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.

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.

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.

Cumulative life stressors and stress response to threatened preterm labour as birth date predictors.

PURPOSE: Preterm birth represents one of the main causes of neonatal morbimortality and a risk factor for neurodevelopmental disorders. Appropriate predictive methods for preterm birth outcome, which consequently would facilitate prevention programs, are needed. We aim to predict birth date in women with a threatened preterm labour (TPL) based on stress response to TPL diagnosis, cumulative life stressors, and relevant obstetric variables. METHODS: A prospective cohort of 157 pregnant women with TPL diagnosis between 24 and 31 weeks gestation formed the study sample. To estimate the stress response to TPL, maternal salivary cortisol, α-amylase levels, along with anxiety and depression symptoms were measured. To determine cumulative life stressors, previous traumas, social support, and family functioning were registered. Then, linear regression models were used to examine the effect of potential predictors of birth date. RESULTS: Lower family adaptation, higher Body Mass Index (BMI), higher cortisol levels and TPL diagnosis week were the main predictors of birth date. Gestational week at TPL diagnosis showed a non-linear interaction with cortisol levels: TPL women with middle- and high-cortisol levels before 29 weeks of gestation went into imminent labour. CONCLUSION: A combination of stress response to TPL diagnosis (salivary cortisol) and cumulative life stressors (family adaptation) together with obstetric factors (TPL gestational week and BMI) was the best birth date predictor. Therefore, a psychosocial therapeutic intervention program aimed to increase family adaptation and decrease cortisol levels at TPL diagnosis as well as losing weight, may prevent preterm birth in symptomatic women.

Artificial Intelligence on FDG PET Images Identifies Mild Cognitive Impairment Patients with Neurodegenerative Disease.

The purpose of this project is to develop and validate a Deep Learning (DL) FDG PET imaging algorithm able to identify patients with any neurodegenerative diseases (Alzheimer's Disease (AD), Frontotemporal Degeneration (FTD) or Dementia with Lewy Bodies (DLB)) among patients with Mild Cognitive Impairment (MCI). A 3D Convolutional neural network was trained using images from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. The ADNI dataset used for the model training and testing consisted of 822 subjects (472 AD and 350 MCI). The validation was performed on an independent dataset from La Fe University and Polytechnic Hospital. This dataset contained 90 subjects with MCI, 71 of them developed a neurodegenerative disease (64 AD, 4 FTD and 3 DLB) while 19 did not associate any neurodegenerative disease. The model had 79% accuracy, 88% sensitivity and 71% specificity in the identification of patients with neurodegenerative diseases tested on the 10% ADNI dataset, achieving an area under the receiver operating characteristic curve (AUC) of 0.90. On the external validation, the model preserved 80% balanced accuracy, 75% sensitivity, 84% specificity and 0.86 AUC. This binary classifier model based on FDG PET images allows the early prediction of neurodegenerative diseases in MCI patients in standard clinical settings with an overall 80% classification balanced accuracy.

Plasma isoprostanoids assessment as Alzheimer's disease progression biomarkers.

Alzheimer's Disease (AD) is the most common neurodegenerative disease worldwide. So, there is a need to identify AD early diagnosis and monitoring biomarkers in blood samples. The aim of this study was to analyse the utility of lipid peroxidation biomarkers in AD progression evaluation. Participants (n = 19) were diagnosed with AD at early stages (Time 0, T0), and they were re-evaluated 2 years later (Time 1, T1). Plasma biomarkers from AD patients were determined at both times. Some analytes, such as dihomo-isoprostanes (17-epi-17-F2t-dihomo-IsoP, 17-F2t-dihomo-IsoP, Ent-7(RS)-7-F2t-dihomo-IsoP), and neuroprostanes (10-epi-10-F4t-NeuroP) showed very high probability of showing an increasing trend over time. Baseline values allowed to develop an affordable preliminary regression model to predict long-term cognitive status. So, some lipid peroxidation biomarkers would deserve consideration as useful progression AD biomarkers. The developed prediction model would constitute an important minimally invasive approach in AD personalized prognosis and perhaps could have some interest also in experimental treatments evaluation.

Non-invasive monitoring of saliva can be used to identify oxidative stress biomarkers in preterm and term newborn infants.

AIM: The aim of this study was to appraise the feasibility and reproducibility of applying a validated analytical method to determine salivary oxidative stress biomarkers in newborn infants. METHODS: Prospective observational single-centre study was carried out in level III neonatal intensive care unit. Eligible patients were preterm infants and healthy full-term newborn infants. Salivary samples were analysed in the chromatographic system. RESULTS: A total of 23 premature newborn infants and 13 full-term newborns were included. We analysed salivary levels of oxidative stress biomarkers for 5-F2t isoprostane, 15-E2t isoprostane, prostaglandin E2 and prostaglandin F2α. The multivariate predictive model showed a positive association between female and 5-F2t isoprostonae, and between female sex and prostglandin F2α. In addition, we found a positive association between gestational age and levels of prostaglandin E2 . Furthermore, in the premature group, we found a positive association between the inspired fraction of oxygen and levels of prostaglandin G2 . CONCLUSION: We identified and determined lipid peroxidation biomarkers in term and preterm newborn infants' saliva using specific and validated mass spectrometry technology.

Newly validated biomarkers of brain damage may shed light into the role of oxidative stress in the pathophysiology of neurocognitive impairment in dietary restricted phenylketonuria patients.

Despite a strict dietary control, patient with hyperphenylalaninemia or phenylketonuria may show cognitive and/or behavioral disorders. These comorbid deficits are of great concern to patients, families, and health organizations. However, biomarkers capable of detecting initial stages of neurological damage are not commonly employed. The pathogenesis of phenylketonuria is complex in nature. Increasingly, the role of oxidative stress has gained acceptance and biomarkers reflecting oxidative damage to the brain and easily accessible in peripheral biofluids have been validated using mass spectrometry techniques. In the present review, the role of oxidative stress in the pathogenesis of phenylketonuria and hyperphenylalaninemia has been updated. Moreover, we report on newly validated brain-specific lipid peroxidation biomarkers and inform on their relevance in the detection and monitoring of neurological damage in phenylketonuric patients. In preliminary studies, a correlation between lipid peroxidation biomarkers and neurological dysfunction in patients with PKU was reported. However, there is a need of adequately powered trials to confirm the validity of these biomarkers for early detection of brain damage, initiation of treatment, and reliably monitor evolving disease both in phenylketonuria and hyperphenylalaninemia.

Oxidative Damage of DNA as Early Marker of Alzheimer's Disease.

Alzheimer's Disease (AD) is the most common cause of dementia, and its characteristic histopathological hallmarks are neurofibrillary tangles and senile plaques. Among involved mechanisms, oxidative stress plays an important role in damaging cell components (e.g., proteins, nucleic acids). In this study, different oxidized products of proteins and DNA were determined in the urine samples from mild cognitive impairment due to AD patients (n = 53) and healthy controls (n = 27) by means of ultra-performance liquid chromatography-tandem mass spectrometry analysis. A multivariate model developed by partial least squares generated a diagnostic model for AD with an AUC-ROC (area under the curve-receiver operating characteristic) of 0.843. From the studied analytes, 8-OHdG (8-hydroxy-2'-deoxyguanosine) and the ratio 8-OHdG/2dG (2'-deoxyguanosine) were able to distinguish between AD and healthy participants, showing statistically significant differences between groups, postulating DNA oxidation as a molecular pathway involved in early AD.

Anxiety and depressive symptoms, and stress biomarkers in pregnant women after in vitro fertilization: a prospective cohort study.

STUDY QUESTION: Does in vitro fertilization (IVF) affect the course of anxiety and depressive symptoms as well as physiological stress from pregnancy to postpartum period? SUMMARY ANSWER: IVF mothers have more anxiety symptoms and higher stress biomarker levels but fewer depression symptoms than natural conception mothers at the third trimester of pregnancy, but these differences are negligible during postpartum period. WHAT IS KNOWN ALREADY: Cross-sectional studies have found an association between IVF and high stress levels during the prenatal period. There is, however, no follow-up study about the IVF effect on the mental health status from pregnancy to postpartum, adopting simultaneous measurement of self-reported symptoms and stress biomarkers. STUDY DESIGN, SIZE, DURATION: This is a prospective cohort study. A total of 243 eligible women were recruited during the third trimester of pregnancy (60 women after successful IVF and 183 who conceived naturally). The recruitment was performed during a 12-month period, and the follow-up was carried out until 3 months after delivery. PARTICIPANTS/MATERIALS, SETTING, METHODS: This study was performed in the Division of Obstetrics in a regional referral center. The State scale of the State-Trait Anxiety Inventory (STAI-S) and the Beck Depression Inventory-Sort Form (BDI/SF) were used as anxiety and depression indicators, respectively; salivary cortisol and α-amylase levels as stress biomarkers. Anxiety, depression and stress biomarkers were measured at the third trimester of pregnancy (T1), at 48 h after birth (T2) and at 3 months after birth (T3). Associations with IVF were assessed using ordinal mixed models for anxiety and depressive symptoms and linear quantile models for stress biomarkers. MAIN RESULTS AND THE ROLE OF CHANCE: Relative to natural conception mothers, IVF mothers had higher STAI-S scores at T1 (P = 0.016, odds ratio (OR) = 2.46), and this difference remained steady from T1 to T2 (P = 0.37, OR = 0.70) and from T2 to T3 (P = 0.36, OR = 0.69). In the case of depressive symptoms, the IVF group obtained lower BDI/SF scores at T1 (P < 0.001, OR = 0.192). This difference was apparently reduced from T1 to T2 (P = 0.072, OR = 2.21) and remained constant from T2 to T3 (P = 0.107, OR = 2.09). It is important to note that whereas the mean BDI/SF score was not clinically significant for any group (it was lower than the cut-off 4), the mean STAI-S score of the IVF group at T1 was so (it was higher than the cut-off 19). As for stress biomarkers, IVF mothers had higher cortisol levels at T1 (P = 0.043, Δlog(cortisol) = 0.88) compared to natural conceptions. From T1 to T2 cortisol levels of both groups increased at the relatively same rate (P = 0.81, Δlog(cortisol) = -0.16). However, the progressions tended to be different from T2 to T3, with IVF mothers exhibiting a sharp decrease in cortisol levels (P = 0.059, Δlog(cortisol) = -0.94), while natural conceptions value remained steady. In the case of α-amylase, there were no statistically significant differences between both groups at T1 (P = 0.7, Δlog(α-amylase) = -0.095). On the contrary, while IVF mothers showed sustained α-amylase levels across the time, the progression was different in the natural conception group, who showed a decrease in α-amylase levels from T1 to T2 (P = 0.049, Δlog(α-amylase) = 0.596) and a non-significant increase from T2 to T3 (P = 0.53, Δlog(α-amylase) = -0.283). LIMITATIONS REASON FOR CAUTION: Since this follow-up study has been carried out from the third trimester of pregnancy, the findings cannot be generalized to extremely preterm births. WIDER IMPLICATIONS OF THE FINDINGS: IVF women may have lower depressive symptoms for being pregnant. However, due to the potential pregnancy complications associated with IVF, they may have higher physiological stress and clinically significant anxiety at the third trimester of pregnancy but not during postpartum. Taking into account that both prenatal high maternal cortisol levels and prenatal clinically significant anxiety increase the risk of disturbance in the fetal neurodevelopment, psychological therapy should be extended during pregnancy in IVF women. STUDY FUNDING/COMPETING INTEREST(S): MV funded by FIS PI17/0131 grant from the Instituto de Salud Carlos III (ISCIII) and RETICS funded by the PN 2018-2011, and the European Regional Development Fund, reference RD16/0022/0001; AG-B funded by a 'Juan Rodés' Grant (JR17/00003) from the ISCIII. CC-P funded by a 'Miguel Servet I' Grant (CP16/00082) from the ISCIII. Authors declare no competing interests.

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.

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%).

Relationship between neuroimaging and emotion recognition in mild cognitive impairment patients.

OBJECTIVE: Dementia is a major public health problem with high needs for early detection, efficient treatment, and prognosis evaluation. Social cognition impairment could be an early dementia indicator and can be assessed with emotion recognition evaluation tests. The purpose of this study is to investigate the link between different brain imaging modalities and cognitive status in Mild Cognitive Impairment (MCI) patients, with the goal of uncovering potential physiopathological mechanisms based on social cognition performance. METHODS: The relationship between the Reading the Mind in the Eyes Test (RMET) and some clinical and biochemical variables ([18 F]FDG PET-CT and anatomical MR parameters, neuropsychological evaluation, and CSF biomarkers) was studied in 166 patients with MCI by using a correlational approach. RESULTS: The RMET correlated with neuropsychological variables, as well as with structural and functional brain parameters obtained from the MR and FDG-PET imaging evaluation. However, significant correlations between the RMET and CSF biomarkers were not found. DISCUSSION: Different neuroimaging parameters were found to be related to an emotion recognition task in MCI. This analysis identified potential minimally-invasive biomarkers providing some knowledge about the physiopathological mechanisms in MCI.

Dispersive solid-phase extraction and immunoassay with internal reference calibration using fatty acid-coated inorganic fluorescent nanoparticles.

Dispersive solid-phase extraction (dSPE) using fatty acid-coated Eu2O3 nanoparticles (NPs) was developed, and a direct immunoassay was carried out employing these NPs as support. Secondary antibodies labeled with fluorophore groups were used as reporters, and the intrinsic optical properties of the Eu2O3 NPs were employed as an internal calibration of the detection system. The methodology was optimized for both dSPE-NP amount, sample volume, extraction time, ionic strength, and pH-and immunoassay-immunoreagent concentrations, ionic strength, and incubation time. As proof of concept, the methodology was applied to the bovine serum albumin (BSA)/anti-BSA system, and precision of the method was between 5% and 17% with an IC50 of 100 nM. Then, water samples with high saline content (sea water) were assayed to observe the matrix effect, and average recoveries (n = 3) between 78% and 108% were obtained, demonstrating the reliability of the developed analytical method. Finally, the simultaneous dSPE-immunoassay methodology was applied to other compounds with very different chemical characteristics such as an oligonucleotide, the antibiotic sulfamerazine, and the pesticide chlorpyriphos. Although the IC50 values for sulfamerazine were approximately 2400 nM, satisfactory standard curves were obtained. However, poor reproducibility and sensitivity results were obtained for the oligonucleotide and chlorpyriphos preliminary assays.

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.

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.

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.

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.