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

Elevated 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. To 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. Individuals 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. Higher 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. Increased 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

Quantification of mutant huntingtin protein in cerebrospinal fluid from Huntington's disease patients.

Quantification of disease-associated proteins in the cerebrospinal fluid (CSF) has been critical for the study and treatment of several neurodegenerative disorders; however, mutant huntingtin protein (mHTT), the cause of Huntington's disease (HD), is at very low levels in CSF and, to our knowledge, has never been measured previously

Plasma neurofilament light and phosphorylated tau 181 as biomarkers of Alzheimer's disease pathology and clinical disease progression.

To assess the performance of plasma neurofilament light (NfL) and phosphorylated tau 181 (p-tau181) to inform about cerebral Alzheimer's disease (AD) pathology and predict clinical progression in a memory clinic setting. Plasma NfL and p-tau181, along with established cerebrospinal fluid (CSF) biomarkers of AD pathology, were measured in participants with normal cognition (CN) and memory clinic patients with cognitive impairment (mild cognitive impairment and dementia, CI). Clinical and neuropsychological assessments were performed at inclusion and follow-up visits at 18 and 36 months. Multivariate analysis assessed associations of plasma NfL and p-tau181 levels with AD, single CSF biomarkers, hippocampal volume, and clinical measures of disease progression. Plasma NfL levels were higher in CN participants with an AD CSF profile (defined by a CSF p-tau181/Aβ <sub>1-42</sub> > 0.0779) as compared with CN non-AD, while p-tau181 plasma levels were higher in CI patients with AD. Plasma NfL levels correlated with CSF tau and p-tau181 in CN, and with CSF tau in CI patients. Plasma p-tau181 correlated with CSF p-tau181 in CN and with CSF tau, p-tau181, Aβ <sub>1-42</sub> , and Aβ <sub>1-42</sub> /Aβ <sub>1-40</sub> in CI participants. Compared with a reference model, adding plasma p-tau181 improved the prediction of AD in CI patients while adding NfL did not. Adding p-tau181, but not NfL levels, to a reference model improved prediction of cognitive decline in CI participants. Plasma NfL indicates neurodegeneration while plasma p-tau181 levels can serve as a biomarker of cerebral AD pathology and cognitive decline. Their predictive performance depends on the presence of cognitive impairment

Plasma neurofilament light and phosphorylated tau 181 as biomarkers of Alzheimer's disease pathology and clinical disease progression.

BACKGROUND: To assess the performance of plasma neurofilament light (NfL) and phosphorylated tau 181 (p-tau181) to inform about cerebral Alzheimer's disease (AD) pathology and predict clinical progression in a memory clinic setting. METHODS: Plasma NfL and p-tau181, along with established cerebrospinal fluid (CSF) biomarkers of AD pathology, were measured in participants with normal cognition (CN) and memory clinic patients with cognitive impairment (mild cognitive impairment and dementia, CI). Clinical and neuropsychological assessments were performed at inclusion and follow-up visits at 18 and 36 months. Multivariate analysis assessed associations of plasma NfL and p-tau181 levels with AD, single CSF biomarkers, hippocampal volume, and clinical measures of disease progression. RESULTS: Plasma NfL levels were higher in CN participants with an AD CSF profile (defined by a CSF p-tau181/Aβ1-42 > 0.0779) as compared with CN non-AD, while p-tau181 plasma levels were higher in CI patients with AD. Plasma NfL levels correlated with CSF tau and p-tau181 in CN, and with CSF tau in CI patients. Plasma p-tau181 correlated with CSF p-tau181 in CN and with CSF tau, p-tau181, Aβ1-42, and Aβ1-42/Aβ1-40 in CI participants. Compared with a reference model, adding plasma p-tau181 improved the prediction of AD in CI patients while adding NfL did not. Adding p-tau181, but not NfL levels, to a reference model improved prediction of cognitive decline in CI participants. CONCLUSION: Plasma NfL indicates neurodegeneration while plasma p-tau181 levels can serve as a biomarker of cerebral AD pathology and cognitive decline. Their predictive performance depends on the presence of cognitive impairment

Erlangen Score Predicts Cognitive and Neuroimaging Progression in Mild Cognitive Impairment Stage of Alzheimer's Disease

Background: To alleviate the interpretation of the core Alzheimer’s disease (AD) cerebrospinal fluid (CSF) biomarkers, amyloid β1–42 (Aβ42), total tau (T-tau), and phosphorylated tau (P-tau), the Erlangen Score (ES) interpretation algorithm has been proposed. // Objective: In this study, we aim to assess the predictive properties of the ES algorithm on cognitive and neuroimaging outcomes in mild cognitive impairment (MCI). // Methods: All MCI subjects with an available baseline CSF sample from ADNI-1 were included (n = 193), and assigned an ES between 0 and 4 based on their baseline CSF biomarker profile. Structural magnetic resonance imaging brain scans and MMSE and ADAS-Cog scores were collected at up to 7 times in follow-up examinations. // Results: We observed strong and significant correlations between the ES at baseline and neuroimaging and cognitive results with patients with neurochemically probable AD (ES = 4) progressing significantly (p≤0.01) faster than those with a neurochemically improbable AD (ES = 0 or 1), and the subjects with neurochemically possible AD (ES = 2 or 3) in-between these two groups. // Conclusion: This study further demonstrates the utility of the ES algorithm as a as a tool in predicting cognitive and imaging progression in MCI patients

MAGGnet : an international network to foster mitigation of agricultural greenhouse gases

Liebig, M. A. USDA-ARS, Mandan, ND, USA.Franzluebbers, A. J. USDA-ARS, Raleigh, NC, USA.Alvarez, C. Instituto Nacional de Tecnología Agropecuaria (INTA). Centro Regional Córdoba. Estación Experimental Agropecuaria Manfredi (EEA Manfredi). Córdoba, Argentina.Chiesa, T. D. Universidad de Buenos Aires. Facultad de Agronomía. Instituto de Investigaciones Fisiológicas y Ecológicas Vinculadas a la Agricultura (IFEVA). Buenos Aires, Argentina.Lewczuk, N. Instituto Nacional de Tecnología Agropecuaria (INTA). Buenos Aires, Argentina.Piñeiro, Gervasio. Universidad de Buenos Aires. Facultad de Agronomía. Instituto de Investigaciones Fisiológicas y Ecológicas Vinculadas a la Agricultura (IFEVA). Buenos Aires, Argentina.Posse, Graciela Noemí. Instituto Nacional de Tecnología Agropecuaria (INTA). Buenos Aires, Argentina.Yahdjian, María Laura. Universidad de Buenos Aires. Facultad de Agronomía. Instituto de Investigaciones Fisiológicas y Ecológicas Vinculadas a la Agricultura (IFEVA). Buenos Aires, Argentina.8Research networks provide a framework for review, synthesis and systematic testing of theories by multiple scientists across international borders critical for addressing global-scale issues. In 2012, a GHG research network referred to as MAGGnet (Managing Agricultural Greenhouse Gases Network) was established within the Croplands Research Group of the Global Research Alliance on Agricultural Greenhouse Gases (GRA). With involvement from 46 alliance member countries, MAGGnet seeks to provide a platform for the inventory and analysis of agricultural GHG mitigation research throughout the world. To date, metadata from 315 experimental studies in 20 countries have been compiled using a standardized spreadsheet. Most studies were completed (74%) and conducted within a 1-3-year duration (68%). Soil carbon and nitrous oxide emissions were measured in over 80% of the studies. Among plant variables, grain yield was assessed across studies most frequently (56%), followed by stover (35%) and root (9%) biomass. MAGGnet has contributed to modeling efforts and has spurred other research groups in the GRA to collect experimental site metadata using an adapted spreadsheet. With continued growth and investment, MAGGnet will leverage limited-resource investments by any one country to produce an inclusive, globally shared meta-database focused on the science of GHG mitigation

Cardiac Surgery is Associated with Biomarker Evidence of Neuronal Damage

BACKGROUND: Anesthesia and surgery is commonly associated with central nervous system sequelae and cognitive symptoms, which may be caused by neuronal injury. Neuronal injury can be monitored by plasma concentrations of the neuronal biomarkers tau and neurofilament light protein (NFL). Currently, there are no studies examining whether neuronal injury varies between surgical procedures. OBJECTIVE: Our aim was to investigate if neuronal damage is more frequent after cardiac than after otolaryngeal surgery, as estimated by tau and NFL concentrations in plasma. METHODS: Blood samples were drawn before, during, and after surgery and concentrations of tau, NFL, Aβ40, and Aβ42 were measured in 25 patients undergoing cardiac surgery (9 off-pump and 16 on-pump) and 26 patients undergoing otolaryngeal surgery. RESULTS: Tau increased during surgery (1752%, p = 0.0001) and NFL rose seven days post-surgery (1090%, p < 0.0001) in patients undergoing cardiac surgery; even more in patients on-pump than off-pump. No changes were observed in patients undergoing otolaryngeal surgery and only minor fluctuations were observed for Aβ40 and Aβ42. CONCLUSION: Cardiac surgery is associated with neuronal injury, which is aggravated by extracorporeal circulation. Analyses of NFL and tau in blood may guide development of surgical procedures to minimize neuronal damage, and may also be used in longitudinal clinical studies to assess the relationship of surgery with future neurocognitive impairment or dementia

Incremental value of biomarker combinations to predict progression of mild cognitive impairment to Alzheimer’s dementia

Background The progression of mild cognitive impairment (MCI) to Alzheimer’s disease (AD) dementia can be predicted by cognitive, neuroimaging, and cerebrospinal fluid (CSF) markers. Since most biomarkers reveal complementary information, a combination of biomarkers may increase the predictive power. We investigated which combination of the Mini-Mental State Examination (MMSE), Clinical Dementia Rating (CDR)-sum-of-boxes, the word list delayed free recall from the Consortium to Establish a Registry of Dementia (CERAD) test battery, hippocampal volume (HCV), amyloid-beta1–42 (Aβ42), amyloid-beta1–40 (Aβ40) levels, the ratio of Aβ42/Aβ40, phosphorylated tau, and total tau (t-Tau) levels in the CSF best predicted a short-term conversion from MCI to AD dementia. Methods We used 115 complete datasets from MCI patients of the “Dementia Competence Network”, a German multicenter cohort study with annual follow-up up to 3 years. MCI was broadly defined to include amnestic and nonamnestic syndromes. Variables known to predict progression in MCI patients were selected a priori. Nine individual predictors were compared by receiver operating characteristic (ROC) curve analysis. ROC curves of the five best two-, three-, and four-parameter combinations were analyzed for significant superiority by a bootstrapping wrapper around a support vector machine with linear kernel. The incremental value of combinations was tested for statistical significance by comparing the specificities of the different classifiers at a given sensitivity of 85%. Results Out of 115 subjects, 28 (24.3%) with MCI progressed to AD dementia within a mean follow-up period of 25.5 months. At baseline, MCI-AD patients were no different from stable MCI in age and gender distribution, but had lower educational attainment. All single biomarkers were significantly different between the two groups at baseline. ROC curves of the individual predictors gave areas under the curve (AUC) between 0.66 and 0.77, and all single predictors were statistically superior to Aβ40. The AUC of the two-parameter combinations ranged from 0.77 to 0.81. The three-parameter combinations ranged from AUC 0.80–0.83, and the four- parameter combination from AUC 0.81–0.82. None of the predictor combinations was significantly superior to the two best single predictors (HCV and t-Tau). When maximizing the AUC differences by fixing sensitivity at 85%, the two- to four-parameter combinations were superior to HCV alone. Conclusion A combination of two biomarkers of neurodegeneration (e.g., HCV and t-Tau) is not superior over the single parameters in identifying patients with MCI who are most likely to progress to AD dementia, although there is a gradual increase in the statistical measures across increasing biomarker combinations. This may have implications for clinical diagnosis and for selecting subjects for participation in clinical trials

Cerebrospinal fluid and blood biomarkers for neurodegenerative dementias: An update of the Consensus of the Task Force on Biological Markers in Psychiatry of the World Federation of Societies of Biological Psychiatry

Contains fulltext : 191138.pdf (Publisher’s version ) (Open Access

A Specific Reduction in A beta(1-42) vs. a Universal Loss of A beta Peptides in CSF Differentiates Alzheimer's Disease From Meningitis and Multiple Sclerosis

A reduced concentration of A beta(1-42) in CSF is one of the established biomarkers of Alzheimer's disease Reduced CSF concentrations of A beta(1-42) have also been shown in multiple sclerosis, viral encephalitis and bacterial meningitis As neuroinflammation is one of the neuropathological hallmarks of Alzheimer's disease, an infectious origin of the disease has been proposed According to this hypothesis, amyloid pathology is a consequence of a microbial infection and the resulting immune defense Accordingly, changes in CSF levels of amyloid-beta peptides should be similar in AD and inflammatory brain diseases A beta(1-42) and A beta(1-40) levels were measured in cerebrospinal fluid by ELISA and Western blotting in 34 patients with bacterial meningitis (n = 9), multiple sclerosis (n = 5) or Alzheimer's disease (n = 9) and in suitable controls (n = 11) Reduced concentrations of A beta(1-42) were detected in patients with bacterial meningitis, multiple sclerosis and Alzheimer's disease However, due to a concurrent reduction in A beta(1-40) in multiple sclerosis and meningitis patients, the ratio of A beta(1-42)/A beta(1-40) was reduced only in the CSF of Alzheimer's disease patients Urea-SDS-PAGE followed by Western blotting revealed that all A beta peptide variants are reduced in bacterial meningitis, whereas in Alzheimer's disease, only A beta(1-42) is reduced These results have two implications First, they confirm the discriminatory diagnostic power of the A beta(1-42)/A beta(1-40) ratio Second, the differential pattern of A beta peptide reductions suggests that the amyloid pathology in meningitis and multiple sclerosis differs from that in AD and does not support the notion of AD as an infection-triggered immunopathology