Assessment of Plasma and Cerebrospinal Fluid Biomarkers in Different Stages of Alzheimer's Disease and Frontotemporal Dementia.

Alzheimer's disease (AD) is the primary type of dementia, followed by frontotemporal lobar degeneration (FTLD). They share some clinical characteristics, mainly at the early stages. So, the identification of early, specific, and minimally invasive biomarkers is required. In this study, some plasma biomarkers (Amyloid ß42, p-Tau181, t-Tau, neurofilament light (NfL), TAR DNA-binding protein 43 (TDP-43)) were determined by single molecule array technology (SIMOA®) in control subjects (n = 22), mild cognitive impairment due to AD (MCI-AD, n = 33), mild dementia due to AD (n = 12), and FTLD (n = 11) patients. The correlations between plasma and cerebrospinal fluid (CSF) levels and the accuracy of plasma biomarkers for AD early diagnosis and discriminating from FTLD were analyzed. As result, plasma p-Tau181 and NfL levels correlated with the corresponding CSF levels. Additionally, plasma p-Tau181 showed good accuracy for distinguishing between the controls and AD, as well as discriminating between AD and FTLD. Moreover, plasma NfL could discriminate dementia-AD vs. controls, FTLD vs. controls, and MCI-AD vs. dementia-AD. Therefore, the determination of these biomarkers in plasma is potentially helpful in AD spectrum diagnosis, but also discriminating from FTLD. In addition, the accessibility of these potential early and specific biomarkers may be useful for AD screening protocols in the future.

Early Alzheimer's Disease Screening Approach Using Plasma Biomarkers.

Alzheimer's disease (AD) is the most prevalent dementia, but it shows similar initial symptoms to other neurocognitive diseases (Lewy body disease (LBD) and frontotemporal dementia (FTD)). Thus, the identification of reliable AD plasma biomarkers is required. The aim of this work is to evaluate the use of a few plasma biomarkers to develop an early and specific AD screening method. Plasma p-Tau181, neurofilament light (NfL), and glial fibrillary acid protein (GFAP) were determined by Single Molecule Assay (SIMOA® Quanterix, Billerica, MA, USA) in patients with mild cognitive impairment due to AD (MCI-AD, n = 50), AD dementia (n = 10), FTD (n = 20), LBD (n = 5), and subjective cognitive impairment (SCI (n = 21)). Plasma p-Tau181 and GFAP showed the highest levels in AD dementia, and significant correlations with clinical AD characteristics; meanwhile, NfL showed the highest levels in FTD, but no significant correlations with AD. The partial least squares (PLS) diagnosis model developed between the AD and SCI groups showed good accuracy with a receiver operating characteristic (ROC) area under curve (AUC) of 0.935 (CI 95% 0.87-0.98), sensitivity of 86%, and specificity of 88%. In a first screen, NfL plasma levels could identify FTD patients among subjects with cognitive impairment. Then, the developed PLS model including p-Tau181 and GFAP levels could identify AD patients, constituting a simple, early, and specific diagnosis approach.

Plasma lipidomics in early APP/PS1 female mouse model and its relationship with brain: Is it affected by the estrous cycle?

BACKGROUND: Alzheimer's disease (AD) is the most prevalent dementia, showing higher incidence in women. Besides, lipids play an essential role in brain, and they could be dysregulated in neurodegeneration. Specifically, impaired plasma lipid levels could predict early AD diagnosis. This work aims to identify the main plasma lipids altered in early AD female mouse model and evaluate their relationship with brain lipidome. Also, the possible involvement of the estrous cycle in lipid metabolism has been evaluated. METHODS: Plasma samples of wild-type (n = 10) and APP/PS1 (n = 10) female mice of 5 months of age were collected, processed, and analysed using a lipidomic mass spectrometry-based method. A statistical analysis involving univariate and multivariate approaches was performed to identify significant lipid differences related to AD between groups. Also, cytology tests were conducted to confirm estrous cycle phases. RESULTS: Three hundred thirty lipids were detected in plasma, 18 of them showed significant differences between groups; specifically, some triacylglycerols, cholesteryl esters, lysophosphatidylcholines, phosphatidylcholines, and ether-linked phosphatidylcholines, increased in early AD; while other phosphatidylcholines, phosphatidylethanolamines, ceramides, and ether-linked phosphatidylethanolamines decreased in early AD. A multivariate approach was developed from some lipid variables, showing high diagnostic indexes (70% sensitivity, 90% specificity, 80% accuracy). From brain and plasma lipidome, some significant correlations were observed, mainly in the glycerophospholipid family. Also, some differences were found in both plasma and brain lipids, according to the estrous cycle phase. CONCLUSIONS: Therefore, lipid alterations can be identified in plasma at early AD stages in mice females, with a relationship with brain lipid metabolism for most of the lipid subfamilies, suggesting some lipids as potential AD biomarkers. In addition, the estrous cycle monitoring could be relevant in female studies.

Brain areas lipidomics in female transgenic mouse model of Alzheimer's disease.

Lipids are the major component of the brain with important structural and functional properties. Lipid disruption could play a relevant role in Alzheimer's disease (AD). Some brain lipidomic studies showed significant differences compared to controls, but few studies have focused on different brain areas related to AD. Furthermore, AD is more prevalent in females, but there is a lack of studies focusing on this sex. This work aims to perform a lipidomic study in selected brain areas (cerebellum, amygdala, hippocampus, entire cortex) from wild-type (WT, n = 10) and APPswe/PS1dE9 transgenic (TG, n = 10) female mice of 5 months of age, as a model of early AD, to identify alterations in lipid composition. A lipidomic mass spectrometry-based method was optimized and applied to brain tissue. As result, some lipids showed statistically significant differences between mice groups in cerebellum (n = 68), amygdala (n = 49), hippocampus (n = 48), and the cortex (n = 22). In addition, some lipids (n = 15) from the glycerolipid, phospholipid, and sphingolipid families were statistically significant in several brain areas simultaneously between WT and TG. A selection of lipid variables was made to develop a multivariate approach to assess their discriminant potential, showing high diagnostic indexes, especially in cerebellum and amygdala (sensitivity 70-100%, sensibility 80-100%).

Systematic review of brain and blood lipidomics in Alzheimer's disease mouse models.

Alzheimer's disease (AD) diagnosis is based on invasive and expensive biomarkers. Regarding AD pathophysiological mechanisms, there is evidence of a link between AD and aberrant lipid homeostasis. Alterations in lipid composition have been observed in blood and brain samples, and transgenic mouse models represent a promising approach. Nevertheless, there is great variability among studies in mice for the determination of different types of lipids in targeted and untargeted methods. It could be explained by the different variables (model, age, sex, analytical technique), and experimental conditions used. The aim of this work is to review the studies on lipid alteration in brain tissue and blood samples from AD mouse models, focusing on different experimental parameters. As result, great disparity has been observed among the reviewed studies. Brain studies showed an increase in gangliosides, sphingomyelins, lysophospholipids and monounsaturated fatty acids and a decrease in sulfatides. In contrast, blood studies showed an increase in phosphoglycerides, sterols, diacylglycerols, triacylglycerols and polyunsaturated fatty acids, and a decrease in phospholipids, lysophospholipids and monounsaturated fatty acids. Thus, lipids are closely related to AD, and a consensus on lipidomics studies could be used as a diagnostic tool and providing insight into the mechanisms involved in AD.

Assessment of Lipid Peroxidation in Alzheimer's Disease Differential Diagnosis and Prognosis.

Alzheimer's disease (AD) and other dementias are becoming increasingly common in the older population, and the number of people affected is expected to increase in a few years. Nowadays, biomarkers used in early AD diagnosis are expensive and invasive. Therefore, this research field is growing. In fact, peroxidation by-products derived from the oxidation of brain lipids (arachidonic (AA), docosahexanoic (DHA) and adrenic acid (AdA)) could be potential biomarkers, participating in the mechanisms of inflammation, neurotoxicity and cell death in AD pathology. Previous studies have shown specificity between lipid peroxidation compounds and other dementias (e.g., Lewy bodies (DLB), frontotemporal dementia (FTD)), but more research is required. Lipid peroxidation compounds (prostaglandins, isoprostanes, isofurans, neuroprostanes, neurofurans, dihomo-isoprostanes and dihomo-isofurans) were analysed by liquid chromatography and mass spectrometry in plasma samples from participants classified into a healthy group (n = 80), a mild cognitive impairment due to AD group (n = 106), a mild dementia due to AD group (n = 70), an advanced dementia due to AD group (n = 11) and a group of other non-AD dementias (n = 20). Most of these compounds showed statistically significant differences between groups (p < 0.05), showing higher levels for the healthy and non-AD groups than the AD groups. Then, a multivariate analysis was carried out on these compounds, showing good diagnosis indexes (AUC 0.77, sensitivity 81.3%, positive predictive value 81%). Moreover, evaluating AD disease prognosis, two compounds (15-F2t-IsoP and 14(RS)-14-F4t-NeuroP) and three total parameters (isoprostanes, isofurans and neurofurans) showed significant differences among groups. Some compounds derived from the oxidation of AA, DHA and AdA have demonstrated their potential use in differential AD diagnosis. Specifically, 15-F2t-IsoP, 14(RS)-14-F4t-NeuroP and the total parameters for isoprostanes, isofurans and neurofurans have shown prognostic value for AD from its earliest stages to its most severe form.

Plasma microRNAs as potential biomarkers in early Alzheimer disease expression.

The microRNAs (miRNAs) are potential biomarkers for complex pathologies due to their involvement in the regulation of several pathways. Alzheimer Disease (AD) requires new biomarkers in minimally invasive samples that allow an early diagnosis. The aim of this work is to study miRNAS as potential AD biomarkers and their role in the pathology development. In this study, participants (n = 46) were classified into mild cognitive impairment due to AD (MCI-AD, n = 19), preclinical AD (n = 8) and healthy elderly controls (n = 19), according to CSF biomarkers levels (amyloid ß42, total tau, phosphorylated tau) and neuropsychological assessment. Then, plasma miRNAomic expression profiles were analysed by Next Generation Sequencing. Finally, the selected miRNAs were validated by quantitative PCR (q-PCR). A panel of 11 miRNAs was selected from omics expression analysis, and 8 of them were validated by q-PCR. Individually, they did not show statistically significant differences among participant groups. However, a multivariate model including these 8 miRNAs revealed a potential association with AD for three of them. Specifically, relatively lower expression levels of miR-92a-3p and miR-486-5p are observed in AD patients, and relatively higher levels of miR-29a-3p are observed in AD patients. These biomarkers could be involved in the regulation of pathways such as synaptic transmission, structural functions, cell signalling and metabolism or transcription regulation. Some plasma miRNAs (miRNA-92a-3p, miRNA-486-5p, miRNA-29a-3p) are slightly dysregulated in AD, being potential biomarkers of the pathology. However, more studies with a large sample size should be carried out to verify these results, as well as to further investigate the mechanisms of action of these miRNAs.

Assessment of Screening Approach in Early and Differential Alzheimer's Disease Diagnosis.

BACKGROUND: Alzheimer's disease (AD) is the leading cause of dementia in the elderly population. Currently, diagnosis is based on invasive and expensive techniques, so there is a growing need to look for other possible tests, as well as carry out clinical validation. Studies from the literature showed potential diagnosis models, including some AD risk factors (age, gender, ApoE-ε4 genotype) and other variables (biomarkers levels, neuroimaging). Specifically, a recent model was performed from lipid peroxidation compounds in plasma samples to identify patients with early AD. However, there is a lack of studies about clinical validation of these preliminary diagnosis models. METHODS: Plasma samples from participants classified into AD (n = 61), non-AD (n = 17), and healthy (n = 44) were analyzed. In fact, lipid peroxidation compounds were determined by liquid chromatography and mass spectrometry. Then, a previously developed diagnosis model was clinically validated, evaluating some diagnosis indexes. RESULTS: The validation of the preliminary diagnosis model showed satisfactory diagnosis indexes (accuracy 77%, sensitivity 89%, specificity 61%, diagnostic odds ratio 12.5, positive predictive value 76%). Next, a useful screening tool, including the ApoE genotype, was developed, identifying patients with a higher risk of developing AD and improving the corresponding diagnosis indexes (accuracy 82%, sensitivity 81%, specificity 85%, diagnostic odds ratio 23.2, positive predictive value 90.5%). CONCLUSION: A new screening approach could improve the early, minimally invasive, and differential AD diagnosis in the general population.