Levels Of CSF Research Articles

Evaluation of the effect of an amniotic membrane derived bio-nano product (LifeCell) on human endometrial cells proliferation and gene expression: An in-vitro study

ObjectiveSuccessful assisted reproductive technology (ART) requires a receptive endometrium with appropriate thickness and the presence of specific cytokines, chemokines, and growth factors. Despite advancements in ART, the success rates remain suboptimal, particularly in individuals with thin endometrium resistant to treatment. In this study, we evaluated the potential effects of LifeCell, a product of BioNano Technology, on the growth, development, and acceptance of endometrial cells. Study designWe cultured endometrial cells in a defined medium with different concentrations of LifeCell and examined cell growth, development, and the expression of genes involved in endometrial receptivity. ResultsCo-culture of primary human endometrial cells with 5 % Life cell solution significantly stimulated the endometrial cell growth, development and receptivity genes expression. The expression levels of FGF2 and CSF in the 72 h co-cultured were significantly increased compared with other groups (P < 0.01). HOXA10 and LIF significantly increased in the 72 h co-cultured compared with 24 h co-cultured and control groups but had no significant level compared with 48 h cocultured. HOXA10 significantly increased in the 48 h cocultured compared with control group. IL-6 and Hb-EGF increased in the 48 h co-cultured compared to other groups but had no significant level. VEGF increased in the treated groups compared to control but had no significant level. The expression of OPN, unlike the other genes, decreased in the treated group compared to the control, which was not significant. ConclusionsThese findings suggest that LifeCell may be a potential option for patients with treatment-resistant thin endometrium in cases of infertility.

A glycan biomarker predicts cognitive decline in amyloid- and tau-negative patients.

Early detection of Alzheimer's disease is vital for timely treatment. Existing biomarkers for Alzheimer's disease reflect amyloid- and tau-related pathology, but it is unknown whether the disease can be detected before cerebral amyloidosis is observed. N-glycosylation has been suggested as an upstream regulator of both amyloid and tau pathology, and levels of the N-glycan structure bisecting N-acetylglucosamine (GlcNAc) correlate with tau in blood and CSF already at pre-clinical stages of the disease. Therefore, we aimed to evaluate whether bisecting GlcNAc could predict future cognitive decline in patients from a memory clinic cohort, stratified by amyloid/tau status. We included 251 patients (mean age: 65.6 ± 10.6 years, 60.6% female) in the GEDOC cohort, from the Memory Clinic at Karolinska University Hospital, Stockholm, Sweden. Patients were classified as amyloid/tau positive or negative based on CSF biomarkers. Cognitive decline, measured by longitudinal Mini-Mental State Examination scores, was followed for an average of 10.7 ± 4.1 years and modelled using non-linear mixed effects models. Additionally, bisecting GlcNAc levels were measured in hippocampus and cortex with lectin-based immunohistochemistry in 10 Alzheimer's disease and control brains. We found that CSF bisecting GlcNAc levels were elevated in tau-positive individuals compared with tau-negative individuals, but not in amyloid-positive individuals compared with amyloid-negative individuals. In the whole sample, high levels of CSF bisecting GlcNAc predicted earlier cognitive decline. Strikingly, amyloid/tau stratification showed that high CSF bisecting GlcNAc levels predicted earlier cognitive decline in amyloid-negative patients (β = 2.53 ± 0.85 years, P = 0.003) and tau-negative patients (β = 2.43 ± 1.01 years, P = 0.017), but not in amyloid- or tau-positive patients. Finally, histochemical analysis of bisecting GlcNAc showed increased levels in neurons in hippocampus and cortex of Alzheimer's disease compared with control brain (fold change = 1.44-1.49, P < 0.001). In conclusion, high CSF levels of bisecting GlcNAc reflected neuronal pathology and predicted cognitive decline in amyloid- and tau-negative individuals, suggesting that abnormal glycosylation precedes cerebral amyloidosis and tau hyper-phosphorylation in Alzheimer's disease. Bisecting GlcNAc is a promising novel early biomarker for Alzheimer's disease.

Killer Function of Circulating Neutrophils in Relation to Cytokines in Uterine Myoma and Endometrial Cancer.

The study presents the killer functions of circulating neutrophils: myeloperoxidase activity, the ability to generate ROS, phagocytic activity, receptor status, NETosis, as well as the level of cytokines IL-2, IL-4, IL-6, IL-17A, and IL-18, granulocyte CSF, monocyte chemotactic protein 1, and neutrophil elastase in the serum of patients with uterine myoma and endometrial cancer (FIGO stages I-III). The phagocytic ability of neutrophils in uterine myoma was influenced by serum levels of granulocyte CSF and IL-2 in 54% of the total variance. The degranulation ability of neutrophils in endometrial cancer was determined by circulating IL-18 in 50% of the total variance. In uterine myoma, 66% of the total variance in neutrophil myeloperoxidase activity was explained by a model dependent on blood levels of IL-17A, IL-6, and IL-4. The risk of endometrial cancer increases when elevated levels of monocyte chemotactic protein 1 in circulating neutrophils are associated with reduced ability to capture particles via extracellular traps (96% probability).

Cerebrospinal fluid biomarkers at presentation associate with etiologic diagnosis and treatment responsiveness in patients with rapidly progressive dementia

AbstractBackgroundThe causes of rapidly progressive dementia are heterogeneous, including neurodegenerative, vascular, and autoimmune/inflammatory diseases. Overlap in presenting symptoms and signs, results of cognitive testing, and findings on brain imaging and other common diagnostic tests confounds the etiologic diagnosis, contributing to diagnostic delays, missed opportunities for treatment, and poorer outcomes in patients with RPD. New tools and approaches are needed to improve diagnostic accuracy, with particular emphasis on improving early recognition of patients with potentially treatable causes of RPD.MethodsEstablished and emerging biomarkers of Alzheimer disease neuropathology (Aβ42/40, p‐tau181, p‐tau231), neuroaxonal and neuronal injury (neurofilament light [NfL], VILIP‐1, total tau), neuroinflammation (YKL‐40, sTREM2, GFAP, MCP‐1), and synaptic dysfunction (SNAP‐25, neurogranin) were measured in cerebrospinal fluid obtained at presentation from 78 prospectively accrued patients with RPD due to neurodegenerative (n = 35), vascular (n = 9), and autoimmune/inflammatory (n = 34) diseases, and 72 age‐ and sex‐similar cognitively normal individuals (controls). Causes of RPD were further classified as potentially treatment‐responsive or nonresponsive, referencing the extant literature. Biomarker levels were compared across etiologic diagnoses and by treatment responsiveness, referencing control values. Analyses were adjusted for the effects of age (ANCOVA).ResultsAlzheimer disease biomarkers (low Aβ42/40 and elevated p‐tau181 and p‐tau231) were associated with neurodegenerative causes of RPD (ANCOVA, p = 0.02 p = 0.30, p = 0.15), while high NfL (p = 0.61), low VILIP‐1 (p = 0.009), and elevated markers of inflammation (sTREM2, p = 0.009; YKL‐40, p&lt;0.001) identified patients with autoimmune/inflammatory diseases (Figure). MCP‐1 levels were highest in patients with vascular causes of RPD (p = 0.08). 44 patients (56.4%) had potentially treatment‐responsive causes of RPD. Treatment responsiveness was associated with higher levels of CSF Aβ42/40 (p = 0.003), NfL (p&lt;0.001), sTREM2 (p&lt;0.001) and YKL‐40 (p&lt;0.001); and lower levels of p‐tau‐181 and p‐tau231 (p&lt;0.001, p&lt;0.001) and VILIP‐1 (p&lt;0.001).ConclusionSelected biomarkers measured in CSF at presentation associate with etiologic diagnosis and treatment responsiveness in patients with neurodegenerative, vascular, and autoimmune/inflammatory causes of RPD. Biomarker panels may be adapted to improve recognition of patients with treatment‐responsive causes of RPD early in the symptomatic course when treatments may be most effective.

57 CSF Markers of AD-Related Pathology Relate to aMCI among People with HIV

Objective:Older people with HIV (PWH) are at-risk for Alzheimer’s disease (AD) and its precursor, amnestic mild cognitive impairment (aMCI). Identifying aMCI among PWH is challenging because memory impairment is also common in HIV-associated neurocognitive disorders (HAND). The neuropathological hallmarks of aMCI/AD are amyloid-ß42 (Aß42) plaque and phosphorylated tau (p-tau) accumulation. Neurofilament light chain protein (NfL) is a marker of neuronal injury in AD and other neurodegenerative diseases. In this study, we assessed the prognostic value of the CSF AD pathology markers of lower Aß42, and higher p-tau, p-tau/Aß42 ratio, and NfL levels to identify an aMCI-like profile among older PWH and differentiating it from HAND. We assessed the relationship between aMCI and HAND diagnosis and AD biomarker levelsParticipants and Methods:Participants included 74 PWH (Mean age=48 [SD=8.5]; 87.4% male, 56.5% White) from the National NeuroAIDS Tissue Consortium (NNTC). CSF Aß42, Aß40, p-tau and NfL were measured by commercial immunoassay. Participants completed a neurocognitive evaluation assessing the domains of learning, recall, executive function, speed of information processing, working memory, verbal fluency, and motor. Memory domains were assessed with the Hopkins Verbal Learning Test-Revised and the Brief Visuospatial Memory Test-Revised, and aMCI was defined as impairment (&lt;1.0 SD below normative mean) on two or more memory outcomes among HVLT-R and BVMT-R learning, delayed recall and recognition with at-least one recognition impairment required. HAND was defined as impairment (&lt;1.0 SD below normative mean) in 2 or more cognitive domains. A series of separate linear regression models were used to examine how the levels of CSF p-tau, Aß42, p-tau/Aß42 ratio, and NfL relate to aMCI and HAND status while controlling for demographic variables (age, gender, race and education). Covariates were excluded from the model if they did not reach statistical significance.Results:58% percent of participants were diagnosed with HAND, 50.5% were diagnosed with aMCI. PWH with aMCI had higher levels of CSF p-tau/Aß42 ratio compared to PWH without aMCI (ß=.222, SE=.001, p=.043) while controlling for age (ß=.363, p=.001). No other AD biomarker significantly differed by aMCI or HAND status.Conclusions:Our results indicate that the CSF p-tau/Aß42 ratio relates specifically to an aMCI-like profile among PWH with high rates of cognitive impairment across multiple domains in this advanced HIV disease cohort. Thus, the p-tau/Aß42 ratio may have utility in disentangling aMCI from HAND and informing the need for further diagnostic procedures and intervention. Further research is needed to fully identify, among a broader group of PWH, who is at greatest risk for aMCI/AD and whether there is increased risk for aMCI/AD among PWH as compared to those without HIV.

A systematic review of locus coeruleus degeneration detected by neuromelanin sensitive MRI technique in patients with Alzheimer’s disease

AbstractBackgroundThe locus coeruleus(LC) is a bilateral nucleus located in the dorsal pontine tegmentum and is the major source of noradrenaline(NA), which plays a key role in cognition. While cognitive decline in Alzheimer disease(AD) has primarily been related to dysfunction within the cholinergic system in the nucleus basalis, there is considerable research evidence indicating extensive LC degeneration in AD, with some suggesting that it is among the earliest pathologies. Therefore, the early vulnerability of the LC to AD is of considerable clinical significance, as this raises the possibility that changes of the LC activity may provide early detection markers for diagnosis as well as early intervention targets to delay AD progression. However, the contribution of LC degeneration to cognitive decline in the development of AD has been underappreciated due to methodological difficulties, with most evidence coming from animal and post‐mortem studies. The absence of reliable non‐invasive direct measures of the LC remains the biggest challenge. Recent research indicates that LC visibility is driven by neuromelanin content of noradrenergic neurons and the intrinsic neuromelanin‐sensitive MRI technique enables direct visualisation of the LC.MethodsA systematic search of the literature was performed on electronic databases including PubMed, Web of Science, and Embase. Human imaging studies employing neuromelanin‐sensitive MRI technique to measure LC degeneration were included in this review. Screening, data extraction, and quality assessment were undertaken following PRISMA guidelines for preferred reporting of systematic reviews.ResultsLC‐contrast ratio or LC‐signal intensity detected by the neuromelanin‐sensitive MRI were found to be significantly reduced in patient groups with Alzheimer's disease compared with the healthy control group in all included studies, with recent evidence indicating its significant association with levels of CSF amyloid.ConclusionsThe current systematic review strongly supports the use of the neuromelanin‐sensitive MRI technique to detect the LC degeneration as a biomarker for AD neuropathology. Future research are warranted to characterize how LC signals evolve at different stages of AD, which could lead to novel intervention approaches to delay or prevent cognitive decline.

Clinical utility of plasma biomarkers to identify preclinical Alzheimer’s disease in the community

AbstractBackgroundSeveral plasma biomarkers have shown good correlation with brain amyloidosis measured by CSF biomarkers and PET, but their utility to identify subjects with Alzheimer’s disease(AD) brain pathology at the community level is not well known. Neuropsychological tests might be a more accessible alternative.MethodOur aims were to assess the utility of plasma p‐tau231, plasma GFAP, and plasma NFL to identify individuals with preclinical AD, and to compare it with the utility of current neuropsychological tests for early AD detection: Preclinical Alzheimer's Cognitive Composite 5(PACC5), Spanish version of Face‐Name Memory Exam(S‐FNAME), Logical Memory Test (LMT‐WMSIII), and Free and Cued Selective Reminding Test(FCSRT). Our study population was a community‐based cohort that enrolls individuals older than 55 living in Cantabria, a region in northern Spain. Exclusion criteria include a diagnosis of dementia or other cognitive disorders. AD+ status was defined by abnormal levels of both CSF amyloid‐β1‐42/1‐40 ratio and CSF p‐tau181. General linear models were used to compare biomarker and cognitive results between AD+ subjects and the rest of the population, with age and sex as covariates. ROC curves were built to compare the utility of each test to identify AD+ cases.ResultThe total sample included 156 individuals, 30 of them AD+. AD+ subjects showed significantly higher levels of GFAP (mean difference 78.04, p&lt;0.00001) and p‐tau231 (mean difference 5.53, p 0.00040), but not NFL (mean difference 1.16, p 0.63), compared to non‐AD (table 1). After adjusting by age, sex, APOE4 carrier status, and AD status, age and sex were still independent predictors of GFAP levels, but not of p‐tau231 (table 2). FCSRT delayed recall and LMT‐WMSIII total score were significantly lower in AD+ than in non‐AD cases, but not S‐FNAME nor PACC5 (table 1). Both plasma GFAP and p‐tau231 showed an AUC of 0.75 to identify AD+ individuals (table 3, figure 1). Neuropsychological tests obtained non‐significantly smaller AUC than plasma biomarkers.ConclusionIn our community‐based population, plasma GFAP and p‐tau231 were useful to identify individuals with preclinical AD, but not plasma NFL. Although probably with a lower performance, early detection cognitive tests may also be helpful to identify AD cases in the community.

A Pragmatic, Data-Driven Method to Determine Cutoffs for CSF Biomarkers of Alzheimer Disease Based on Validation Against PET Imaging.

Background and ObjectivesTo elaborate a new algorithm to establish a standardized method to define cutoffs for CSF biomarkers of Alzheimer disease (AD) by validating the algorithm against CSF classification derived from PET imaging.MethodsLow and high levels of CSF phosphorylated tau were first identified to establish optimal cutoffs for CSF β-amyloid (Aβ) peptide biomarkers. These Aβ cutoffs were then used to determine cutoffs for CSF tau and phosphorylated tau markers. We compared this algorithm to a reference method, based on tau and amyloid PET imaging status (ADNI study), and then applied the algorithm to 10 large clinical cohorts of patients.ResultsA total of 6,922 patients with CSF biomarker data were included (mean [SD] age: 70.6 [8.5] years, 51.0% women). In the ADNI study population (n = 497), the agreement between classification based on our algorithm and the one based on amyloid/tau PET imaging was high, with Cohen's kappa coefficient between 0.87 and 0.99. Applying the algorithm to 10 large cohorts of patients (n = 6,425), the proportion of persons with AD ranged from 25.9% to 43.5%.DiscussionThe proposed novel, pragmatic method to determine CSF biomarker cutoffs for AD does not require assessment of other biomarkers or assumptions concerning the clinical diagnosis of patients. Use of this standardized algorithm is likely to reduce heterogeneity in AD classification.

Asymptomatic Survivors of Childhood Acute Lymphoblastic Leukemia Demonstrate a Biological Profile of Inflamm-Aging Early in Life.

Simple SummaryThe most common malignancy diagnosed in childhood is acute lymphoblastic leukemia (ALL). With significant advances in ALL treatment and excellent supportive care, overall survival is now up to 90%, depending on the risk group. As a result, the survivor population is growing significantly. At the same time, it is observed that survivors experience many health problems that substantially reduce their quality of life. Emerging evidence suggests that the increased susceptibility to multiple disorders related to accelerated aging in CCS may be attributed to chronic inflammation. Therefore, this study aimed to investigate whether asymptomatic survivors of ALL have a biological phenotype of accelerated cellular senescence early in life. For this purpose, a broad panel of 51 cytokines was tested. We show that survivors after ALL treatment have an inflammatory profile associated with premature cellular aging. Factors that increase the risk of immunological alterations include younger age at diagnosis, high-risk protocols, and radiation therapy.Childhood acute lymphoblastic leukemia (ALL) survivors are at higher risk of developing many late effects later in life. They experience multiple health problems that have significant public health implications, such as frailty, premature onset of lifestyle diseases, and second tumors. There is some evidence that chronic inflammation causes accelerated aging in childhood cancer survivors; however, the available data are very limited. The aim of the study was to evaluate the broad panel of cytokines among asymptomatic ALL survivors after anticancer treatment. The study included 56 subjects with a mean age of 16.11 ± 3.98 years. The commercially available Bio-Plex Pro Human Cytokine Screening 48-Plex Panel Assay and Bio-Plex TGF-β Assay were used for simultaneous determination of 48 cytokines and 3 isoforms of TGF-β. Among 51 tested cytokines, the levels of 33 were statistically significantly higher in ALL survivors than in the control group (p < 0.05). Increased levels of pro-inflammatory cytokines, including the IL-1 family (IL-1 β, IL-1Ra; p < 0.0001), IL-6 (p < 0.001), IL-17 (p < 0.001), IL-18 (p < 0.05), TNFα (p < 0.01), IFNα2 (p < 0.05), and IFNγ (p < 0.01), were found elevated in the entire study group, compared with the controls. Subjects treated previously according to the high-risk protocol had higher IL-18 levels than low- and intermediate-risk groups (p < 0.05). Elevated levels of IL-1ra, IL-6, IL-12 (p70), IL-17, LIF, M-CSF, CSF, and VEGF were found in ALL survivors treated before the age of 5, compared with subjects treated over 5 years of age (p < 0.05). Moreover, individuals who received radiotherapy presented elevated levels of both IL-18 (p < 0.05) and MIG (p < 0.05). In conclusion, we found that young asymptomatic survivors after ALL treatment demonstrated a biological profile of complex low-grade chronic inflammation.

Levodopa-induced dyskinesias in Parkinson's disease increase cerebrospinal fluid nitric oxide metabolites' levels.

Levodopa-induced dyskinesia (LID) is a common complication of Parkinson's disease (PD) therapy. Nitric oxide in the central nervous system may have a role in its pathophysiology. The present work investigates plasma and CSF levels of nitric oxide metabolites nitrite and nitrate in patients with PD, LID, and healthy control. We measured plasma and CSF nitrite and nitrate levels in patients with PD with and without LID and in healthy controls. The levels of plasma and CSF nitrite and nitrate were measured by ozone-based chemiluminescence. Sixty-seven participants were enrolled. CSF nitrite levels in patients with PD and LID were higher than in patients with PD without LID and healthy controls. CSF/plasma ratio of nitrite was higher in patients with PD and LID than in patients with PD without LID. The CSF/plasma ratio of nitrite in patients with PD and LID was higher than 1, indicating an intrathecal production of NO in patients with this motor complication. There was an increase in nitrate levels of CSF and CSF/plasma ratio of nitrate in patients with PD and LID compared to the healthy controls. Sex, age at evaluation, disease duration, and levodopa equivalent daily doses, as well as processing and storage time, did not critically influence these results. The present study demonstrated an increase in nitrite and nitrate levels in the central nervous system of patients with PD and LID. This finding strengthens the role of NO on LID pathophysiology.

Associations between psychophysiological stress responses, inflammatory markers, and CSF biomarkers in the spectrum of Alzheimer’s disease

AbstractBackgroundAlthough genetic factors associated with the aggregation of misfolded proteins clearly play a role in Alzheimer’s disease (AD), several individual difference factors have been seen to confer an increased risk for the clinical manifestation of AD as well as the development of AD pathology. One of the key factors is an individual’s susceptibility to psychological stress. The goal of this study was to examine the relationships between psychophysiological stress responses measured by plasma stress hormones and neuropsychiatric symptoms, inflammatory markers, and AD pathology along the spectrum of AD.MethodAlzheimer’s Disease Neuroimaging Initiative (ADNI) consists of 819 adult subjects— 229 cognitively normal older adults (CNs), 398 participants with mild cognitive impairment (MCIs), and 192 patients with AD. Of these subjects, we included 58 CNs, 396 MCIs, and 112 AD patients whose plasma stress measures were available. Plasma cortisol and cytokines and CSF Aβ1‐42, t‐tau, and p‐tau181 data were downloaded from ADNI. Neuropsychiatric Inventory (NPI‐Q) total scores were used to indicate a psychological stress level.ResultAD stages were significantly related to the level of plasma cortisol and NPI‐Q total scores showing that AD patients exhibit the highest level of cortisol and greater severity of psychological symptoms followed by MCIs and CNs. AD stages were also significantly related to the level of inflammatory markers measured by cytokines, although the level of inflammatory markers in relation to the diagnostic groups varied across different types of cytokines. Plasma cortisol levels did not relate to concurrent levels of CSF Aβ1‐42 either across diagnostic groups or within diagnostic groups. Higher plasma cortisol, however, corresponded to higher CSF p‐tau among CNs, but not in MCIs and ADs.ConclusionPsychophysiological stress responses and inflammatory markers are significantly associated with the disease severity. A positive relationship between plasma cortisol level and CSF p‐tau in CNs may indicate a role of individuals’ susceptibility to stress in neuronal hyperexcitability in the early stage of AD and confer a risk of neurodegeneration and the development of AD. Alleviating stress and regulating stress responses may be important modifiable factors that help prevent AD.

Associations between longitudinal neuropsychiatric symptoms and biomarkers of beta‐amyloid, tau, neurodegeneration, and cognitive decline

AbstractBackgroundA better understanding of drivers behind neuropsychiatric symptoms (NPS) in neurocognitive diseases, such as Alzheimer’s disease, can potentially guide drug development. Cross‐sectional studies have related apathy, depression and anxiety to beta‐amyloid‐ (Aβ) and tau‐pathology, neurodegeneration as well as cognitive deficits already at preclinical stages. However, longitudinal studies are scarce and often small. We investigated effects of neuropathology and cognition on the longitudinal trajectories of NPS in a large group of cognitively unimpaired subjects (CU).MethodThe sample originated from the Swedish BioFINDER study. CU subjects with at least one NPS assessment during the biennial follow‐up of maximum 8 years were included (n=356). The Apathy Evaluation Scale (AES) and the Hospital Depression and Anxiety Scale (HADS) assessed apathy as well as anxious and depressive symptoms, respectively. The Mini Mental State Examination (MMSE) and a modified Preclinical Alzheimer Cognitive Composite (mPACC) measured cognition longitudinally. Plasma P‐tau217, CSF Aβ42/Aβ40 ratio and CSF neurofilament light (NfL) were quantified at baseline using immunoassays. Magnetic Resonance Imaging quantified white matter lesions (WML). Subject‐specific cognitive change per year (slope) was obtained by linear regression models. Linear mixed effect models were used to test associations between longitudinal NPS and other measures (including longitudinal cognition).ResultsSubjects with lower levels of CSF Aβ42/40 (β=‐0.060, p=0.01) or higher plasma P‐tau217 (β=0.253, p=0.015) at study start demonstrated accelerated levels of apathy over time. On a trend level, a high load of WML predicted over time high levels of apathy (β=0.183, p=0.053). Increased levels of longitudinal anxiety were predicted by the interaction between time and lower CSF Aβ42/40 (β=‐0.283, p=0.005) or higher CSF NfL (β=0.054, p=0.024). Furthermore, more rapid decline in mPACC was associated with more rapid progression of apathy (β=‐0.478, p=&lt;0.001) and anxiety (β=‐0.066, p=&lt;0.023). Similar results were obtained for longitudinal associations between MMSE and apathy (β=‐0.673, p=&lt;0.001).ConclusionThese results suggests that the longitudinal trajectories of apathy and anxiety already in CU subjects are related to key hallmarks of Alzheimer´s disease, including Aβ‐ or tau‐pathology at baseline, and further are parallel with cognitive decline over time.

Comparison of plasma and CSF biomarkers across ethnoracial groups in ADNI

AbstractBackgroundDifferences in CSF and plasma Alzheimer’s disease biomarkers between African Americans (AA), Latinos (LA), and non‐Hispanic Whites (NHW) have been reported. The Alzheimer’s Disease Neuroimaging Initiative (ADNI) may offer insights into ethnoracial biomarker differences important for understanding disease trajectory variations among diverse populations.MethodWe queried the ADNI database for all participants with available plasma pTau181 and NfL (Simoa) and linked CSF biomarkers within 1 year of blood draw (Aβ42, pTau181, T‐tau, Elecsys). Baseline data for 47 AA and 43 LA with plasma biomarkers were matched to separate groups of NHW (1:3 nearest neighbor matching on propensity score), considering age, sex, education, CDR, APOE ε4 alleles and family history of dementia (Table 1). Cross‐sectional analyses compared biomarker levels between matched cohorts without (non‐parametric Mann‐Whitney U‐test) and with adjustment for demographics, clinical, biomarker, and medical characteristics (multi‐linear regression). Statistical threshold was set at two‐tailed p&lt;0.05.ResultUnadjusted comparisons between AA and NHW revealed no significant differences in plasma NfL [29.3 (IQR: 21.6‐42.5) vs 35.5 (27.0‐49.6), p=.12], plasma pTau181 [14.5 (9.4‐22.9) vs 15.5 (10.1‐22.8), p=.83], CSF Aβ42 [933.1 (649.5‐1590.8) vs 926.7 (677.7‐1697.8), p=.83], CSF T‐tau [214.6 (152.4‐290.7) vs 251.9 (194.5‐351.4), p=.17] or CSF pTau181 [19.6 (14.4‐27.3) vs 22.7 (17.0‐33.3), p=.32] (Fig. 1a‐b). No significant differences were identified in any of the biomarkers after adjustment for relevant covariates. Unadjusted comparisons between LA and NHW revealed no significant differences in plasma NfL [36.7 (24.4‐50.4) vs 35.6 (25.6‐47.1), p=1], plasma pTau181 [18.0 (11.3‐25.0) vs 15.7 (10.9‐23.4), p=.81], or CSF Aβ42 [852.7 (787.1‐1213.0) vs 951.6 (651.1‐1530.5), p=1]. A trend towards lower CSF T‐Tau [216.5 (147.1‐270.5) vs 257.2 (197.2‐360.9), p=.076] and CSF pTau181 [19.4 (13.6‐27.9) vs 24.7 (17.5‐33.4), p=.076] in LA was observed (Fig. 2a‐b). After adjustment for covariates, LA were found to have significantly lower levels of CSF T‐tau (β=0.154, p&lt;.05) and CSF pTau181 (β=0.164, p&lt;.05), while differences in plasma markers were not significant.ConclusionNo significant biomarker differences between AA and NHW were observed. Lower CSF pTau181 and CSF T‐Tau in LA compared to NHW after covariate adjustment may represent subtle differences driven by biological factors or unmeasured sociocultural determinants (income, occupation, neighborhood environment); larger studies are needed.

Minimal detection of cerebrospinal fluid escape after initiation of antiretroviral therapy in acute HIV-1 infection.

Despite suppression of HIV-1 replication in the periphery by antiretroviral therapy (ART), up to 10% of treated individuals have quantifiable HIV-1 in the CSF, termed CSF escape. CSF escape may be asymptomatic but has also been linked to progressive neurological disease, and may indicate persistence of HIV in the central nervous system (CNS). CSF escape has not yet been assessed after initiation of ART during acute HIV-1 infection (AHI). Prospective cohort study. Major voluntary counseling and testing site in Bangkok, Thailand. Participants identified and initiated on ART during AHI who received an optional study lumbar puncture at pre-ART baseline or after 24 or 96 weeks of ART. Paired levels of CSF and plasma HIV-1 RNA, with CSF greater than plasma HIV-1 RNA defined as CSF escape. Two hundred and four participants had paired blood and CSF sampling in at least one visit at baseline, week 24, or week 96. Twenty-nine participants had CSF sampling at all three visits. CSF escape was detected in 1/90 at week 24 (CSF HIV-1 RNA 2.50 log10 copies/ml, plasma HIV-1 RNA <50 copies/ml), and 0/55 at week 96. Although levels of CSF HIV-1 RNA in untreated AHI are high, initiating treatment during AHI results in a very low rate of CSF escape in the first 2 years of treatment. Early treatment may improve control of HIV-1 within the CNS compared with treatment during chronic infection, which may have implications for long-term neurological outcomes and CNS HIV-1 persistence.

Gait disturbances are associated with increased CSF tau levels in a memory clinic cohort

AbstractBackgroundGait analysis with accelerometers is a relatively inexpensive and easy to use method to potentially support clinical diagnoses of Alzheimer’s Disease and other dementias. It is not clear however, which gait features are most informative and how these measures relate to Alzheimer pathology. In this study, we used in‐depth evaluation of gait in cognitively normal (CN) subjects, Mild Cognitive Impairment (MCI) patients, and dementia patients. We evaluated the associations between dynamics of gait, level of cognitive impairment and CSF biomarkers of Alzheimer’s pathology.MethodWe included CN participants (n=58), MCI patients (n=58) and participants with different types of dementia (n=26) of the multicenter PredictND cohort. Participants performed gait tests in two conditions: a normal walk task and a cognitively complex dual task. Gait was measured using tri‐axial accelerometers attached to the fifth lumbar vertebra (L5). Following principal component analysis, calculated gait features were clustered into four domains: pace, rhythm, time variability and length variability. Associations between gait domains, clinical diagnosis and CSF biomarkers (Aβ42, total tau, pTau) were examined using linear mixed models, included an interaction term with condition (normal and dual walk task) and were corrected for age, sex and center.ResultDementia patients showed gait disturbances in the pace domain ((p&lt;0.05), Figure 1, first row), meaning that dementia patients walk slower and with a smaller step length compared to CN and MCI participants. Rhythm disturbances were associated with increased levels of CSF (p)tau in the dual task (Figure 1, third and fourth row). No associations were found with CSF Aβ42 levels in any gait domain (Figure 1, second row).ConclusionThese findings suggest that gait disturbances increase with level of syndrome diagnosis. Moreover, rhythm disturbances increase with higher levels of CSF total tau and pTau, providing evidence for a direct link with neurodegeneration. These results demonstrate that in‐depth gait analysis with accelerometers might be a potential helpful tool to support clinical diagnosis or can be used as clinical outcome tool in clinical trials.

Astragalus polysaccharides mediate the immune response and intestinal microbiota in grass carp (Ctenopharyngodon idellus)

The immunomodulatory effect of Astragalus polysaccharides (APS) has been revealed in aquatic animals. However, the fundamental mechanisms in grass carp (Ctenopharyngodon idellus) are not well characterized. This research has explored the impacts of APS on immune response, gut microbes and transcriptome profiles of grass carp. The eight week feeding trial was executed with the basal diet (Control) complemented with APS at diverse concentrations (0 and 1 g/kg). Firstly, the enzyme activity assay results indicated that dietary APS could considerably increase the activities of antioxidant and digestive enzymes. Furthermore, gut microbial analysis data showed that the intestinal microbial diversity and composition of grass carp were altered at the phylum level between the Control and APS groups. Additionally, beta-diversity revealed that APS had influenced the bacterial assembly in the foregut and hindgut of grass carp. The transcriptomic profiling was used to further explicate the mechanism fundamental to the effects of APS on molecular evidences in the intestines; the results revealed that the APS could activate immune related genes. Further study results revealed that the immune response stimulated by APS, the mRNA expression levels of TNF-α, IL-1β, CSF, ILF2, DCLK1 and TAGAP genes were all significantly up-regulated after dietary APS supplementation. Finally, histopathological changes of different tissues and bacterial load levels in the liver between the A. hydrophila and A. hydrophila + APS groups illustrated that APS protected the tissues under A. hydrophila challenge. Overall, the present study revealed that APS could modulate the intestinal microbiota and activate the immune response to protect the grass carp from bacterial infection.

Emerging beta‐amyloid pathology is associated with tau, synaptic, neurodegeneration and gray matter volume differences

AbstractBackgroundNew clinical trials, like the A3, are targeting participants with emerging amyloid pathology (between 20‐40 centiloids (CL). The aim of this study is to describe if there are detectable differences in tau, synaptic, inflammatory, neurodegeneration CSF markers and brain structure in participants with emerging amyloid pathology.MethodCSF Aß42, Aß40, t‐tau, p‐tau, neurogranin, GFAP, IL‐6, YKL‐40, sTREM2, NfL, S100B and α‐synuclein were measured with Elecsys® CSF assays and the Roche NeuroToolKit robust prototype assays in 303 cognitively unimpaired participants of the ALFA+ cohort. Participants also underwent APOE genotyping, structural MRI, as well as [18F]flutemetamol PET. Emerging amyloid pathology was defined in two different ways for checking results consistency: (1) Participants with less than 40 CL and a positive Aß42/40 ratio to be compared with those having less than 20 CL and a negative ratio (amyloid‐negative) and those with more than 40 CL and a positive ratio (amyloid‐positive). (2) Participants having between 20‐40 CL to be compared with those having less than 20 CL (amyloid‐negative) and more than 40 (amyloid‐positive). All CSF biomarker levels were compared between the emerging amyloid and its corresponding amyloid‐negative and ‐positive groups. SPM12 was used to seek for differences in gray matter volumes (GMv) among groups, after accounting for age, sex, APOE, education.Result89 and 16 participants fulfilled emergent amyloid criteria 1 and 2 respectively (demographics Table 1). Compared to the amyloid‐negative group, significantly increased levels of CSF p‐tau, t‐tau, neurogranin, and NfL could already be observed in the emerging amyloid group (both definitions, Figure 1a), whereas the remaining biomarkers only demonstrated increased abnormality in the amyloid‐positive group. Subjects with emerging amyloid pathology compared with the amyloid‐negative ones had greater GMv in the angular, supramarginal, fusiform, anterior temporal and medial frontal pole (Figure 1b). The association of the GMv differences and its interactions with the different biomarkers will also be presented.ConclusionThese results provide evidence that multiple biological pathways, such as tau, synaptic and neurodegenerative, are already altered in participants with emergent amyloid pathology, which also have greater gray matter volumes. Therefore, intervening very early in the Alzheimer’s continuum may be a priority.

Effects of oligochitosan on the growth, immune responses and gut microbes of tilapia (Oreochromis niloticus)

The immunomodulatory effects of oligochitosan have been demonstrated in several fish. However, the underlying mechanisms are not well characterized. The profound interplay between gut microbes and aquaculture has received much scientific attention but understanding the alternations of microbes populating in gut of tilapia (Oreochromis niloticus) fed with oligochitosan remains enigmatic. In this study, the effects of oligochitosan on the growth, immune responses and gut microbes of tilapia were investigated. The feeding trial was conducted in triplicates with the control diet supplemented with oligochitosan at different concentrations (0, 100, 200, 400 or 800 mg/kg). Following a six-week feeding trial, body weights of the fish supplemented with 200 mg/kg and 400 mg/kg oligochitosan were significantly higher than that of the control group. To address the immune responses stimulated by oligochitosan, by the quantitative real time PCR (qRT-PCR), the mRNA expression levels of CSF, IL-1β, IgM, TLR2 and TLR3 genes from head kidney were all significantly up-regulated in the 400 mg/kg group compared to the control. To characterize the gut microbes, bacterial samples were collected from the foregut, midgut, and hindgut, respectively and were subjected to high-throughput sequencing of 16S rDNA. The results showed that significantly lower abundance of Fusobacterium was detected in the hindgut of 400 mg/kg group compared to the control. Additionally, beta-diversity revealed that both gut habitat and oligochitosan had effects on the gut bacterial assembly. To further elucidate the mechanism underlying the effects of oligochitosan on bacterial assembly, the results showed that difference dosages of dietary oligochitosan could alter the specific metabolic pathways and functions of the discriminatory bacterial taxa, resulting in the different bacterial assemblies. To test the antibacterial ability of tilapia fed with oligochitosan, when the tilapias were challenged with Aeromonas hydrophila, the mortality of groups fed with dietary oligochitosan was significantly lower than that of the control. Taken together, appropriate dietary oligochitosan could improve growth, immune responses and alter the bacterial flora in the intestine of tilapia, so as to play a role in fighting against the bacterial infection.

Association Between Cerebrospinal Fluid Biomarkers and Age-related Brain Changes in Patients with Normal Pressure Hydrocephalus

Our study aimed to: 1)investigate the diagnostic utility of CSF Aβ42, t-tau, and p-tau to differentiate normal-pressure-hydrocephalus(NPH) from Alzheimer’s-disease(AD) and normal-controls; and 2)investigate if age and ventricular size affect the levels of CSF biomarkers in NPH patients. We recruited 131 participants: (a)Suspected-NPH: 72 with ventriculomegaly and clinical symptoms of NPH. These participants were then divided into two groups of 1)Probable-NPH (N = 38) and 2)Unlikely-NPH (N = 34) based on whether participants experienced gait improvement after removal of a large amount of CSF; (b)AD group: 30 participants with CSF biomarkers and cognitive symptoms consistent with AD; (c)Control-group: 29 participants who were cognitively and functionally normal. Lower levels of CSF Aβ42 and p-tau were observed in the probable-NPH compared to the normal controls(444.22 ± 163.3 vs. 1213.75 ± 556.5; and 26.05 ± 9.2 vs. 46.16 ± 13.3 pg/mL; respectively). Lower levels of CSF p-tau and t-tau were found in the probable-NPH compared to the AD(26.05 ± 9.2 vs. 114.95 ± 28.2; and 193.29 ± 92.3 vs. 822.65 ± 311.5 pg/mL; respectively) but the CSF-Aβ42 was low in both the probable-NPH and AD. CSF-Aβ42 correlated with age and Evans-index only in the probable-NPH(r = 0.460, p = 0.004; and r = −0.530, p = 0.001; respectively). Our study supports the hypothesis that age-related atrophy results in better Aβ42 clearance in the CSF because of the increase in the interstitial space.

CSF total and oligomeric \u03b1-Synuclein along with TNF-\u03b1 as risk biomarkers for Parkinson\u2019s disease: a study in LRRK2 mutation carriers

BackgroundAsymptomatic carriers of leucine-rich repeat kinase 2 (LRRK2) gene mutations constitute an ideal population for discovering prodromal biomarkers of Parkinson’s disease (PD). In this study, we aim to identify CSF candidate risk biomarkers of PD in individuals with LRRK2 mutation carriers.MethodsWe measured the levels of CSF total- (t-), oligomeric (o-) and phosphorylated S129 (pS129-) α-syn, total-tau (tTau), phosphorylated threonine 181 tau (pTau), amyloid-beta 40 (Aβ-40), amyloid-beta-42 (Aβ-42) and 40 inflammatory chemokines in symptomatic (n = 23) and asymptomatic (n = 51) LRRK2 mutation carriers, subjects with a clinical diagnosis of PD (n = 60) and age-matched healthy controls (n = 34). General linear models corrected for age and gender were performed to assess differences in CSF biomarkers between the groups. Markers that varied significantly between the groups were then analyzed using backward-elimination logistic regression analysis to identify an ideal biomarkers panel of prodromal PD.ResultsDiscriminant function analysis revealed low levels of CSF t-α-syn, high levels of CSF o-α-syn and TNF-α best discriminated asymptomatic LRRK2 mutation carriers from both symptomatic PD and healthy controls. Assessing the discriminative power using receiver operating curve analysis, an area under the curve > 0.80 was generated.ConclusionsThe current study suggests that CSF t-, o-α-syn and TNF-α are candidate risk biomarkers for the detection of PD at the prodromal stage. Our findings also highlight the dynamic interrelationships between CSF proteins and the importance of using a biomarkers’ panel approach for an accurate and timely diagnosis of PD.