Aikaterini Oikonomidi

Markers of neuroinflammation associated with Alzheimer's disease pathology in older adults

BACKGROUND In vitro and animal studies have linked neuroinflammation to Alzheimers disease (AD) pathology. Studies on markers of inflammation in subjects with mild cognitive impairment or AD dementia provided inconsistent results. We hypothesized that distinct blood and cerebrospinal fluid (CSF) inflammatory markers are associated with biomarkers of amyloid and tau pathology in older adults without cognitive impairment or with beginning cognitive decline. OBJECTIVE To identify blood-based and CSF neuroinflammation marker signatures associated with AD pathology (i.e. an AD CSF biomarker profile) and to investigate associations of inflammation markers with CSF biomarkers of amyloid, tau pathology, and neuronal injury. DESIGN/METHODS Cross-sectional analysis was performed on data from 120 older community-dwelling adults with normal cognition (n=48) or with cognitive impairment (n=72). CSF Aβ1-42, tau and p-tau181, and a panel of 37 neuroinflammatory markers in both CSF and serum were quantified. Least absolute shrinkage and selection operator (LASSO) regression was applied to determine a reference model that best predicts an AD CSF biomarker profile defined a priori as p-tau181/Aβ1-42 ratio >0.0779. It was then compared to a second model that included the inflammatory markers from either serum or CSF. In addition, the correlations between inflammatory markers and CSF Aβ1-42, tau and p-tau181 levels were assessed. RESULTS Forty-two subjects met criteria for having an AD CSF biomarker profile. The best predictive models included 8 serum or 3 CSF neuroinflammatory markers related to cytokine mediated inflammation, vascular injury, and angiogenesis. Both models improved the accuracy to predict an AD biomarker profile when compared to the reference model. In analyses separately performed in the subgroup of participants with cognitive impairment, adding the serum or the CSF neuroinflammation markers also improved the accuracy of the diagnosis of AD pathology. None of the inflammatory markers correlated with the CSF Aβ1-42 levels. Six CSF markers (IL-15, MCP-1, VEGFR-1, sICAM1, sVCAM-1, and VEGF-D) correlated with the CSF tau and p-tau181 levels, and these associations remained significant after controlling for age, sex, cognitive impairment, and APOEε4 status. CONCLUSIONS The identified serum and CSF neuroinflammation biomarker signatures improve the accuracy of classification for AD pathology in older adults. Our results suggest that inflammation, vascular injury, and angiogenesis as reflected by CSF markers are closely related to cerebral tau pathology.

Homocysteine metabolism is associated with cerebrospinal fluid levels of soluble amyloid precursor protein and amyloid beta

Disturbed homocysteine metabolism may contribute to amyloidogenesis by modulating the amyloid precursor protein (APP) production and processing. The objective of this study was to investigate the relationships between cerebral amyloid production and both blood and cerebrospinal fluid (CSF) markers of the homocysteine metabolism. We assessed CSF concentrations of soluble APPα, soluble APPβ, and amyloid β1‐42 (Aβ1‐42), as well as plasma levels of homocysteine (Hcys), total vitamin B12, and folate, and CSF concentrations of homocysteine (Hcys‐CSF), 5‐methyltetrahydrofolate (5‐MTHF), S‐adenosylmethionine (SAM), and S‐adenosylhomocysteine (SAH) in 59 subjects with normal cognition. Linear regression analyses were performed to assess associations between homocysteine metabolism parameters and amyloid production. The study was approved by the Ethical Committee of the University of Bonn. After controlling for age, gender, APOEe4 status, and albumin ratio (Qalb), higher Aβ1‐42 CSF levels were associated with high Hcys and low vitamin B12 plasma levels as well as with high Hcys, high SAH, and low 5‐MTHF CSF levels. Higher CSF concentrations of sAPPα and sAPPβ were associated with high SAH levels. The results suggest that disturbed homocysteine metabolism is related to increased CSF levels of sAPP forms and Aβ1‐42, and may contribute to the accumulation of amyloid pathology in the brain.

One-carbon metabolism, cognitive impairment and CSF measures of Alzheimer pathology: Homocysteine and beyond

BackgroundHyperhomocysteinemia is a risk factor for cognitive decline and dementia, including Alzheimer disease (AD). Homocysteine (Hcy) is a sulfur-containing amino acid and metabolite of the methionine pathway. The interrelated methionine, purine, and thymidylate cycles constitute the one-carbon metabolism that plays a critical role in the synthesis of DNA, neurotransmitters, phospholipids, and myelin. In this study, we tested the hypothesis that one-carbon metabolites beyond Hcy are relevant to cognitive function and cerebrospinal fluid (CSF) measures of AD pathology in older adults.MethodsCross-sectional analysis was performed on matched CSF and plasma collected from 120 older community-dwelling adults with (n = 72) or without (n = 48) cognitive impairment. Liquid chromatography-mass spectrometry was performed to quantify one-carbon metabolites and their cofactors. Least absolute shrinkage and selection operator (LASSO) regression was initially applied to clinical and biomarker measures that generate the highest diagnostic accuracy of a priori-defined cognitive impairment (Clinical Dementia Rating-based) and AD pathology (i.e., CSF tau phosphorylated at threonine 181 [p-tau181]/β-Amyloid 1–42 peptide chain [Aβ1–42] >0.0779) to establish a reference benchmark. Two other LASSO-determined models were generated that included the one-carbon metabolites in CSF and then plasma. Correlations of CSF and plasma one-carbon metabolites with CSF amyloid and tau were explored. LASSO-determined models were stratified by apolipoprotein E (APOE) ε4 carrier status.ResultsThe diagnostic accuracy of cognitive impairment for the reference model was 80.8% and included age, years of education, Aβ1–42, tau, and p-tau181. A model including CSF cystathionine, methionine, S-adenosyl-L-homocysteine (SAH), S-adenosylmethionine (SAM), serine, cysteine, and 5-methyltetrahydrofolate (5-MTHF) improved the diagnostic accuracy to 87.4%. A second model derived from plasma included cystathionine, glycine, methionine, SAH, SAM, serine, cysteine, and Hcy and reached a diagnostic accuracy of 87.5%. CSF SAH and 5-MTHF were associated with CSF tau and p-tau181. Plasma one-carbon metabolites were able to diagnose subjects with a positive CSF profile of AD pathology in APOE ε4 carriers.ConclusionsWe observed significant improvements in the prediction of cognitive impairment by adding one-carbon metabolites. This is partially explained by associations with CSF tau and p-tau181, suggesting a role for one-carbon metabolism in the aggregation of tau and neuronal injury. These metabolites may be particularly critical in APOE ε4 carriers.

Macrophage Migration Inhibitory Factor is Associated with Biomarkers of Alzheimer’s Disease Pathology and Predicts Cognitive Decline in Mild Cognitive Impairment and Mild Dementia

BACKGROUND Macrophage migration inhibitory factor (MIF) is a pro-inflammatory protein playing a regulatory role in the immune response. First evidence from in vitro and animal studies suggests that MIF may be involved in the development of Alzheimers disease (AD) pathology. OBJECTIVE To address in older subjects (i) the relationships between AD pathology and MIF plasma and cerebrospinal fluid (CSF) levels; and (ii) to investigate whether increased MIF-related systemic and CNS inflammation is associated with clinical disease progression. METHODS CSF and plasma concentrations of MIF as well as biomarkers of amyloid, neuronal injury, and tau hyperphosphorylation (CSF Aβ1-42, tau, and ptau, respectively) were assessed in 97 subjects with MCI or mild dementia (cognitive impairment, CI) and 52 healthy volunteers with normal cognition. Clinical and neuropsychological evaluations were performed at inclusion and at follow up visits. RESULTS CSF MIF levels were higher in participants with CI with an AD CSF biomarker profile, but not in CI with a non-AD profile, compared to the healthy controls. Higher MIF CSF levels were associated with higher CSF tau and ptau and lower CSF Aβ1-42 after adjusting for potential confounders. In CI, MIF CSF independently predicted cognitive decline at a follow-up visit after controlling for potential confounders including CSF Aβ1-42 and tau levels. CONCLUSION Our study provides evidence that MIF-related inflammation is related to amyloid pathology, tau hyperphosphorylation, and neuronal injury at the early clinical stages of AD. Higher MIF CSF levels are associated with accelerated cognitive decline in MCI and mild dementia.

Plasma Proteomic Profiles of Cerebrospinal Fluid-Defined Alzheimer’s Disease Pathology in Older Adults

BACKGROUND Cerebrospinal fluid (CSF) biomarkers of the beta-amyloid and microtubule associated protein tau metabolism have proven the capacity to improve classification of subjects developing Alzheimers disease (AD). The blood plasma proteome was characterized to further elaborate upon the mechanisms involved and identify proteins that may improve classification of older adults developing an AD dementia. OBJECTIVE Identify and describe plasma protein expressions that best classify subjects with CSF-defined presence of AD pathology and cerebral amyloidosis. METHODS We performed a cross-sectional analysis of samples collected from community-dwelling elderly with (n = 72) or without (n = 48) cognitive impairment. CSF Aβ1-42, tau, and phosphorylated tau (P-tau181) were measured using ELISA, and mass spectrometry quantified the plasma proteomes. Presence of AD pathology was defined as CSF P-tau181/Aβ1-42 > 0.0779, and presence of amyloidosis was defined as CSF Aβ1-42 < 724 pg/mL. RESULTS Two hundred and forty-eight plasma proteins were quantified. Plasma proteins did not improve classification of the AD CSF biomarker profile in the whole sample. When the analysis was separately performed in the cognitively impaired individuals, the diagnosis accuracy of AD CSF profile was 88.9% with 19 plasma proteins included. Within the full cohort, there were 16 plasma proteins that improved diagnostic accuracy of cerebral amyloidosis to 92.4%. CONCLUSION Plasma proteins improved classification accuracy of AD pathology in cognitively-impaired older adults and appeared representative of amyloid pathology. If confirmed, those candidates could serve as valuable blood biomarkers of the preclinical stages of AD or risk of developing AD.

LC-HRMS data as a result of untargeted metabolomic profiling of human cerebrospinal fluid of elderly cognitively healthy subjects

Cerebrospinal fluid (CSF) is a key body fluid that maintains the homeostasis in central nervous system (CNS). As a biofluid whose content reflects the brain metabolic activity, the CSF is analyzed in the context of neurological diseases and is rarely collected from healthy subjects. For this reason, the metabolite variation associated with general phenotypic characteristics such as gender and age have hardly ever been studied. Here we present the hydrophilic interaction liquid chromatography-high resolution mass spectrometry (HILIC-HRMS) data as a result of untargeted metabolomics analysis of a cohort of elderly cognitively healthy volunteers (n = 32). 146 unambiguously identified water soluble metabolites (using accurate mass, retention time and MS/MS matching against spectral libraries) were measured and their abundances across all the subjects depending on their gender are provided in this article. Data tables are available at https://data.mendeley.com/datasets/c73xtsd4s5/1. its published on mendeley, the DOI is DOI:10.17632/c73xtsd4s5.1. The data presented in this article are related to the research article entitled “A global HILIC-MS approach to measure polar human cerebrospinal fluid metabolome: Exploring gender-associated variation in a cohort of elderly cognitively healthy subjects” (Gallart-Ayala et al., 2018, In press).

Blood-brain barrier breakdown, neuroinflammation, and cognitive decline in older adults

Blood‐brain barrier (BBB) breakdown is observed in older versus younger adults and in late‐onset Alzheimers disease versus age‐matched controls, but its causes and consequences in aging are unclear. We tested the hypothesis that BBB breakdown is associated with cognitive decline and inflammation in nondemented elders.

Alzheimer disease pathology and the cerebrospinal fluid proteome

BackgroundAltered proteome profiles have been reported in both postmortem brain tissues and body fluids of subjects with Alzheimer disease (AD), but their broad relationships with AD pathology, amyloid pathology, and tau-related neurodegeneration have not yet been fully explored. Using a robust automated MS-based proteomic biomarker discovery workflow, we measured cerebrospinal fluid (CSF) proteomes to explore their association with well-established markers of core AD pathology.MethodsCross-sectional analysis was performed on CSF collected from 120 older community-dwelling adults with normal (n = 48) or impaired cognition (n = 72). LC-MS quantified hundreds of proteins in the CSF. CSF concentrations of β-amyloid 1–42 (Aβ1–42), tau, and tau phosphorylated at threonine 181 (P-tau181) were determined with immunoassays. First, we explored proteins relevant to biomarker-defined AD. Then, correlation analysis of CSF proteins with CSF markers of amyloid pathology, neuronal injury, and tau hyperphosphorylation (i.e., Aβ1–42, tau, P-tau181) was performed using Pearson’s correlation coefficient and Bonferroni correction for multiple comparisons.ResultsWe quantified 790 proteins in CSF samples with MS. Four CSF proteins showed an association with CSF Aβ1–42 levels (p value ≤ 0.05 with correlation coefficient (R) ≥ 0.38). We identified 50 additional CSF proteins associated with CSF tau and 46 proteins associated with CSF P-tau181 (p value ≤ 0.05 with R ≥ 0.37). The majority of those proteins that showed such associations were brain-enriched proteins. Gene Ontology annotation revealed an enrichment for synaptic proteins and proteins originating from reelin-producing cells and the myelin sheath.ConclusionsWe used an MS-based proteomic workflow to profile the CSF proteome in relation to cerebral AD pathology. We report strong evidence of previously reported CSF proteins and several novel CSF proteins specifically associated with amyloid pathology or neuronal injury and tau hyperphosphorylation.

ONE-CARBON METABOLISM, COGNITIVE IMPAIRMENT AND CSF MARKERS OF ALZHEIMER PATHOLOGY: HOMOCYSTEINE AND BEYOND

was a significant relationship between the number of retinal microhemorrhages and Fazekas ratings for WMH in the CAA patients (r1⁄4.853, p<.01), and this trended towards significance when examining the area of retinal micro-hemorrhages (r1⁄4.615, p1⁄4.078). Finally, there was a relationship between area (r1⁄4-.695, p<.05) and number (r1⁄4-.573, p1⁄4.107) of retinal micro-hemorrhages and performance on measures of episodic memory in the CAA group. Conclusions:There were significantly more retinal micro-hemorrhages in a group of CAA patients than a group of healthy controls, and this relationship was moderated by blood pressure. The strong association between retinal micro-hemorrhages and cerebral WMH parallels literature indicating a progressive increase in cerebral WMH with lobar hemorrhages in CAA (Chen et al., 2006). The relationship between retinal micro-hemorrhages, cerebral WMH, and cognitive performance warrants further exploration in larger samples using longitudinal design, and retinal micro-hemorrhages merit further exploration as a potential biomarker of CAA.