Relationship between Plasma Lipid Profile and Cognitive Status in Early Alzheimer Disease.

Alzheimer disease (AD) is a heterogeneous and complex disease in which different pathophysiological mechanisms are involved. This heterogenicity can be reflected in different atrophy patterns or clinical manifestations. Regarding biochemical pathways involved in early AD, lipid metabolism plays an important role; therefore, lipid levels have been evaluated as potential AD diagnosis biomarkers, and their levels could be related to different AD clinical manifestations. Therefore, the aim of this work is to study AD lipid profiles from early AD patients and evaluate their clinical significance. For this purpose, untargeted plasma lipidomic analysis was carried out in early AD patients (n = 31) diagnosed with cerebrospinal fluid (CSF) biomarkers. Cluster analysis was carried out to define early AD subgroups according to the lipid levels. Then, the clinical significance of each lipid profile subgroup was studied, analyzing differences for other variables (cognitive status, CSF biomarkers, medication, comorbidities, age, and gender). The cluster analysis revealed two different groups of AD patients. Cluster 1 showed higher levels of plasma lipids and better cognitive status than Cluster 2. However, no differences were found for the other variables (age, gender, medication, comorbidities, cholesterol, and triglycerides levels) between both groups. Plasma lipid levels could differentiate two early AD subgroups, which showed different cognitive statuses. However, further research with a large cohort and longitudinal study evaluating the clinical evolution of these patients is required. In general, it would involve a relevant advance in the knowledge of AD pathological mechanisms, potential treatments, and precision medicine.

New approach for early and specific Alzheimer disease diagnosis from different plasma biomarkers.

BACKGROUND: Alzheimer Disease (AD) is a complex pathology, in which several biochemical pathways could be involved. Therefore, the development of clinical studies combining different nature biomarkers in an AD diagnosis approach is required. Specifically, the present study evaluated blood biomarkers from different molecular pathways (epigenomics, lipid metabolism, lipid peroxidation), to obtain an early and specific AD diagnosis approach. METHODS: The participants were classified into early AD (n = 53), and non-AD (healthy controls, other dementias) (n = 83). Blood samples were collected and biochemical determinations (microRNAs, lipids, lipid peroxidation compounds) were carried out by quantitative PCR and liquid chromatography coupled to mass spectrometry, respectively. Then, a logistic regression model with a Bayesian variable selection procedure was developed. RESULTS: The Bayesian variable selection procedure for microRNAs did not show any relevant variable. Therefore, microRNA biomarkers were excluded. So, the developed model considered only lipids and lipid peroxidation compounds. The corresponding selected variables were age, 18:0 LPC, PGE2, isoprostanes and, isofurans. The validated model (by leave-one-out cross-validation) provided satisfactory diagnosis indexes (AUC 0.83, Sensitivity 87 %, Specificity 79 %). CONCLUSION: The developed model included biomarkers from different pathways (lipid metabolism, oxidative stress), achieving a promising approach to early, specific and, minimally invasive AD diagnosis. Nevertheless, further work to validate clinically these preliminary results with an external cohort is required. Also, the integration of different compounds coming from several biochemical pathways could constitute a relevant research field for the development of AD therapeutic targets.

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.

Assessment of COVID-19 lockdown effect on early Alzheimer Disease progression.

INTRODUCTION: Recently, many aspects of daily life have changed due to the COVID-19 pandemic. Patients with Alzheimer Disease (AD) could be more vulnerable to those daily life changes as experts expected. Mainly, the lockdown involved reduced social contact and cognitive stimulation. So, it could affect the AD expression, increasing the patients' disabilities development. OBJECTIVE: The aim of this study is to evaluate the effect of COVID-19 lockdown on cognitive impairment progression in early AD patients. METHODOLOGY: The participants were patients with mild cognitive impairment due to AD (MCI-AD) from the Neurology Unit (La Fe Hospital), who were neuropsychologically evaluated (cognitive impairment, daily activity tests) twice over 2 years. They were classified into a case group (n = 21), evaluated before and after lockdown condition, and a control group (n = 20), evaluated entirely before the lockdown condition. RESULTS: All the participants showed increasing cognitive impairment and functional deterioration over the 2-year period of evaluation (p < 0.05). However, a faster worsening was not observed as a consequence of the COVID-19 pandemic and the lockdown condition. In fact, the statistical significance observed between the two study groups for daily life activities showed that the worsening was even lesser in the group evaluated under the lockdown condition. CONCLUSION: Medium-term effects of COVID-19 lockdown could not involve an acceleration of the cognitive decline in MCI-AD patients in a 2-year evaluation period. In addition, the least worsening observed for daily living activities in the case group was probably due to the change in routines. Therefore, the common assumption of cognitive worsening of AD progression due to the lockdown in comparison with normal disease progression was not demonstrated in this study, at least for MCI-AD cases. However, more longitudinal studies are required to evaluate long-term effects in these patients.

Misfolded alpha-synuclein detection by RT-QuIC in dementia with lewy bodies: a systematic review and meta-analysis.

Introduction: Dementia with Lewy Bodies (DLB) is the second most common cause of neurodegenerative dementia after Alzheimer's disease (AD), but the field is still lacking a specific biomarker for its core pathology: alpha synuclein (α-syn). Realtime quaking induced conversion (RT-QuIC) has recently emerged as a strong biomarker candidate to detect misfolded α-syn in DLB. However, the variability in the parameters of the technique and the heterogeneity of DLB patients make the reproducibility of the results difficult. Here, we provide an overview of the state-of-the-art research of α-syn RT-QuIC in DLB focused on: (1) the capacity of α-syn RT-QuIC to discriminate DLB from controls, Parkinson's disease (PD) and AD; (2) the capacity of α-syn RT-QuIC to identify prodromal stages of DLB; and (3) the influence of co-pathologies on α-syn RT-QuIC's performance. We also assessed the influence of different factors, such as technical conditions (e.g., temperature, pH, shaking-rest cycles), sample type, and clinical diagnosis versus autopsy confirmation. Methods: We conducted a systematic review following the PRISMA guidelines in August 2022, without any limits in publication dates. Search terms were combinations of "RT-QuIC" and "Lewy Bodies," "DLB" or "LBD". Results: Our meta-analysis shows that α-syn RT-QuIC reaches very high diagnostic performance in discriminating DLB from both controls (pooled sensitivity and specificity of 0.94 and 0.96, respectively) and AD (pooled sensitivity and specificity of 0.95 and 0.88) and is promising for prodromal phases of DLB. However, the performance of α-syn RT-QuIC to discriminate DLB from PD is currently low due to low specificity (pooled sensitivity and specificity of 0.94 and 0.11). Our analysis showed that α-syn RT-QuIC's performance is not substantially influenced by sample type or clinical diagnosis versus autopsy confirmation. Co-pathologies did not influence the performance of α-syn RT-QuIC, but the number of such studies is currently limited. We observed technical variability across published articles. However, we could not find a clear effect of technical variability on the reported results. Conclusion: There is currently enough evidence to test misfolded α-syn by RT-QuIC for clinical use. We anticipate that harmonization of protocols across centres and advances in standardization will facilitate the clinical establishment of misfolded α-syn detection by RT-QuIC.

Angiotensin II Receptor Blockers Reduce Tau/Aß42 Ratio: A Cerebrospinal Fluid Biomarkers' Case-Control Study.

(1) Background: The role of antihypertensives in Alzheimer's Disease (AD) prevention is controversial. This case-control study aims to assess whether antihypertensive medication has a protective role by studying its association with amyloid and tau abnormal levels. Furthermore, it suggests a holistic view of the involved pathways between renin-angiotensin drugs and the tau/amyloidß42 ratio (tau/Aß42 ratio); (2) Methods: The medical records of the participant patients were reviewed, with a focus on prescribed antihypertensive drugs and clinical variables, such as arterial blood pressure. The Anatomical Therapeutic Chemical classification was used to classify each drug. The patients were divided into two groups: patients with AD diagnosis (cases) and cognitively healthy patients (control); (3) Results: Age and high systolic blood pressure are associated with a higher risk of developing AD. In addition, combinations of angiotensin II receptor blockers are associated with a 30% lower t-tau/Aß42 ratio than plain angiotensin-converting enzyme inhibitor consumption; (4) Conclusions: Angiotensin II receptor blockers may play a potential role in neuroprotection and AD prevention. Likewise, several mechanisms, such as the PI3K/Akt/GSK3ß or the ACE1/AngII/AT1R axis, may link cardiovascular pathologies and AD presence, making its modulation a pivotal point in AD prevention. The present work highlights the central pathways in which antihypertensives may affect the presence of pathological amyloid and tau hyperphosphorylation.

¿Cómo evaluar la sepsis neonatal de inicio precoz? Estudio comparativo de tres estrategias de detección / How to assess early-onset neonatal sepsis? Comparison of three detection strategies

Introducción: La sepsis neonatal de inicio precoz puede causar morbimortalidad importante, sobre todo si se retrasa su identificación. La disminución de su incidencia en las últimas décadas motiva que sea importante encontrar un equilibrio entre reducir las pruebas complementarias y seguir detectando los pacientes afectos. Comparamos 3 estrategias de detección en pacientes con factores de riesgo: E1. Cribado analítico; E2. Calculadora de riesgo de sepsis neonatal; E3. Observación clínica. Pacientes y métodos: Estudio observacional retrospectivo, en recién nacidos con edad gestacional ≥34 semanas y con factores de riesgo o sintomatología compatible con sepsis neonatal de inicio precoz. Se analizaron los resultados de nuestra unidad con cribado analítico (E1) y se comparó con las otras 2 estrategias (E2 y E3) para valorar modificar nuestro protocolo. Resultados: Se incluyeron 754 pacientes cuyos factores de riesgo más frecuentes fueron la rotura prologada de membranas (35,5%) y la colonización materna por Streptococcus agalactiae (38,5%). Las E2 y E3 disminuirían la realización de analíticas (E1 56,8% de los pacientes; E2 9,9%; E3 22,4%; p<0,01), los ingresos hospitalarios (E1 11%; E2 6,9%; E3 7,9%; p<0,01) y la administración de antibioterapia (E1 8,6%; E2 6,7%; E3 6,4%; p<0,01). Trece pacientes se diagnosticaron de sepsis, las cuales se hubieran detectado con E2 y E3, salvo un paciente con bacteriemia asintomática por Enterococcusfaecalis. Ningún paciente con clínica leve y autolimitada en que no se inició antibioterapia, se diagnosticó posteriormente de sepsis. Conclusiones: La observación clínica estrecha parece una opción segura y podría disminuir la realización de pruebas complementarias, la tasa de hospitalización y el uso de antibioterapia innecesaria. Mantener una conducta expectante en pacientes con sintomatología leve y autolimitada en las primeras horas de vida parece no relacionarse con la no identificación de sepsis. (AU)

Introduction: Early-onset neonatal sepsis can cause significant morbidity and mortality, especially if it is not detected early. Given the decrease in its incidence in the past few decades, it is important to find a balance between reducing the use of diagnostic tests and continuing to detect affected patients. We compared 3 detection strategies in patients with risk factors (RFs) for infection: laboratory screening (S1), the neonatal sepsis risk calculator (S2) and clinical observation (S3). Patients and methods: Retrospective observational study in neonates born at 34 weeks or gestation or later and with RFs or symptoms compatible with early-onset neonatal sepsis. We analysed outcomes in our unit with the use of laboratory screening (S1) and compared them with the other two strategies (S2 and S3) to contemplate whether to modify our protocol. Results: The study included 754 patients, and the most frequent RFs were prolonged rupture of membranes (35.5%) and maternal colonization by Streptococcus agalactiae (38.5%). Strategies S2 and S3 would decrease the performance of laboratory tests (S1, 56.8% of patients; S2, 9.9%; S3, 22.4%; P<.01), hospital admissions (S1, 11%; S2, 6.9%; S3, 7.9%; P<.01) and the use of antibiotherapy (S1, 8.6%; S2, 6.7%; S3, 6.4%; P<.01). Sepsis was diagnosed in 13 patients, and it would have been detected with S2 and S3 except in 1 patient who had asymptomatic bacteriemia by Enterococcusfaecalis. No patient with mild and self-limited symptoms in whom antibiotherapy was not started received a diagnosis of sepsis later on. Conclusions: Close clinical observation seems to be a safe option and could reduce the use of diagnostic tests, hospital admission and unnecessary antibiotherapy. The watchful waiting approach in patients with mild and self-limiting symptoms in the first hours post birth does not appear to be associated with failure to identify sepsis. (AU)

How to assess early-onset neonatal sepsis? Comparison of three detection strategies.

INTRODUCTION: Early-onset neonatal sepsis (EONS) can cause significant morbidity and mortality, especially if it is not detected early. Given the decrease in its incidence in the past few decades, it is important to find a balance between reducing the use of diagnostic tests and continuing to detect affected patients. We compared 3 detection strategies in patients with risk factors (RFs) for infection: laboratory screening (S1), the Neonatal Sepsis Risk Calculator (S2) and clinical observation (S3). PATIENTS AND METHODS: Retrospective observational study in neonates born at 34 weeks of gestation or later and with RFs or symptoms compatible with EONS. We analysed outcomes in our unit with the use of laboratory screening (S1) and compared them with the other two strategies (S2 and S3) to contemplate whether to modify our protocol. RESULTS: The study included 754 patients, and the most frequent RFs were prolonged rupture of membranes (35.5%) and maternal colonization by Streptococcus agalactiae (38.5%). Strategies S2 and S3 would decrease the performance of laboratory tests (S1, 56.8% of patients; S2, 9.9%; S3, 22.4%; P < 0.01), hospital admissions (S1, 11%; S2, 6.9%; S3, 7.9%; P < 0.01) and the use of antibiotherapy (S1, 8.6%; S2, 6.7%; S3, 6.4%; P < 0.01). Sepsis was diagnosed in 13 patients, and it would have been detected with S2 and S3 except in 1 patient who had asymptomatic bacteriemia by Enterococcus faecalis. No patient with mild and self-limited symptoms in whom antibiotherapy was not started received a diagnosis of sepsis later on. CONCLUSION: Close clinical observation seems to be a safe option and could reduce the use of diagnostic tests, hospital admission and unnecessary antibiotherapy. The watchful waiting approach in patients with mild and self-limiting symptoms in the first hours post birth does not appear to be associated with failure to identify sepsis.

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.

Clinical usefulness of cerebrospinal fluid biomarkers in Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is a complex disease that shares clinical features with other dementias. It is important to establish a specific and reliable diagnosis. Nowadays, AD diagnosis is based on cerebrospinal fluid (CSF) biomarkers. However, the corresponding cut-offs differ amongst studies. This study aims to evaluate the CSF biomarkers in the AD differential diagnosis. METHODS: Clinical relevant biomarkers (amyloid ß42 (Aß42), t-Tau, p-Tau, amyloid ß40 (Aß40), neurofilament light chain (NfL)) were determined in CSF samples from participants classified as AD (n = 124) and non-AD (n = 148) patients from the Neurology Unit. They were included and evaluated consecutively (August 2018-October 2020). The clinical utility of these biomarkers was evaluated by AUC-ROC curves and the corresponding cut-off points were defined. RESULTS: The results showed satisfactory accuracy (AUC-ROC 0.91 for Aß42, 0.890 for t-Tau and 0.933 for p-Tau); whilst Aß40 and NfL did not show good discriminatory capacity (AUC-ROC 0.557 and 0.738, respectively). The ratios Aß42/Aß40 and t-Tau/Aß42 improved the diagnosis indices of each individual biomarker, with AUC-ROC of 0.980 and 0.971, respectively. Also, elevated levels of NfL were found in the frontotemporal dementia group compared with the other participant groups. CONCLUSIONS: The ratio Aß42/Aß40 showed the highest discriminating capacity between AD and non-AD patients and might be useful in clinical practice. Regarding NfL, it is not a specific biomarker for AD; however, it might be helpful for the differential diagnosis of frontotemporal dementia. Nevertheless, further analysis in an external cohort is required in order to validate these results.

Morfología y función del pie en pacientes con ciática. Un estudio descriptivo transversal / Morphology and function of the foot in patients with sciatica. A cross-sectional study

Objetivos: El objetivo de este trabajo es comparar las características articulares de los pies de pacientes con ciática, con las de los pies de personas sin esta patología. Pacientes y métodos: Se trata de un estudio descriptivo transversal. Se incluyeron 20 pacientes con ciática y 20 pacientes sin esta patología emparejados por edad y sexo. Se cuantificó el dolor del pie mediante la Numeric Pain Rating Scale 11 y se midió la movilidad de las articulaciones del tobillo, subastragalina, antepié, primer radio y primer dedo. Se clasificó el tipo de pie mediante el Foot Posture Index, y se cuantificó la discapacidad relacionada con el dolor del pie mediante el cuestionario Manchester Foot Pain and Disability Index. Se compararon estas variables entre los dos grupos de participantes (con ciática y sin ciática). Resultados: Se observó un menor rango de movimiento de pronación subastragalina, así como mayor dolor en el pie y mayor discapacidad relacionada con el dolor en el pie, en los participantes con ciática en comparación con los del grupo control. La extensión del hallux también fue significativamente menor en los sujetos con ciática, aunque solo en el pie izquierdo. Además, la fuerza muscular en estos pacientes fue menor que en los que no tenían ciática. Los participantes de ambos grupos presentaron valores de flexión dorsal del tobillo por debajo de la normalidad. Conclusiones: Los participantes con ciática presentaron ciertas diferencias articulares y musculares con respecto al grupo control, aunque no se puede establecer una relación causa-efecto debido al diseño del estudio (AU)

Objectives: The objective of this work is to compare the joint characteristics of the feet of patients with sciatica, with those of people without this pathology. Patients and methods: This is a cross-sectional descriptive study. Twenty patients with sciatica and 20 patients without this pathology were included. Foot pain was quantified using the Numeric Pain Rating Scale 11, and mobility of the ankle, subtalar, forefoot, first ray, and hallux joints were measured. Foot type was classified using the Foot Posture Index, and disability related to foot pain was quantified using the Manchester Foot Pain and Disability Index questionnaire. These variables were compared between the two groups (participants with and without sciatica). Results: Less subtalar pronation range of motion, as well as greater foot pain and greater foot pain-related disability, were observed in participants with sciatica compared with those in the control group. Hallux dorsalflexion was also significantly less in subjects with sciatica, although only in the left foot. Muscle strength in these patients was lower than in those without sciatica. Participants in both groups presented values of ankle dorsiflexion below normal.Conclusions: The participants with sciatica presented certain joint and muscle differences with respect to the control group, although a cause-effect relationship cannot be established due to the study design (AU)

Discordant Amyloid Status Diagnosis in Alzheimer's Disease.

INTRODUCTION: Early and accurate Alzheimer's disease (AD) diagnosis has evolved in recent years by the use of specific methods for detecting its histopathological features in concrete cases. Currently, biomarkers in cerebrospinal fluid (CSF) and imaging techniques (amyloid PET) are the most used specific methods. However, some results between both methods are discrepant. Therefore, an evaluation of these discrepant cases is required. OBJECTIVE: The aim of this work is to analyze the characteristics of cases showing discrepancies between methods for detecting amyloid pathology. METHODOLOGY: Patients from the Neurology Department of La Fe Hospital (n = 82) were diagnosed using both methods (CSF biomarkers and amyloid-PET). Statistical analyses were performed using logistic regression, and sex and age were included as covariables. Additionally, results of standard neuropsychological evaluations were taken into account in our analyses. RESULTS: The comparison between CSF biomarker (Aß42) and amyloid PET results showed that around 18% of cases were discrepant-mainly CFS-negative and PET-positive cases had CSF levels close to the cut-off point. In addition, a correlation between the episodic memory test and CSF biomarkers levels was observed. However, the same results were not obtained for other neuropsychological domains. In general, CSF- and PET-discrepant cases showed altered episodic memory in around 66% of cases, while 33% showed normal performance. CONCLUSIONS: In common clinical practice at tertiary memory centers, result discrepancies between tests of amyloid status are far more common than expected. However, episodic memory tests remain an important support method for AD diagnosis, especially in cases with discrepant results between amyloid PET and CSF biomarkers.

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.

Plasma Lipidomics Approach in Early and Specific Alzheimer's Disease Diagnosis.

BACKGROUND: The brain is rich in lipid content, so a physiopathological pathway in Alzheimer's disease (AD) could be related to lipid metabolism impairment. The study of lipid profiles in plasma samples could help in the identification of early AD changes and new potential biomarkers. METHODS: An untargeted lipidomic analysis was carried out in plasma samples from preclinical AD (n = 11), mild cognitive impairment-AD (MCI-AD) (n = 31), and healthy (n = 20) participants. Variables were identified by means of two complementary methods, and lipid families' profiles were studied. Then, a targeted analysis was carried out for some identified lipids. RESULTS: Statistically significant differences were obtained for the diglycerol (DG), lysophosphatidylethanolamine (LPE), lysophosphatidylcholine (LPC), monoglyceride (MG), and sphingomyelin (SM) families as well as for monounsaturated (MUFAs) lipids, among the participant groups. In addition, statistically significant differences in the levels of lipid families (ceramides (Cer), LPE, LPC, MG, and SM) were observed between the preclinical AD and healthy groups, while statistically significant differences in the levels of DG, MG, and PE were observed between the MCI-AD and healthy groups. In addition, 18:1 LPE showed statistically significant differences in the targeted analysis between early AD (preclinical and MCI) and healthy participants. CONCLUSION: The different plasma lipid profiles could be useful in the early and minimally invasive detection of AD. Among the lipid families, relevant results were obtained from DGs, LPEs, LPCs, MGs, and SMs. Specifically, MGs could be potentially useful in AD detection; while LPEs, LPCs, and SM seem to be more related to the preclinical stage, while DGs are more related to the MCI stage. Specifically, 18:1 LPE showed a potential utility as an AD biomarker.

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.

Novel Ultrasensitive Detection Technologies for the Identification of Early and Minimally Invasive Alzheimer's Disease Blood Biomarkers.

BACKGROUND: Single molecule array (SIMOA) and other ultrasensitive detection technologies have allowed the determination of blood-based biomarkers of Alzheimer's disease (AD) for diagnosis and monitoring, thereby opening up a promising field of research. OBJECTIVE: To review the published bibliography on plasma biomarkers in AD using new ultrasensitive techniques. METHODS: A systematic review of the PubMed database was carried out to identify reports on the use of blood-based ultrasensitive technology to identify biomarkers for AD. RESULTS: Based on this search, 86 works were included and classified according to the biomarker determined. First, plasma amyloid-ß showed satisfactory accuracy as an AD biomarker in patients with a high risk of developing dementia. Second, plasma t-Tau displayed good sensitivity in detecting different neurodegenerative diseases. Third, plasma p-Tau was highly specific for AD. Fourth, plasma NfL was highly sensitive for distinguishing between patients with neurodegenerative diseases and healthy controls. In general, the simultaneous determination of several biomarkers facilitated greater accuracy in diagnosing AD (Aß42/Aß40, p-Tau181/217). CONCLUSION: The recent development of ultrasensitive technology allows the determination of blood-based biomarkers with high sensitivity, thus facilitating the early detection of AD through the analysis of easily obtained biological samples. In short, as a result of this knowledge, pre-symptomatic and early AD diagnosis may be possible, and the recruitment process for future clinical trials could be more precise. However, further studies are necessary to standardize levels of blood-based biomarkers in the general population and thus achieve reproducible results among different laboratories.

Lipids as Early and Minimally Invasive Biomarkers for Alzheimer's Disease.

Alzheimer's disease (AD) is the most common neurodegenerative disorder worldwide. Specifically, typical late-onset AD is a sporadic form with a complex etiology that affects over 90% of patients. The current gold standard for AD diagnosis is based on the determination of amyloid status by analyzing cerebrospinal fluid samples or brain positron emission tomography. These procedures can be used widely as they have several disadvantages (expensive, invasive). As an alternative, blood metabolites have recently emerged as promising AD biomarkers. Small molecules that cross the compromised AD blood-brain barrier could be determined in plasma to improve clinical AD diagnosis at early stages through minimally invasive techniques. Specifically, lipids could play an important role in AD since the brain has a high lipid content, and they are present ubiquitously inside amyloid plaques. Therefore, a systematic review was performed with the aim of identifying blood lipid metabolites as potential early AD biomarkers. In conclusion, some lipid families (fatty acids, glycerolipids, glycerophospholipids, sphingolipids, lipid peroxidation compounds) have shown impaired levels at early AD stages. Ceramide levels were significantly higher in AD subjects, and polyunsaturated fatty acids levels were significantly lower in AD. Also, high arachidonic acid levels were found in AD patients in contrast to low sphingomyelin levels. Consequently, these lipid biomarkers could be used for minimally invasive and early AD clinical diagnosis.

Epigenomics and Lipidomics Integration in Alzheimer Disease: Pathways Involved in Early Stages.

BACKGROUND: Alzheimer Disease (AD) is the most prevalent dementia. However, the physiopathological mechanisms involved in its development are unclear. In this sense, a multi-omics approach could provide some progress. METHODS: Epigenomic and lipidomic analysis were carried out in plasma samples from patients with mild cognitive impairment (MCI) due to AD (n = 22), and healthy controls (n = 5). Then, omics integration between microRNAs (miRNAs) and lipids was performed by Sparse Partial Least Squares (s-PLS) regression and target genes for the selected miRNAs were identified. RESULTS: 25 miRNAs and 25 lipids with higher loadings in the sPLS regression were selected. Lipids from phosphatidylethanolamines (PE), lysophosphatidylcholines (LPC), ceramides, phosphatidylcholines (PC), triglycerides (TG) and several long chain fatty acids families were identified as differentially expressed in AD. Among them, several fatty acids showed strong positive correlations with miRNAs studied. In fact, these miRNAs regulated genes implied in fatty acids metabolism, as elongation of very long-chain fatty acids (ELOVL), and fatty acid desaturases (FADs). CONCLUSIONS: The lipidomic-epigenomic integration showed that several lipids and miRNAs were differentially expressed in AD, being the fatty acids mechanisms potentially involved in the disease development. However, further work about targeted analysis should be carried out in a larger cohort, in order to validate these preliminary results and study the proposed pathways in detail.

Assessment of apolipoprotein E genotype for ß-amyloid status prediction.

BACKGROUND: Apolipoprotein E (ApoE) is the major genetic risk factor for sporadic Alzheimer's Disease (AD). Some studies showed a relationship between ApoE4 genotype and the cerebrospinal fluid (CSF) biomarkers (ß-amyloid42, p-Tau, t-Tau), as well as with cognitive status. In this sense, it could be interesting to develop an approach to establish amyloid status in a minimally invasive way. METHODS: The present study assessed the ApoE genotype in different participant groups (mild cognitive impairment due to AD (MCI-AD), mild/moderate dementia due to AD, MCI not due to AD (MCI not AD), other neurological diseases, healthy participants) (n = 342). RESULTS: As expected, the ApoE4 allele was more prevalent in AD patients, characterized by impairment in CSF ß-amyloid42 levels (Aß +), than in the other groups (Aß -). In this sense, ApoE4-carrier subjects showed lower CSF levels for ß-amyloid42 and higher CSF levels for t-Tau and p-Tau. From this, a multivariate model to predict Aß status was developed by means of partial least square analysis (PLS) and predictive variables (ApoE genotype, cognitive score, sex, age). This model showed suitable AUC-ROC 0.792 (95% CI, 0.744-0.840) and predictive negative value (81.6%). CONCLUSION: ApoE genotype could be useful in detecting CSF ß-amyloid42 impairment associated with early AD development.

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.