with the apnea‐hypopnea index (p‐values were >0.05).ConclusionFindings from this study provide exploratory evidence that higher apnea‐hypopnea index may be associated with greater brain volume reduction in heart failure patients. Future studies are needed to establish the relationship between sleep‐disordered breathing, brain volume, and cognition in heart failure samples.

Heart failure patients often manifest white matter hyperintensites on brain magnetic resonance imaging (MRI). White matter hyperintnsities have also been linked with cognitive problems in patients with heart failure. Sleep disordered breathing may contribute to structural brain changes in heart failure. The purpose of this study was to test the extent to which the apnea hypopnea index is associated with global and regional white matter hyperintensities, and is a moderating factor in the relationship between age and white matter hyperintensites. A total of 28 HF patients [mean age (SD) = 67.89 (5.8)] underwent T1-weighted and T2FLAIR MRI and a home sleep monitoring study. The apnea hypopnea index cut off of 10 was used to compare between higher and lower risks of sleep disordered breathing. Regression analysis was used to test the association between apnea hypopnea index and both global and regional white matter hyperintensities. The interaction term was entered to identify the moderation effect. Apnea hypopnea index was associated with higher regional white matter hyperintensities but not global white matter hyperintensities. There was a significant interaction between the apnea hypopnea index and age, such that older participants with the apnea hypopnea index ≥10 showed greater regional white matter hyperintensities than those with the apnea hypopnea index <10. The results of this preliminary study indicate that a higher apnea hypopnea index is associated with more white matter hyperintensities. The age-related white matter hyperintensities appear to be exacerbated by apnea hypopnea index in our individuals with heart failure. Future studies are needed to further investigate the underlying mechanisms.

issues that need to be addressed would be whether antiplatelet therapy, tighter glycemic control, other pharmacological or lifestyle modification modalities will decrease WMC associated with MES positive and MES negative patients with DM/Pre-DM, potentially having a role in preventing/slowing cognitive decline.