Combination of plasma amyloid beta(1-42/1-40) and glial fibrillary acidic protein strongly associates with cerebral amyloid pathology

BACKGROUND: Blood-based biomarkers for Alzheimer's disease (AD) might facilitate identification of participants for clinical trials targeting amyloid beta (Abeta) accumulation, and aid in AD diagnostics. We examined the potential of plasma markers Abeta(1-42/1-40), glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) to identify cerebral amyloidosis and/or disease severity. METHODS: We included individuals with a positive (n = 176: 63 ± 7 years, 87 (49%) females) or negative (n = 76: 61 ± 9 years, 27 (36%) females) amyloid PET status, with syndrome diagnosis subjective cognitive decline (18 PET+, 25 PET-), mild cognitive impairment (26 PET+, 24 PET-), or AD-dementia (132 PET+). Plasma Abeta(1-42/1-40), GFAP, and NfL were measured by Simoa. We applied two-way ANOVA adjusted for age and sex to investigate the associations of the plasma markers with amyloid PET status and syndrome diagnosis; logistic regression analysis with Wald's backward selection to identify an optimal panel that identifies amyloid PET positivity; age, sex, and education-adjusted linear regression analysis to investigate associations between the plasma markers and neuropsychological test performance; and Spearman's correlation analysis to investigate associations between the plasma markers and medial temporal lobe atrophy (MTA). RESULTS: Abeta(1-42/1-40) and GFAP independently associated with amyloid PET status (p = 0.009 and p  0.33, p < 0.001). Abeta(1-42/1-40) showed a moderate negative correlation with MTA (Spearman's rho = - 0.24, p = 0.001). DISCUSSION AND CONCLUSIONS: Combination of plasma Abeta(1-42/1-40) and GFAP provides a valuable tool for the identification of amyloid PET status. Furthermore, plasma GFAP and NfL associate with various disease severity measures suggesting potential for disease monitoring

Plasma and CSF biomarkers in a memory clinic: Head-to-head comparison of phosphorylated tau immunoassays

INTRODUCTION: Direct comparisons of the main blood phosphorylated tau immunoassays in memory clinic populations are needed to understand possible differences. METHODS: In the BIODEGMAR study, 197 participants presenting with cognitive complaints were classified into an Alzheimer's disease (AD) or a non-AD cerebrospinal fluid (CSF) profile group, according to their amyloid beta 42/ phosphorylated tau (Aβ42/p-tau) ratio. We performed a head-to-head comparison of nine plasma and nine CSF tau immunoassays and determined their accuracy to discriminate abnormal CSF Aβ42/p-tau ratio. RESULTS: All studied plasma tau biomarkers were significantly higher in the AD CSF profile group compared to the non-AD CSF profile group and significantly discriminated abnormal CSF Aβ42/p-tau ratio. For plasma p-tau biomarkers, the higher discrimination accuracy was shown by Janssen p-tau217 (r = 0.76; area under the curve [AUC] = 0.96), ADx p-tau181 (r = 0.73; AUC = 0.94), and Lilly p-tau217 (r = 0.73; AUC = 0.94). DISCUSSION: Several plasma p-tau biomarkers can be used in a specialized memory clinic as a stand-alone biomarker to detect biologically-defined AD. HIGHLIGHTS: Patients with an Alzheimer's disease cerebrospinal fluid (AD CSF) profile have higher plasma phosphorylated tau (p-tau) levels than the non-AD CSF profile group. All plasma p-tau biomarkers significantly discriminate patients with an AD CSF profile from the non-AD CSF profile group. Janssen p-tau217, ADx p-tau181, and Lilly p-tau217 in plasma show the highest accuracy to detect biologically defined AD. Janssen p-tau217, ADx p-tau181, Lilly p-tau217, Lilly p-tau181, and UGot p-tau231 in plasma show performances that are comparable to their CSF counterparts

Lipids revert inert Aβ amyloid fibrils to neurotoxic protofibrils that affect learning in mice

Although soluble oligomeric and protofibrillar assemblies of Aβ-amyloid peptide cause synaptotoxicity and potentially contribute to Alzheimer's disease (AD), the role of mature Aβ-fibrils in the amyloid plaques remains controversial. A widely held view in the field suggests that the fibrillization reaction proceeds ‘forward' in a near-irreversible manner from the monomeric Aβ peptide through toxic protofibrillar intermediates, which subsequently mature into biologically inert amyloid fibrils that are found in plaques. Here, we show that natural lipids destabilize and rapidly resolubilize mature Aβ amyloid fibers. Interestingly, the equilibrium is not reversed toward monomeric Aβ but rather toward soluble amyloid protofibrils. We characterized these ‘backward' Aβ protofibrils generated from mature Aβ fibers and compared them with previously identified ‘forward' Aβ protofibrils obtained from the aggregation of fresh Aβ monomers. We find that backward protofibrils are biochemically and biophysically very similar to forward protofibrils: they consist of a wide range of molecular masses, are toxic to primary neurons and cause memory impairment and tau phosphorylation in mouse. In addition, they diffuse rapidly through the brain into areas relevant to AD. Our findings imply that amyloid plaques are potentially major sources of soluble toxic Aβ-aggregates that could readily be activated by exposure to biological lipids

Monitoring Electroconvulsive Therapy–Related Anxiety

Objectives: A reliable questionnaire designed to measure electroconvulsive therapy (ECT)-related anxiety is currently not available. We report the development and evaluation of the ECT-Related Anxiety Questionnaire (ERAQ), a questionnaire that measures anxiety with respect to ECT in clinical practice. Methods : Patients 18 years or older who were about to start with or were having an ECT course were asked to complete a self-designed 17-item ECT-related anxiety questionnaire. We investigated the psychometric properties of the ERAQ through the use of an exploratory and confirmatory factor analysis and Item Response Theory analysis. Results: One hundred eighty-three patients were included. From the exploratory factor analysis, we conclude that the scale is unidimensional. The confirmatory factor analysis model did not fit well to the data. The Item Response Theory analysis showed that the slope estimates ranged from 1.23 to 2.95 and that location parameters reflected a sizable underlying anxiety for ECT. Conclusions: The ERAQ is a questionnaire that assesses ECT-related anxiety. It offers a measure of global severity and differentiates between various topics of anxiety. The ERAQ thus informs the clinician about the specific aspects of an ECT course that could trigger a patient's anxiety and can guide clinicians in how to discuss ECT-related anxieties with patients

Monitoring ECT-related anxiety: the ECT-related Anxiety questionnaire (ERAQ)

Introduction:Although electroconvulsive therapy (ECT) is an effective and safe treatment, a significant proportion of patients are afraid of the treatment. Too often, this ECT-related anxiety makes patients refuse or discontinue ECT. A reliable questionnaire designed to measure ECT-related anxiety is currently not available. We report the development and psychometric evaluation of the ECT-related anxiety questionnaire (ERAQ), a questionnaire that measures anxiety with respect to ECT in clinical practice. Methods: This study was conducted at two psychiatric hospitals in Belgium and The Netherlands. Patients who were about to start with or were having an ECT course were included. ECT-related anxiety was measured with a Dutch self-designed questionnaire. The questionnaire contains 17 items further subdivided into a five-point scale. We used an exploratory (EFA) and confirmatory factor analysis (EFA) to investigatepsychometric properties of the ERAQ. We also examined the ERAQ in the context of item response theory (IRT). Results: 185 patients were included. From the EFA we concluded that the scale was unidimensional. The location parameters for the 17 parameters reflected a sizeable underlying anxiety for ECT (-1.06; 2.02). Conclusion: ERAQ is a valid questionnaire to measure ECT-related anxiety. ERAQ offers a global score in the form of the sum of 17 items on a 4-category response scale as a measure of severity of ECT-related anxiety. Moreover, the ERAQ can differentiate between various topics of anxiety and can inform the clinician about the specific aspects of an ECT-course that trigger less or more anxiety. The differentiation of the ERAQ between various topics and intensities of anxiety can have an important role in the future development of psychoeducational programs and in guiding clinicians to talk with their patients and relatives about ECT-related anxieties

Training discrimination diminishes maladaptive avoidance of innocuous stimuli in a fear conditioning paradigm

Anxiety disorders are the most common mental disorder worldwide. Although anxiety disorders differ in the nature of feared objects or situations, they share a common mechanism by which fear generalizes to related but innocuous objects, eliciting avoidance of objects and situations that pose no objective risk. This overgeneralization appears to be a crucial mechanism in the persistence of anxiety psychopathology. In this study we test whether an intervention that promotes discrimination learning reduces generalization of fear, in particular, harm expectancy and avoidance compared to an irrelevant (control) training. Healthy participants (N = 80) were randomly allocated to a training condition. Using a fear conditioning paradigm, participants first learned visual danger and safety signals (set 1). Baseline level of stimulus generalization was tested with ambiguous stimuli on a spectrum between the danger and safety signals. There were no differences between the training groups. Participants then received the stimulus discrimination training or a control training. After training, participants learned a new set of danger and safety signals (set 2), and the level of harm expectancy generalization and behavioural avoidance of ambiguous stimuli was tested. Although the training groups did not differ in fear generalization on a cognitive level (harm expectancy), the results showed a different pattern of avoidance of ambiguous stimuli, with the discrimination training group showing less avoidance of stimuli that resembled the safety signals. These results support the potential of interventions that promote discrimination learning in the treatment of anxiety disorders

Monitoring Electroconvulsive Therapy-Related Anxiety: The ECT-Related Anxiety Questionnaire

Objectives: A reliable questionnaire designed to measure electroconvulsive therapy (ECT)-related anxiety is currently not available. We report the development and evaluation of the ECT-Related Anxiety Questionnaire (ERAQ), a questionnaire that measures anxiety with respect to ECT in clinical practice. Methods : Patients 18 years or older who were about to start with or were having an ECT course were asked to complete a self-designed 17-item ECT-related anxiety questionnaire. We investigated the psychometric properties of the ERAQ through the use of an exploratory and confirmatory factor analysis and Item Response Theory analysis. Results: One hundred eighty-three patients were included. From the exploratory factor analysis, we conclude that the scale is unidimensional. The confirmatory factor analysis model did not fit well to the data. The Item Response Theory analysis showed that the slope estimates ranged from 1.23 to 2.95 and that location parameters reflected a sizable underlying anxiety for ECT. Conclusions: The ERAQ is a questionnaire that assesses ECT-related anxiety. It offers a measure of global severity and differentiates between various topics of anxiety. The ERAQ thus informs the clinician about the specific aspects of an ECT course that could trigger a patient's anxiety and can guide clinicians in how to discuss ECT-related anxieties with patients

Training discrimination diminishes maladaptive avoidance of innocuous stimuli in a fear conditioning paradigm

Anxiety disorders are the most common mental disorder worldwide. Although anxiety disorders differ in the nature of feared objects or situations, they share a common mechanism by which fear generalizes to related but innocuous objects, eliciting avoidance of objects and situations that pose no objective risk. This overgeneralization appears to be a crucial mechanism in the persistence of anxiety psychopathology. In this study we test whether an intervention that promotes discrimination learning reduces generalization of fear, in particular, harm expectancy and avoidance compared to an irrelevant (control) training. Healthy participants (N = 80) were randomly allocated to a training condition. Using a fear conditioning paradigm, participants first learned visual danger and safety signals (set 1). Baseline level of stimulus generalization was tested with ambiguous stimuli on a spectrum between the danger and safety signals. There were no differences between the training groups. Participants then received the stimulus discrimination training or a control training. After training, participants learned a new set of danger and safety signals (set 2), and the level of harm expectancy generalization and behavioural avoidance of ambiguous stimuli was tested. Although the training groups did not differ in fear generalization on a cognitive level (harm expectancy), the results showed a different pattern of avoidance of ambiguous stimuli, with the discrimination training group showing less avoidance of stimuli that resembled the safety signals. These results support the potential of interventions that promote discrimination learning in the treatment of anxiety disorders

A relationship between verbal aggression and personal network size

Aggression has been associated with negative social consequences. Yet, more adaptive views of aggression hold that it can have beneficial correlates as well. In four studies, we examined the relationship between aggression and personal network size, a property associated with important social benefits. The results pointed to a consistent positive relationship between verbal aggression and social network size. This relationship remained after controlling for third variables like extraversion and when using different measures of network size. The fourth study sought to explain the relationships in terms of mutual relationships with status and power, but found no support for mediation