Cerebrospinal Fluid P-tau Levels Research Articles

Cerebrospinal Fluid Cortisol and Dehydroepiandrosterone Sulfate, Alzheimer's Disease Pathology, and Cognitive Decline.

IntroductionElevated cortisol levels have been reported in Alzheimer’s disease (AD) and may accelerate the development of brain pathology and cognitive decline. Dehydroepiandrosterone sulfate (DHEAS) has anti-glucocorticoid effects and it may be involved in the AD pathophysiology.ObjectivesTo investigate associations of cerebrospinal fluid (CSF) cortisol and DHEAS levels with (1) cognitive performance at baseline; (2) CSF biomarkers of amyloid pathology (as assessed by CSF Aβ levels), neuronal injury (as assessed by CSF tau), and tau hyperphosphorylation (as assessed by CSF p-tau); (3) regional brain volumes; and (4) clinical disease progression.Materials and MethodsIndividuals between 49 and 88 years (n = 145) with mild cognitive impairment or dementia or with normal cognition were included. Clinical scores, AD biomarkers, brain MRI volumetry along with CSF cortisol and DHEAS were obtained at baseline. Cognitive and functional performance was re-assessed at 18 and 36 months from baseline. We also assessed the following covariates: apolipoprotein E (APOE) genotype, BMI, and education. We used linear regression and mixed models to address associations of interest.ResultsHigher CSF cortisol was associated with poorer global cognitive performance and higher disease severity at baseline. Cortisol and cortisol/DHEAS ratio were positively associated with tau and p-tau CSF levels, and negatively associated with the amygdala and insula volumes at baseline. Higher CSF cortisol predicted more pronounced cognitive decline and clinical disease progression over 36 months. Higher CSF DHEAS predicted more pronounced disease progression over 36 months.ConclusionIncreased cortisol in the CNS is associated with tau pathology and neurodegeneration, and with decreased insula and amygdala volume. Both CSF cortisol and DHEAS levels predict faster clinical disease progression. These results have implications for the identification of patients at risk of rapid decline as well as for the development of interventions targeting both neurodegeneration and clinical manifestations of AD.

119 NeuroToolkit CSF biomarkers track the progression of Alzheimer’s disease at very early stages

IntroductionNeuroToolkit is a set of cerebrospinal fluid (CSF) biomarkers developed to identify Alzheimer’s disease co-pathologies, identify and characterize disease progression and treatment response. We assess the association between NeuroToolkit biomarkers and cerebral amyloid deposition in the ALFA+ cohort [1].Methods326 cognitively unimpaired individuals from the ALFA+ cohort [1] underwent a lumbar puncture and amyloid [18F]flutemetamol PET imaging. Biomarkers in NeuroToolkit (Figure 1) were determined using prototype Roche Elecsys® assays. CSF pTau levels were measured using the Elecsys® CSF assay. We cal- culated cross-correlation values between NeuroToolkit biomarkers and Centiloids. Voxel-wise associations between NeuroToolkit biomarkers and [18F]flutemetamol images were sought, accounting for the effect of various demographics. Additional analyses were performed after correcting also for the Aα42/40 ratio or Centiloid values.ResultsFigure 1. Shows associations between NeuroToolkit biomarkers and Centiloids. NeuroToolkit bio- markers were significantly associated with cerebral amyloid deposition measured by [18F]flutemetamol PET (Figure 2). Correcting for global amyloid deposition, higher levels CSF YKL-40, an astroglial activity marker, were associated to increased cerebral amyloid deposition in the inferior and lateral temporal lobe, in parietal and orbitofrontal areas, and the caudate heads (Figure 3).ConclusionsResults of NeuroToolkit biomarkers support early involvement of the astroglial response to cerebral amyloid deposition.DisclosureThis study was conducted through a collaboration with Roche Diagnostics International. These data will be presented at Advances in Alzheimer’s and Parkinson’s Therapies. Ref: Molinuevo. TRCI 2 (2016) 82–92gwendlyn.kollmorgen@roche.com

Association between lower body temperature and increased tau pathology in cognitively normal older adults

BackgroundPreclinical studies suggest body temperature (Tb) and consequently brain temperature has the potential to bidirectionally interact with tau pathology in Alzheimer's Disease (AD). Tau phosphorylation is substantially increased by a small (<1 °C) decrease in temperature within the human physiological range, and thermoregulatory nuclei are affected by tau pathology early in the AD continuum. In this study we evaluated whether Tb (as a proxy for brain temperature) is cross-sectionally associated with clinically utilized markers of tau pathology in cognitively normal older adults. MethodsTb was continuously measured with ingestible telemetry sensors for 48 h. This period included two nights of nocturnal polysomnography to delineate whether Tb during waking vs sleep is differentially associated with tau pathology. Tau phosphorylation was assessed with plasma and cerebrospinal fluid (CSF) tau phosphorylated at threonine 181 (P-tau), sampled the day following Tb measurement. In addition, neurofibrillary tangle (NFT) burden in early Braak stage regions was imaged with PET-MR using the [18F]MK-6240 radiotracer on average one month later. ResultsLower Tb was associated with increased NFT burden, as well as increased plasma and CSF P-tau levels (p < 0.05). NFT burden was associated with lower Tb during waking (p < 0.05) but not during sleep intervals. Plasma and CSF P-tau levels were highly correlated with each other (p < 0.05), and both variables were correlated with tau tangle radiotracer uptake (p < 0.05). ConclusionsThese results, the first available for human, suggest that lower Tb in older adults may be associated with increased tau pathology. Our findings add to the substantial preclinical literature associating lower body and brain temperature with tau hyperphosphorylation. Clinical trial number: NCT03053908.

Tau Pathologies Mediate the Association of Cigarette Smoking with Cognitive Impairment in Older Adults Without Dementia: The CABLE Study.

Although cigarette smoking is an important modifiable factor of cognitive impairment, the roles of the Alzheimer's disease (AD) core pathologies in modulating this process have not been fully delineated. This study aimed to explore associations of cigarette smoking with cognition and cerebrospinal fluid (CSF) AD biomarkers. A total of 1,079 non-demented participants were included from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) study. Associations of cigarette smoking with cognition and CSF AD biomarkers were explored by multiple linear regression models. The mediation analyses with 10,000 bootstrapped iterations were conducted to explore the mediation effects. Heavy cigarette smokers (pack-years > 20) had poorer global cognition as well as higher levels of CSF p-tau and t-tau compared with the non-smokers (p < 0.01). Time-dose effect analysis among smokers also suggested that both cognitive impairment and tau pathologies markedly deteriorated with greater cumulative cigarette exposure, independently of the Aβ pathology (p < 0.01). In addition, smokers with older age or APOEɛ4 showed more obvious influences on CSF tau pathologies but not on cognition. Overall, the influence of smoking on cognition was partially mediated by tau pathologies (estimated proportion: 12%), which still remained in late-life (10% ∼11%) and increased in APOEɛ4 carriers (18% ∼24%). Encouragingly, long-term smoking cessation mitigated both cognitive impairment and tau pathologies (p < 0.05). Cigarette smoking was associated with both cognitive impairment and tau pathologies, which were accompanied by time-dose effects. Tau pathology might be a key mediator for influences of cigarette smoking on cognitive impairments.

A Comparison of Cerebrospinal Fluid Beta-Amyloid and Tau in Idiopathic Normal Pressure Hydrocephalus and Neurodegenerative Dementias.

PurposeIdiopathic normal pressure hydrocephalus (iNPH) is the leading reversible cause of cognitive impairment and gait disturbance that has similar clinical manifestations and accompanies to major neurodegenerative disorders in older adults. We aimed to investigate whether cerebrospinal fluid (CSF) biomarker for Alzheimer’s disease (AD) may be useful in the differential diagnosis of iNPH.Patients and MethodsAmyloid-beta (Aß) 42 and 40, total tau (t-tau), phosphorylated tau (p-tau) were measured via ELISA in 192 consecutive CSF samples of patients with iNPH (n=80), AD (n=48), frontotemporal dementia (FTD) (n=34), Lewy body diseases (LBDs) (n=30) consisting of Parkinson’s disease dementia and dementia with Lewy bodies.ResultsThe mean age of the study population was 75.6±7.7 years, and 54.2% were female. CSF Aβ42 levels were significantly higher, and p-tau and t-tau levels were lower in iNPH patients than in those with AD and LBDs patients. Additionally, iNPH patients had significantly higher levels of t-tau than those with FTD. Age and sex-adjusted multi-nominal regression analysis revealed that the odds of having AD relative to iNPH decreased by 37% when the Aβ42 level increased by one standard deviation (SD), and the odds of having LBDs relative to iNPH decreased by 47%. The odds of having LBDs relative to iNPH increased 76% when the p-tau level increased 1SD. It is 2.5 times more likely for a patient to have LBD relative to NPH and 2.1 times more likely to have AD relative to iNPH when the t-tau value increased 1SD.ConclusionOur results suggest that levels of CSF Aβ42, p-tau, and t-tau, in particularly decreased t-tau, are of potential value in differentiating iNPH from LBDs and also confirm previous studies reporting t-tau level is lower and Aβ42 level is higher in iNPH than in AD.

Caspase-1 variant influencing CSF tau and FDG PET levels in non-demented elders from the ADNI cohort

BackgroundGenetic variations in the inflammatory Caspase-1 gene have been shown associated with cognitive function in elderly individuals and in predisposition to Alzheimer’s disease (AD), but its detailed mechanism before the typical AD onset was still unclear. Our current study evaluated the impact of Caspase-1 common variant rs554344 on the pathological processes of brain amyloidosis, tauopathy, and neurodegeneration.MethodsData used in our study were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. We examined the relationship between Caspase-1 rs554344 allele carrier status with AD-related cerebrospinal fluid (CSF), PET, and MRI measures at baseline by using a multiple linear regression model. We also analyzed the longitudinal effects of this variant on the change rates of CSF biomarkers and imaging data using a mixed effect model.ResultsWe found that Caspase-1 variant was significantly associated with FDG PET levels and CSF t-tau levels at baseline in total non-demented elderly group, and especially in mild cognitive impairment (MCI) subgroup. In addition, this variant was also detected associated with CSF p-tau levels in MCI subgroup. The mediation analysis showed that CSF p-tau partially mediated the association between Caspase-1 variant and CSF t-tau levels, accounting for 80% of the total effect.ConclusionsOur study indicated a potential role of Caspase-1 variant in influencing cognitive function might through changing tau related-neurodegeneration process.

The Correlation of Tau Levels with Blood Monocyte Count in Patients with Alzheimer's Disease.

Recent studies have shown that monocytes can phagocytize the tau protein, which may ameliorate tau-type pathology in Alzheimer's disease (AD). However, there are few clinical studies on the relationship between monocytes and tau-type pathology in AD patients. We aimed to explore changes in peripheral monocytes and their association with tau protein in AD patients. A total of 127 clinically diagnosed AD patients and 100 age- and sex-matched cognitively normal controls were recruited for analysis of the correlation of plasma tau levels with the blood monocyte count. Cerebrospinal fluid (CSF) samples from 46 AD patients and 88 controls were further collected to analyze the correlation of CSF tau and amyloid-β (Aβ) levels with the blood monocyte count. 105 clinically diagnosed mild cognitive impairment (MCI) patients and 149 age- and sex-matched cognitively normal controls were recruited from another cohort for verification. Compared to normal controls, AD patients showed a significant reduction in the blood monocyte count. In addition, the monocyte count of AD patients was negatively correlated with CSF t-tau and p-tau levels but not with plasma tau levels. In normal people, monocyte count lack correlation with tau levels both in plasma and CSF. Monocyte count were not correlated with CSF Aβ levels in either group but were negatively correlated with CSF tau/Aβ42 levels in the AD group. We had further verified the correlations of monocyte count with CSF tau levels in another cohort. This study suggests that monocytes may play an important role in the clearance of tau protein in the brain.

Effect of CSF biomarkers on cortical thickness in males and females

AbstractBackgroundThe level of elevated Tau, phosphorylated Tau, and aggregated Amyloid β in the cerebrospinal fluid (CSF) are markers of Alzheimer’s pathology in the brain. In this study, we analyzed how these CSF biomarkers are related to the cortical thickness in males and females, for subjects who are cognitively normal (CN), with mild cognitive impairment (MCI), and diagnosed as Alzheimer’s disease (AD).MethodWe studied the CN (305), MCI (264) and AD (230) subjects from the ADNI dataset at baseline. We first studied the CSF biomarker level differences between males and females in all three groups. The effect of age was controlled using general linear models (GLM) We also looked at the effect of the CSF biomarkers on cortical thickness maps generated separately for males and females for all three groups, also with GLM‐based covariate regression to control the effect of age, ICV, and field strength of the scan.ResultFor the CSF biomarker levels, we observed Tau to be significantly higher in females in the AD group. No other significant sex difference in the biomarker levels were observed. We found MCI males [Figure 1] and AD [Figure 2] females showing a negative relationship between Tau and thickness. When comparing CSF pTau levels to cortical thickness, a negative correlation was found only in males [Figure 3] for the AD group. When comparing Aβ and cortical thickness, negative correlations were found for males in the CN [Figure 4] and AD group [Figure 5], and for females [Figure 6] in the MCI group.ConclusionThe results suggest that the relationship between cortical thickness and CSF biomarkers is different in males and females in CN, MCI, and AD groups. We found that there is a negative relationship between CSF biomarkers and cortical thickness.

Anaemia and cerebrospinal fluid biomarkers of Alzheimer\u2019s pathology in cognitively normal elders: the CABLE study

BackgroundAnaemia has been reported to be associated with cognitive decline and Alzheimer’s disease (AD), but the associations between anaemia and cerebrospinal fluid (CSF) AD biomarkers are still unknown. This study aimed to investigate the associations between anaemia and CSF AD biomarkers.MethodsParticipants were included from the Chinese Alzheimer’s Biomarker and LifestylE (CABLE) study. The associations of anaemia and its severity with CSF AD biomarkers including β-amyloid 1–42 (Aβ42), total tau (t-tau) and phosphorylated tau (p-tau) were analysed by multiple linear regression models. Adjusted for age, gender, educational levels, APOE ε4 alleles, comorbidities (history of coronary heart disease, history of stroke, hypertension, diabetes mellitus, dyslipidaemia) and glomerular filtration rate.ResultsA total of 646 cognitively normal older adults, consisting of 117 anaemia patients and 529 non-anaemia individuals, were included in this study. Anaemia patients had lower levels of CSF Aβ42 than individuals without anaemia (p = 0.035). Besides, participants with more severe anaemia had lower CSF Aβ42 levels (p = 0.045). No significant association of anaemia with CSF t-tau and p-tau levels was found.ConclusionCross-sectionally, anaemia was associated with lower CSF Aβ42 levels. These findings consolidated the causal close relationship between anaemia and AD.

Tau pathology mediates age effects on medial temporal lobe structure

Hippocampal atrophy is endemic in ‘normal aging’ but it is unclear what factors drive age-related changes in medial temporal lobe (MTL) structural measures. We investigated cross-sectional (n = 191) and longitudinal (n = 164) MTL atrophy patterns in cognitively normal older adults from ADNI-GO/2 with no to low cerebral β-amyloid and assessed whether white matter hyperintensities (WMHs) and cerebrospinal fluid (CSF) phospho tau (p-tau) levels can explain age-related changes in the MTL. Age was significantly associated with hippocampal volumes and Brodmann Area (BA) 35 thickness, regions affected early by neurofibrillary tangle pathology, in the cross-sectional analysis and with anterior and/or posterior hippocampus, entorhinal cortex and BA35 in the longitudinal analysis. CSF p-tau was significantly associated with hippocampal volumes and atrophy rates. Mediation analyses showed that CSF p-tau levels partially mediated age effects on hippocampal atrophy rates. No significant associations were observed for WMHs. These findings point toward a role of tau pathology, potentially reflecting Primary Age-Related Tauopathy, in age-related MTL structural changes and suggests a potential role for tau-targeted interventions in age-associated neurodegeneration and memory decline.

Digital Speech Analysis in Progressive Supranuclear Palsy and Corticobasal Syndromes.

Progressive supranuclear palsy syndrome (PSPS) and corticobasal syndrome (CBS) as well as non-fluent/agrammatic primary progressive aphasia (naPPA) are often associated with misfolded 4-repeat tau pathology, but the diversity of the associated speech features is poorly understood. Investigate the full range of acoustic and lexical properties of speech to test the hypothesis that PSPS-CBS show a subset of speech impairments found in naPPA. Acoustic and lexical measures, extracted from natural, digitized semi-structured speech samples using novel, automated methods, were compared in PSPS-CBS (n = 87), naPPA (n = 25), and healthy controls (HC, n = 41). We related these measures to grammatical performance and speech fluency, core features of naPPA, to neuropsychological measures of naming, executive, memory and visuoconstructional functioning, and to cerebrospinal fluid (CSF) phosphorylated tau (pTau) levels in patients with available biofluid analytes. Both naPPA and PSPS-CBS speech produced shorter speech segments, longer pauses, higher pause rates, reduced fundamental frequency (f0) pitch ranges, and slower speech rate compared to HC. naPPA speech was distinct from PSPS-CBS with shorter speech segments, more frequent pauses, slower speech rate, reduced verb production, and higher partial word production. In both groups, acoustic duration measures generally correlated with speech fluency, measured as words per minute, and grammatical performance. Speech measures did not correlate with standard neuropsychological measures. CSF pTau levels correlated with f0 range in PSPS-CBS and naPPA. Lexical and acoustic speech features of PSPS-CBS overlaps those of naPPA and are related to CSF pTau levels.

Associations of healthy lifestyles with cerebrospinal fluid biomarkers of Alzheimer\u2019s disease pathology in cognitively intact older adults: the CABLE study

ObjectiveWe aimed to investigate the associations between healthy lifestyles and Alzheimer’s disease (AD) biomarkers in cerebrospinal fluid (CSF).MethodsA total of 1108 cognitively intact individuals from Chinese Alzheimer’s Biomarker and LifestylE (CABLE) study were examined to evaluate the associations of AD biomarkers with healthy lifestyle factors, including no current smoking, no harmful drinking, absence of social isolation, and regular physical activity. The participants were categorized into groups of favorable, intermediate, and unfavorable lifestyles according to the lifestyle factors. The associations between overall lifestyle and CSF biomarkers were also analyzed.ResultsAmong cognitively intact older adults, those having more social engagement had lower CSF tau (p = 0.009) and p-tau (p < 0.001) than those who had social isolation. Regular physical activity was associated with higher CSF Aβ42 (p = 0.013) and lower levels of CSF tau (p = 0.036) and p-tau (p = 0.007). However, no significant associations were found of smoking status or alcohol intake with CSF biomarkers. When the overall lifestyle of the participants was evaluated by all the four lifestyle factors, favorable lifestyle profiles were related to lower levels of CSF tau (p < 0.001) and p-tau (p < 0.001).ConclusionsThese findings suggest that healthy lifestyles had a beneficial effect on AD pathology among cognitively intact elders.

Tau protein in cerebrospinal fluid: a novel biomarker of the time of death?

Tau proteins are recognized biomarkers of neurodegeneration and neuronal damage in the cerebrospinal fluid (CSF). It has also been suggested that these CSF proteins could increase post-mortem due to neuronal death. The aim of this study was to investigate the changes in CSF total and phosphorylated tau (p-tau) levels in the early post-mortem interval (PMI), to determine whether these proteins could be relevant biomarkers of time since death. Tau and p-tau levels were measured by ELISA in lumbar and cisternal CSF samples from 82 corpses (46 men, 36 women, mean age: 72.4 ± 15.2years) with a PMI < 12h. Forty-eight of them were considered neurologically healthy at the time of death. Rectal and tympanic temperatures were also measured in 37 individuals, and two validated temperature-based methods of PMI estimation were applied (Henssge's nomogram and Baccino's method). CSF tau and p-tau levels were significantly increased, with respective median values of 3315pg/mL and 68.5pg/mL in the whole cohort, while lower but still increased levels were observed in neurologically healthy patients. Sub-occipital punctures systematically provided higher tau and p-tau values (p < 0.0001). Despite a great inter-individual variability, the concentrations of both biomarkers were positively correlated with the early PMI, with the highest correlation for cisternal p-tau (r = 0.50, p < 0.0001 in the whole cohort; r = 0.58, p = 0.0003 in the neurologically healthy patients). Higher levels of CSF biomarkers were observed for PMI > 6h versus PMI ≤ 6h, the discriminatory power of the biomarkers being higher in the subgroup of neurologically healthy patients. Based on cut-off values obtained by ROC curve analysis, the CSF biomarkers could rectify or adjust the time interval provided by the temperature-based methods in a significant number of cases. A predictive model combining tympanic temperature and cisternal tau values was found to be particularly accurate to assign individuals according to their PMI (≤ or > 6h), with a Se of 83% and a Sp of 100% (AUC = 0.95). Our findings suggest that CSF tau and p-tau proteins could serve as potential biomarkers of time since death, in association with tympanic temperature. The practical applicability of such an integrated approach has to be assessed by further studies.

TNFRSF1B Gene Variants and Related Soluble TNFR2 Levels Impact Resilience in Alzheimer's Disease.

Tumor necrosis factor receptor 2 (TNFR2) promotes neuronal survival downstream. This longitudinal study evaluated whether the TNFRSF1B gene encoding TNFR2 and levels of its soluble form (sTNFR2) affect Alzheimer disease (AD) biomarkers and clinical outcomes. Data analyzed included 188 patients in the Alzheimer's Disease Neuroimaging Initiative (ADNI) who had mild cognitive impairment (MCI) and AD dementia. Further, a replication study was performed in 48 patients with MCI with positive AD biomarkers who were treated at a memory clinic. Cerebrospinal fluid (CSF) sTNFR2 levels along with two related TNFRSF1B gene single nucleotide polymorphisms (SNPs) rs976881 and rs1061622 were assessed. General linear models were used to evaluate the effect of CSF sTNFR2 levels and each SNP in relationship to CSF t-tau and p-tau, cognitive domains, MRI brain measures, and longitudinal cognitive changes after adjustments were made for covariates such as APOE ε4 status. In the ADNI cohort, a significant interaction between rs976881 and CSF sTNFR2 modulates CSF t-tau and p-tau levels; hippocampal and whole brain volumes; and Digit Span Forwards subtest scores. In the replication cohort, a significant interaction between rs976881 and CSF sTNFR2 modulates CSF p-tau. A significant interaction between rs976881 and CSF sTNFR2 also impacts Clinical Dementia Rating Sum of Boxes scores over 12 months in the ADNI cohort. The interaction between TNFRSF1B variant rs976881 and CSF sTNFR2 levels was noted to modulate multiple AD-associated severity markers and cognitive domains. This interaction impacts resilience-related clinical outcomes in AD and lends support to sTNFR2 as a promising candidate for therapeutic targeting to improve clinical outcomes of interest.

Association of weight change with cerebrospinal fluid biomarkers and amyloid positron emission tomography in preclinical Alzheimer\u2019s disease

BackgroundRecognizing clinical manifestations heralding the development of Alzheimer’s disease (AD)-related cognitive impairment could improve the identification of individuals at higher risk of AD who may benefit from potential prevention strategies targeting preclinical population. We aim to characterize the association of body weight change with cognitive changes and AD biomarkers in cognitively unimpaired middle-aged adults.MethodsThis prospective cohort study included data from cognitively unimpaired adults from the ALFA study (n = 2743), a research platform focused on preclinical AD. Cognitive and anthropometric data were collected at baseline between April 2013 and November 2014. Between October 2016 and February 2020, 450 participants were visited in the context of the nested ALFA+ study and underwent cerebrospinal fluid (CSF) extraction and acquisition of positron emission tomography images with [18F]flutemetamol (FTM-PET). From these, 408 (90.1%) were included in the present study. We used data from two visits (average interval 4.1 years) to compute rates of change in weight and cognitive performance. We tested associations between these variables and between weight change and categorical and continuous measures of CSF and neuroimaging AD biomarkers obtained at follow-up. We classified participants with CSF data according to the AT (amyloid, tau) system and assessed between-group differences in weight change.ResultsWeight loss predicted a higher likelihood of positive FTM-PET visual read (OR 1.27, 95% CI 1.00–1.61, p = 0.049), abnormal CSF p-tau levels (OR 1.50, 95% CI 1.19–1.89, p = 0.001), and an A+T+ profile (OR 1.64, 95% CI 1.25–2.20, p = 0.001) and was greater among participants with an A+T+ profile (p < 0.01) at follow-up. Weight change was positively associated with CSF Aβ42/40 ratio (β = 0.099, p = 0.032) and negatively associated with CSF p-tau (β = − 0.141, p = 0.005), t-tau (β = − 0.147 p = 0.004) and neurogranin levels (β = − 0.158, p = 0.002). In stratified analyses, weight loss was significantly associated with higher t-tau, p-tau, neurofilament light, and neurogranin, as well as faster cognitive decline in A+ participants only.ConclusionsWeight loss predicts AD CSF and PET biomarker results and may occur downstream to amyloid-β accumulation in preclinical AD, paralleling cognitive decline. Accordingly, it should be considered as an indicator of increased risk of AD-related cognitive impairment.Trial registrationNCT01835717, NCT02485730, NCT02685969.

Left Ventricular Ejection Fraction and Cerebrospinal Fluid Biomarkers of Alzheimer's Disease Pathology in Cognitively Normal Older Adults: The CABLE Study.

Heart failure has been considered as a potential modifiable risk factor for cognitive impairment and dementia. Left ventricular ejection fraction (LVEF), an indicator of cardiac dysfunction, has also been associated with cognitive aging. However, the effect of LVEF on Alzheimer's disease (AD) pathology is still less known. We aimed to investigate the associations of LVEF with cerebrospinal fluid (CSF) biomarkers for AD in cognitively normal elders. A total of 423 cognitively normal individuals without heart failure were included from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) study. Participants were divided into low LVEF group (50%≤LVEF < 60%) and high LVEF group (LVEF≥60%). The associations of LVEF with CSF AD biomarkers including CSF amyloid-β 42 (Aβ42), total-tau (t-tau), and phosphorylated tau (p-tau) were analyzed using multivariate linear regression models. Participants with low LVEF had higher levels of CSF t-tau (β= -0.009, p = 0.006) and t-tau/Aβ42 ratios (β= -0.108, p = 0.026). Subgroup analyses showed that the associations only existed in female and middle-aged groups (< 65 years old). Besides, participants with low LVEF had higher levels of CSF p-tau (β= -0.002, p = 0.043) in middle-aged group. In conclusion, our findings revealed the associations between LVEF and AD pathology, which may provide new insights into AD prevention through maintaining cardiac function.

Characteristics and prognosis of patients with mild cognitive impairment by cerebrospinal fluid biomarker profiles

AbstractBackgroundBiomarkers have an important diagnostic and prognostic value in neurodegenerative diseases, especially in early stages. We analyzed the differences in baseline characteristics and clinical evolution of patients with mild cognitive impairment (MCI) according to their cerebrospinal fluid (CSF) Alzheimer Disease biomarkers profile.MethodWe retrospectively selected all patients evaluated in the Sant Pau Memory Unit that had a neuropsychological evaluation compatible with MCI, analysis of Alzheimer CSF biomarkers and clinical follow‐up for at least 6 months. Patients were classified applying our internal cutoffs for CSF levels of Aβ1‐42 as a marker of amyloidosis (A+/A‐) and CSF levels of pTau as a marker of Tau pathology (T+/T‐).We compared demographic characteristics, cognitive progression, and final clinical diagnoses between groups.ResultWe included 274 participants: 103 A‐/T‐, 43 A+/T‐, 40 A‐/T+ and 88 A+/T+. The mean follow‐up was 3.4 years. Patients in the A‐/T‐ group were younger (67.8 years) compared to those in the A+/T+ group (72.3 years, p=0.002). During follow‐up, the A+/T+ group showed greater global cognitive impairment (‐1.5 MMSE score/year; p &lt;0.001)and higher risk of progression to dementia (OR=3,13, p&lt;0.001). There were no differences in baseline neuropsychological scores between A+/T‐ and A‐/T+ groups. The proportions of patients with a final clinical diagnosis of Alzheimer's dementia (AD), Lewy body Dementia (LBD) and frontotemporal lobar degeneration related syndromes(FTLD) were 37%, 16% and 12% in the A+/T‐ group, and 25%, 10% and 5% in the A‐/T+ group, respectively. Compared to the A+/T‐ group, the A‐/T+ group had a higher proportion of patients whose final clinical diagnosis was non‐neurodegenerative or undetermined (60% vs. 35%, respectively; p=0.022) and a lower risk of progression to dementia (OR=0.37; p=0.032).ConclusionA CSF profile suggestive of AD pathophysiology is associated with greater global cognitive impairment and a higher risk of progression to dementia. Although we did not find differences in baseline neuropsychological scores between patients with positive markers of amyloidosis and those with tau pathology only, patients with amyloidosis showed a higher risk of progression to dementia in follow‐up. The benefit of using additional markers of amyloidosis and/or tau pathology in the assessment of prognosis of these patients needs to be further explored.

Tau phosphorylation by glycogen synthase kinase 3β modulates enzyme acetylcholinesterase expression.

In Alzheimer's disease (AD), the enzyme acetylcholinesterase (AChE) co‐localizes with hyperphosphorylated tau (P‐tau) within neurofibrillary tangles. Having demonstrated that AChE expression is increased in the transgenic mouse model of tau Tg‐VLW, here we examined whether modulating phosphorylated tau levels by over‐expressing wild‐type human tau and glycogen synthase kinase‐3β (GSK3β) influences AChE expression. In SH‐SY5Y neuroblastoma cells expressing higher levels of P‐tau, AChE activity and protein increased by (20% ± 2%) and (440% ± 150%), respectively. Western blots and qPCR assays showed that this increment mostly corresponded to the cholinergic ACHE‐T variant, for which the protein and transcript levels increased ~60% and ~23%, respectively. Moreover, in SH‐SY5Y cells differentiated into neurons by exposure to retinoic acid (10 µM), over‐expression of GSK3β and tau provokes an imbalance in cholinergic activity with a decrease in the neurotransmitter acetylcholine in the cell (45 ± 10%). Finally, we obtained cerebrospinal fluid (CSF) from AD patients enrolled on a clinical trial of tideglusib, an irreversible GSK3β inhibitor. In CSF of patients that received a placebo, there was an increase in AChE activity (35 ± 16%) respect to basal levels, probably because of their treatment with AChE inhibitors. However, this increase was not observed in tideglusib‐treated patients. Moreover, CSF levels of P‐tau at the beginning measured by commercially ELISA kits correlated with AChE activity. In conclusion, this study shows that P‐tau can modulate AChE expression and it suggests that AChE may possibly increase in the initial phases of AD.

IL-1β, IL-6, IL-10, and TNFα Single Nucleotide Polymorphisms in Human Influence the Susceptibility to Alzheimer’s Disease Pathology

Neuroinflammation plays an important role in Alzheimer's disease (AD). During this process, activated microglia release pro-inflammatory cytokines such as interleukin (IL)-1α, IL-1β, IL-6, and tumor necrosis factor α (TNFα) that participate in neuron damage, but also anti-inflammatory cytokines (such as IL-10), which maintain homeostasis of immune response. Previous studies showed the association of IL-1α -889C/T (rs1800587), IL-1β-1473G/C (rs1143623), IL-6 -174C/G (rs1800795), IL-10 -1082G/A (rs1800896), and TNFα -308A/G (rs1800629) polymorphisms with AD. We aimed to investigate whether people with certain IL-1α, IL-1β, IL-6, IL-10, and TNFα genotypes in these polymorphisms are more prone to develop AD-related pathology, reflected by pathological levels of cerebrospinal fluid (CSF) AD biomarkers including amyloid-β1-42, total tau (t-tau), tau phosphorylated at Thr 181 (p-tau181), Ser 199 (p-tau199), and Thr 231 (p-tau231), and visinin-like protein 1 (VILIP-1). The study included 115 AD patients, 53 patients with mild cognitive impairment, and 11 healthy controls. The polymorphisms were determined using real-time polymerase chain reaction. Levels of CSF biomarkers were determined by enzyme-linked immunosorbent assay. A significant increase in p-tau CSF levels was found in patients with the AA IL-10 -1082G/A and GG TNFα -308A/G genotypes, and in carriers of a G allele in IL-1β -1473C/G and IL-6 -174C/G polymorphisms. t-tau levels were increased in carriers of a G allele in IL-1β -1473C/G polymorphism. An increase in VILIP-1 levels was observed in patients with CG and GG IL-1β -1473C/G, GC IL-6 -174C/G, and GG TNFα -308A/G genotype. These results suggest that persons carrying certain genotypes in IL10 (-1082G/A), IL1β (1473C/G), IL6 (-174C/G), and TNFIα (-308A/G) could be more vulnerable to development of neuroinflammation, and consequently of AD.

0057 Actigraphy-Based Circadian Measures and Cerebrospinal Fluid Biomarkers of Neurodegeneration in Alzheimer’s Disease with Mild Cognitive Impairment

Abstract Introduction Although recent data implicates sleep and circadian disruption to neurodegeneration in Alzheimer’s Disease (AD), the association of objective circadian biomarkers and neurodegeneration remains understudied. We hypothesize that actigraphy-based circadian measures are associated with cerebrospinal fluid (CSF) biomarkers of neurodegeneration in those mild cognitive impairment due to AD (MCI-AD). Methods Eighteen patients with CSF biomarker-confirmed MCI-AD underwent actigraphy monitoring generating the following circadian measures: amplitude, F-ratio and mesor and morning collection of CSF biomarkers of neurodegeneration (Aβ42,t-tau,p-tau). Linear models were used to evaluate the association of circadian and CSF measures; logarithmic transformations were performed on neurodegenerative markers for greater normality. Analysis was performed using SAS software. A significance level of 0.05 was assumed for all tests. Results Eighteen MCI-AD patients who were 68± 6.2 years, 44% female, with median AHI=12 and underwent actigraphy monitoring for 8.2+/-3.2 days were included. There was no significant association of circadian measures and Aβ42 nor with mesor and neurodegeneration biomarkers. Amplitude was associated with both p-tau and t-tau, such that each 10 unit increase in amplitude resulted in a predicted increase in p-tau of 8% (95% CI:1%-15%, p=0.018) and an increase of 13% (3%-23%; p=0.01) in t-tau. F-ratio was positively associated with p-tau and t-tau; each 1000 unit increase in F-ratio resulted in a predicted 12% (4%-22%; p=0.007) increase in P-tau and 20%(6%-35%; p=0.005) increase in t-tau. Associations of these circadian measures and CSF levels of p-tau and t-tau remained statistically significant after adjustment for age and sex. Conclusion Among patients with symptomatic MCI stages of AD, objective measures of circadian rhythm disruption are associated with CSF-based biomarkers of neurodegeneration even after consideration of age and sex. Future investigation should clarify directionality of this association and potential utility of circadian-based interventions in the mitigation of AD progression. Support N/A