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Highlights: [•] Preclinical Alzheimer's disease is common and can be diagnosed by CSF markers. [•] Preclinical AD and future cognitive decline and mortality are strongly associated. [•] Delay of onset of cognitive impairment in preclinical AD is a therapeutic target. [•] Subtle cognitive deficits can be remotely assessed using modern digital platforms. [•] A public–private collaborative approach may be required for AD prevention trials. [ABSTRACT FROM AUTHOR]

Abstract: The serotonergic system is implicated in the regulation of mood and cognition. Acute tryptophan depletion (ATD) is an experimental procedure for lowering central serotonin levels. Here, the effects of ATD on psychomotor processing, declarative memory, working memory, executive functions and attention are discussed. The most robust finding is that ATD impairs the consolidation of episodic memory for verbal information. Semantic memory appears to be unaffected by ATD although a limited variety of tasks examined effects in this domain. Similarly, evidence suggests ATD does not influence verbal, spatial and affective working memory. Most studies investigating effects on executive functions have produced non-specific or negative findings. In terms of attention, ATD either does not affect or may improve focused attention and ATD likely does not impact sustained and divided attention or attentional set-shifting. Although ATD is known to affect mood in certain vulnerable populations, the effects of ATD on cognition in non-vulnerable participants are independent of mood changes. Suggestions for future directions and implications for psychiatric illnesses are discussed. [Copyright &y& Elsevier]

The aim of this study was to establish the association of trait anxiety and anger with hormonal responses to acute challenges with two different 5-HT agonists in a mixed group of patients with depressed mood. Fifteen patients and 16 normal controls received single oral doses of 0.5 mg/kg meta-chlorophenylpiperazine (MCPP), a 5-HT2C agonist, and 10 mg of ipsapirone, a 5-HT1A agonist, according to a double-blind, placebo-controlled, cross-over design. Dutch-adapted versions of the Spielberger Trait-Anxiety Inventory and the Spielberger Trait-Anger Scale administered assessed at study entry. Hormonal responses, expressed as drug–placebo differences, to MCPP and ipsapirone (changes in cortisol, ACTH and prolactin) were measured. Blood levels of MCPP and ipsapirone were also measured. MCPP and ipsapirone elevated cortisol, ACTH and prolactin. In the patient group, there was a significant correlation between trait anxiety and the cortisol response to MCPP. No significant correlations between the ACTH and prolactin responses to MCPP and levels of anxiety/anger were observed in the patients. No significant correlations could be established between levels of anxiety/anger and hormonal responses to ipsapirone. This study provided evidence for an association between measures of anxiety/aggression and the hormonal response to MCPP. Thus, in subjects with depressed mood, high levels of anxiety suggest a higher probability of 5-HT2C disturbances. [Copyright &y& Elsevier]

Background: Methylphenidate improves motor response inhibition, typically assessed with the stop-signal task. The exact underlying mechanism for this, however, remains unknown. In addition, recent studies highlight that stop signals can have a confounding attentional-capture effect because of their low frequency in the task. In the current study, we assessed the effects of methylphenidate on neural networks of inhibitory control and attentional-capture within the context of two inhibitory control tasks. Methods: The effects of methylphenidate (40 mg) were assessed using functional magnetic resonance imaging in 16 healthy volunteers in a within-subject, double-blind, placebo-controlled design. Results: Methylphenidate significantly reduced activation of different regions within the right inferior frontal gyrus/insula to infrequent stimuli associated with successful inhibition, failed inhibition, and attentional capture. These inferior frontal gyrus regions showed different interregional connections with inhibitory and attention networks. For failed inhibitions, methylphenidate increased activation within performance-monitoring regions, including the superior frontal, anterior cingulate, and parietal-occipital cortices, but only after controlling for attentional capture. Conclusions: Our findings suggest that the improvement of response inhibition seen following methylphenidate administration is due to its influence on underlying attentional mechanisms linked to response control requirements. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Abnormalities of the auditory P300 are a robust finding in patients with psychosis. The purposes of this study were to determine whether patients with a psychotic disorder and their unaffected siblings show abnormalities in P300 and N100 and to establish test–retest reliabilities for these ERP components. Methods: Using an auditory oddball paradigm, P300 and N100 latency and amplitude were acquired from 19 patients with a psychotic disorder, 28 unaffected siblings, and 37 healthy controls, on two separate occasions. ERP components were compared between groups, using multilevel random regression analyses. Intraclass correlations were used to determine consistency of ERP components between the sessions. Results: A delayed target N100 latency was found in unaffected siblings. Patients showed significantly delayed P300 latency and diminished P300 amplitude compared to controls. Most ERP parameters showed good test–retest reliability. However, patients did not show sufficient reliability for N100 latency for standard stimuli. Conclusions: The present study failed to find significant P300 abnormalities in unaffected siblings. However, N100 latency is delayed in siblings and can be reliably measured in all groups for target stimuli, suggesting that this component, rather than P300, may serve as liability marker. Significance: N100 latency is a promising biomarker for psychosis liability. [Copyright &y& Elsevier]

Abstract: The investigation of novel drug targets for treating cognitive impairments associated with neurological and psychiatric disorders remains a primary focus of study in central nervous system (CNS) research. Many promising new therapies are progressing through preclinical and clinical development, and offer the potential of improved treatment options for neurodegenerative diseases such as Alzheimer''s disease (AD) as well as other disorders that have not been particularly well treated to date like the cognitive impairments associated with schizophrenia (CIAS). Among targets under investigation, cholinergic receptors have received much attention with several nicotinic agonists (α7 and α4β2) actively in clinical trials for the treatment of AD, CIAS and attention deficit hyperactivity disorder (ADHD). Both glutamatergic and serotonergic (5-HT) agonists and antagonists have profound effects on neurotransmission and improve cognitive function in preclinical experiments with animals; some of these compounds are now in proof-of-concept studies in humans. Several histamine H3 receptor antagonists are in clinical development not only for cognitive enhancement, but also for the treatment of narcolepsy and cognitive deficits due to sleep deprivation because of their expression in brain sleep centers. Compounds that dampen inhibitory tone (e.g., GABAA α5 inverse agonists) or elevate excitatory tone (e.g., glycine transporter inhibitors) offer novel approaches for treating diseases such as schizophrenia, AD and Down syndrome. In addition to cell surface receptors, intracellular drug targets such as the phosphodiesterases (PDEs) are known to impact signaling pathways that affect long-term memory formation and working memory. Overall, there is a genuine need to treat cognitive deficits associated with many neuropsychiatric conditions as well as an increasingly aging population. [Copyright &y& Elsevier]

Abstract: Acute tryptophan depletion (ATD) studies have shown that serotonin plays a role in learning and memory processes. In this study, we performed a pooled analysis of nine ATD studies in order to examine the nature of the memory-impairing effects of ATD and mediating factors, such as gender, age and vulnerability for disease in which disturbed serotonin was hypothesized to play a role. All studies that were used in this pooled analysis assessed declarative episodic memory using a verbal learning task paradigm. Immediate recall, delayed recall, and delayed recognition scores were examined. A total of 211 participants were included in the analysis. The analysis revealed that ATD impaired not only delayed recall, but also immediate recall. The ATD-induced impairments were larger in females than in males. Furthermore, ATD did not interact with any other serotonergic vulnerability and age. This suggests that the only factor that actually has the properties of a serotonergic vulnerability factor for declarative memory performance is female gender. The findings provide further support for a critical role of serotonin in declarative episodic memory. [Copyright &y& Elsevier]

Abstract: Background: It has frequently been demonstrated that experimental lowering of serotonin (5-HT) neurotransmission by acute tryptophan depletion (ATD) induces a transient depressed mood in 50–60% of patients treated with a selective serotonin reuptake inhibitor (SSRI) who are in remission from depression. In unmedicated depressed patients, ATD has no immediate effect on symptoms. The effects in currently depressed medicated patients have not been investigated. Methods: Fourteen currently depressed patients (seven patients treated with a selective serotonin–noradrenalin reuptake inhibitor (SSNRI); seven other treatment, non-SSNRI) received ATD in a double-blind, crossover design. Different strengths of the ATD mixture (aimed at 50% and 90% reduction of tryptophan) were used on separate days. Psychiatric symptoms were assessed at both sessions prior to, at +6.5 h, and at +24 h after ATD. Results: The ATD mixtures induced the expected reductions of plasma tryptophan levels. Full but not partial depletion improved mood and other psychiatric symptoms at +24 h in patients who received SSNRI treatment, as indicated by clinical ratings and self-report. Subjective sleep quality also improved. Conclusions: The effects of ATD on psychiatric symptoms in currently depressed patients are remarkably different from the results in recently remitted SSRI-treated patients. ATD in currently depressed patients treated with serotonergic antidepressants possibly provides important information about the mechanism of action of SSRIs. [Copyright &y& Elsevier]

Background: We evaluated the cognitive profile of 48 patients with major depression following their first myocardial infarction (MI). Methods: The cognitive performance of the patients was compared with the performance of 48 non-depressed MI patients and 48 healthy controls. Results: Depressed MI patients performed slower on a simple cognitive speed related measure compared with non-depressed MI patients and healthy controls. Attention and speed-related aspects of cognitive functioning were not affected. Surprisingly, (depressed) MI patients showed even better performances with respect to memory function. Limitation: No patients with non-MI-related depression were included. Conclusions: The cognitive profile of major depression after MI differs from that of non-cardiac-related depressive disorder, as described in the literature. This may reflect a different etiology of post MI depression from non-cardiac-related depression. [Copyright &y& Elsevier]