Cerebrospinal Fluid Markers of Alzheimer’s Disease Pathology and Microglial Activation are Associated with Altered White Matter Microstructure in Asymptomatic Adults at Risk for Alzheimer’s Disease

Abstract

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.

Fungal Enolase, β-Tubulin, and Chitin Are Detected in Brain Tissue from Alzheimer’s Disease Patients

“…Chitin-like bodies have been observed in AD brains stained with the flurochrome dye calcofluor (Castellani et al, 2005). Moreover, levels of chitinase (chitotriosidase), a human enzyme synthesized by macrophages, are very high in serum and CSF from AD patients (Choi et al, 2011; Watabe-Rudolph et al, 2012; Rosen et al, 2014; Melah et al, 2015). We therefore tested for the first time specific anti-chitin antibodies to survey potential fungal structures in AD brains.…”

Association of longitudinal white matter degeneration and cerebrospinal fluid biomarkers of neurodegeneration, inflammation and Alzheimer’s disease in late-middle-aged adults

“…This is evidenced by a significant difference in YKL-40 plasma and CSF concentrations in patients with early AD compared to healthy controls, but no difference in late stage AD patients compared to healthy controls (Choi et al 2011; Antonell et al 2014). Perhaps more compellingly, biomarkers of inflammation have also proved to be useful predictors of microstructural pathology even in a group of asymptomatic late-middle-aged adults, whereby YKL-40 was associated with higher NFL and total tau in the CSF (Melah et al 2015). …”

“…Relationships between abnormal CSF biomarkers and altered brain microstructure have also been previously explored in cognitively healthy older adults cross-sectionally. For instance, studies have demonstrated relationships most commonly between DTI measures and CSF Aβ42, tau, or their ratio (Gold et al 2014; Molinuevo et al 2014; Bendlin et al 2012) but also monocyte chemoattractant protein-1 (Melah et al 2015). Currently, investigations of longitudinal relationships between CSF biomarkers and brain microstructure are much more limited.…”

Cerebrospinal Fluid and Plasma Levels of Inflammation Differentially Relate to CNS Markers of Alzheimer’s Disease Pathology and Neuronal Damage

“…In addition, inclusion criteria consisted of normal cognitive function determined by comprehensive neuropsychological evaluation and consensus review; negative history of psychiatric or neurological disease or untreated depression; and no history of head trauma. Please see prior publications for further description of this cohort[17, 24]. Participants were also required to have previously undergone lumbar puncture and blood draws for CSF and plasma assays, respectively, and were excluded from the analysis if their CSF and plasma blood draws occurred greater than 6 months apart.…”

“…Moreover, the relative contribution of CNS versus peripheral inflammation to biomarker indicators of neuronal cell damage or AD pathology remains an unresolved question. A recent study by our colleagues demonstrated an association between higher levels of a CSF marker of inflammation (YKL-40) and higher levels of CSF neurofilament light chain and total tau in an aging cohort at risk for AD[17]; while this suggests that CNS inflammation may reflect evidence of neuronal damage, it does not pinpoint whether CNS inflammation is a more robust indicator of AD biomarkers and neuronal cell damage than peripheral inflammation. Development of novel in-vivo immune biomarkers for AD may depend upon a better understanding of the relationship between immune dysfunction and AD pathogenesis, which could establish earlier detection methods and new targets for future therapeutics.…”