Specificity of Neurobehavioral Outcomes Associated with Prenatal Alcohol Exposure

A current issue in alcohol research is whether a "neurobehavioral profile" can be identified for prenatal alcohol exposure, even when dysmorphic features are not present, or whether comparable neurobehavioral deficits are detected when damage is incurred by numerous neurotoxicants to which the fetus is exposed during a common developmental period. Failure to detect such differences may, in part, be an artifact of the global developmental tests used to assess outcome. Cognitive effects of prenatal exposure to three different teratogens [polychlorinated biphenyls (PCBs), alcohol, and cocaine] are examined to determine whether exposure to each substance results in a common or different pattern of impairment on the same set of newer, more narrow band infant tests. Comparison of findings from three independent cohorts indicate that PCB exposure was related to poorer recognition memory on the Fagan Test of Infant Intelligence (FTII) in Michigan infants exposed prenatally to PCB-contaminated fish, whereas prenatal alcohol exposure was unrelated to recognition memory but to slower processing speed on a new FTII measure and slower reaction time on Haith's Visual Expectancy Paradigm (VExP) in our Detroit alcohol-exposed infants. Preliminary findings from a new study of infants recently born to Taiwanese women accidentally contaminated with sizable amounts of PCBs indicate recognition memory deficits, confirming our Michigan findings, but no processing speed effects on the FTII. Recent findings from our Detroit cohort suggest that heavy prenatal cocaine exposure is related to poorer recognition memory on the FTII, but faster reaction times on the VExP, a pattern different from that seen for either PCBs or alcohol.     

Stakeholder perspectives on pharmacist involvement in a memory clinic to review patients’ medication management and assist with deprescribing

BackgroundMemory clinics usually involve a team of health professionals who assess and review people with memory impairment. Memory clinic patients are typically older, have multiple comorbidities and potentially inappropriate polypharmacy. Pharmacists are not typically part of memory clinic teams.ObjectiveTo explore stakeholder perspectives on pharmacist involvement in a memory clinic to conduct medication reviews and assist with deprescribing potentially inappropriate/unnecessary medications.MethodsQuantitative and qualitative evaluation of stakeholder perspectives within a deprescribing feasibility study. Patient/carer questionnaires were administered at 6-month follow-up. Fax-back surveys were sent to general practitioners (GPs) shortly after the pharmacist review. A focus group was conducted with memory clinic staff and semi-structured interviews with pharmacists at conclusion of the study. Focus group/interviews were transcribed and thematically analysed.ResultsMost patients/carers found the pharmacist medication review helpful (84%, 31/37) and believed it was important to have pharmacists in the memory clinic (92%, 36/39). Twenty-one (48%) GPs responded to the survey; most found the pharmacist reports useful for identifying inappropriate medication and providing deprescribing recommendations (86% and 81%, respectively), and 90% thought a pharmacist review should be part of the memory clinic service. Feedback from memory clinic staff and pharmacists was largely positive. Questions were raised by some staff about whether deprescribing fell within the clinic's scope of practice. Challenges associated with memory clinic-GP communication were highlighted.ConclusionPatients, GPs and memory clinic staff were receptive to increased pharmacist involvement in the memory clinic. Stakeholder feedback will inform the development and delivery of pharmacist medication reviews and deprescribing in memory clinics.     

Caspase-6 activity predicts lower episodic memory ability in aged individuals

Caspase-6 (Casp6), a cysteinyl protease that induces axonal degeneration, is activated early in Alzheimer Disease (AD) brains. To determine whether Casp6 activation is responsible for early cognitive impairment, we investigated the abundance of Casp6 activity, paired helical filament–1 (PHF-1) phosphorylated Tau and amyloid beta peptide (Aβ) pathology by immunohistochemistry in the hippocampal formation of aged non–cognitively impaired (NCI) individuals. Casp6 activity was restricted to the entorhinal cortex (ERC) and CA1 regions of the hippocampus. Pathology scores were then correlated with cognitive scores obtained within 1 year of death. Regression analyses revealed that ERC and CA1 Casp6 activity were the main contributor to lower episodic memory performance, whereas ERC PHF-1 pathology predicted lower semantic and working memory performance. Aβ did not correlate with any of the cognitive tests. Because Casp6 activity and PHF-1 pathology are intimately associated with AD pathology and memory decline is an early event in AD, we conclude that Casp6 activity and PHF-1 immunoreactivity in ERC identifies aged individuals at risk for developing AD.     

CD27 costimulation contributes substantially to the expansion of functional memory CD8+ T cells after peptide immunization

Naive T cells require signals from multiple costimulatory receptors to acquire full effector function and differentiate to long‐lived memory cells. The costimulatory receptor, CD27, is essential for optimal T‐cell priming and memory differentiation in a variety of settings, although whether CD27 is similarly required during memory CD8⁺ T‐cell reactivation remains controversial. We have used OVA and anti‐CD40 to establish a memory CD8⁺ T‐cell population and report here that their secondary expansion, driven by peptide and anti‐CD40, polyI:C, or LPS, requires CD27. Furthermore, antigenic peptide and a soluble form of the CD27 ligand, CD70 (soluble recombinant CD70 (sCD70)), is sufficient for secondary memory CD8⁺ T‐cell accumulation at multiple anatomical sites, dependent on CD80/86. Prior to boost, resting effector‐ and central‐memory CD8⁺ T cells both expressed CD27 with greater expression on central memory cells. Nonetheless, both populations upregulated CD27 after TCR engagement and accumulated in proportion after boosting with Ag and sCD70. Mechanistically, sCD70 increased the frequency of divided and cytolytic memory T cells, conferred resistance to apoptosis and enabled retardation of tumor growth in vivo. These data demonstrate the central role played by CD27/70 during secondary CD8⁺ T‐cell activation to a peptide Ag, and identify sCD70 as an immunotherapeutic adjuvant for antitumor immunity.     

Competition between T cells maintains clonal dominance during memory inflation induced by MCMV

Both human cytomegalovirus (HCMV) and murine cytomegalovirus (MCMV) establish persistent infections that induce the accumulation of virus‐specific T cells over time in a process called memory inflation. It has been proposed that T cells expressing T‐cell receptors (TCRs) with high affinity for HCMV‐derived peptides are preferentially selected after acute HCMV infection. To test this in the murine model, small numbers of OT‐I transgenic T cells, which express a TCR with high affinity for the SIINFEKL peptide, were transferred into congenic mice and recipients were challenged with recombinant MCMV expressing SIINFEKL. OT‐I T cells were selectively enriched during the first 3 weeks of infection. Similarly, in the absence of OT‐I T cells, the functional avidity of SIINFEKL‐specific T cells increased from early to late times postinfection. However, even when exceedingly small numbers of OT‐I T cells were transferred, their inflation limited the inflation of host‐derived T cells specific for SIINFEKL. Importantly, subtle minor histocompatibility differences led to late rejection of the transferred OT‐I T cells in some mice, which allowed host‐derived T cells to inflate substantially. Thus, T cells with a high functional avidity are selected shortly after MCMV infection and continuously sustain their clonal dominance in a competitive manner.     

Retrospective attention enhances visual working memory in the young but not the old: An ERP study

Behavioral evidence from the young suggests spatial cues that orient attention toward task‐relevant items in visual working memory (VWM) enhance memory capacity. Whether older adults can also use retrospective cues (“retro‐cues”) to enhance VWM capacity is unknown. In the current event‐related potential (ERP) study, young and old adults performed a VWM task in which spatially informative retro‐cues were presented during maintenance. Young but not older adults' VWM capacity benefited from retro‐cueing. The contralateral delay activity (CDA) ERP index of VWM maintenance was attenuated after the retro‐cue, which effectively reduced the impact of memory load. CDA amplitudes were reduced prior to retro‐cue onset in the old only. Despite a preserved ability to delete items from VWM, older adults may be less able to use retrospective attention to enhance memory capacity when expectancy of impending spatial cues disrupts effective VWM maintenance.     

What the heart forgets: Cardiac timing influences memory for words and is modulated by metacognition and interoceptive sensitivity

Mental functions are influenced by states of physiological arousal. Afferent neural activity from arterial baroreceptors at systole conveys the strength and timing of individual heartbeats to the brain. We presented words under limited attentional resources time‐locked to different phases of the cardiac cycle, to test a hypothesis that natural baroreceptor stimulation influences detection and subsequent memory of words. We show memory for words presented around systole was decreased relative to words at diastole. The deleterious memory effect of systole was greater for words detected with low confidence and amplified in individuals with low interoceptive sensitivity, as indexed using a heartbeat counting task. Our observations highlight an important cardiovascular channel through which autonomic arousal impacts a cognitive function, an effect mitigated by metacognition (perceptual confidence) and interoceptive sensitivity.     

H1 but not H2 histamine antagonist receptors mediate anxiety-related behaviors and emotional memory deficit in mice subjected to elevated plus-maze testing

This study investigated the role of H₁ and H₂ receptors in anxiety and the retrieval of emotional memory using a Trial 1/Trial 2 (T1/T2) protocol in an elevated plus-maze (EPM). Tests were performed on 2 consecutive days, designated T1 and T2. Before T1, the mice received intraperitoneal injections of saline (SAL), 20 mg/kg zolantidine (ZOL, an H₂ receptor antagonist), or 8.0 or 16 mg/kg chlorpheniramine (CPA, an H₁ receptor antagonist). After 40 min, they were subjected to the EPM test. In T2 (24 h later), each group was subdivided into two additional groups, and the animals from each group were re-injected with SAL or one of the drugs. In T1, the Student t-test showed no difference between the SAL and ZOL or 8 mg/kg CPA groups with respect to the percentages of open arm entries (%OAE) and open arm time (%OAT). However, administration of CPA at the highest dose of 16 mg/kg decreased %OAE and %OAT, but not locomotor activity, indicating anxiogenic-like behavior. Emotional memory, as revealed by a reduction in open arm exploration between the two trials, was observed in all experimental groups, indicating that ZOL and 8 mg/kg CPA did not affect emotional memory, whereas CPA at the highest dose affected acquisition and consolidation, but not retrieval of memory. Taken together, these results suggest that H₁ receptor, but not H₂, is implicated in anxiety-like behavior and in emotional memory acquisition and consolidation deficits in mice subjected to EPM testing.     

Influence of weight status at 2 years on memory performance at 4–5 years of age

Background: Memory performance is a cognitive function that is affected by environmental, genetic and socioeconomic factors, as well as by weight status.

Aim: To evaluate the association of weight status at 2?years of age with the memory performance of children at 4–5?years of age.

Subjects and methods: A cross-sectional study that used baseline data (2012) and data from two follow-up periods (2014 and 2016) of the PREDI Cohort Study. Participants were mother–child pairs 4–5?years after delivery who were seen between July 2016 and August 2017. The children’s memory performance was evaluated individually using a validated Brazilian instrument.

Results: Of the 203 children included in the study, 117 (57.6%), 52 (25.6%) and 34 (16.8%) had low, moderate and high memory performance, respectively. After adjusting for potential confounders, children with a BMI > 85th percentile had 3.33-times higher odds of exhibiting lower memory performance at 4–5?years of age than those with a BMI ≤ 85th percentile. In addition to the children’s BMI at 2?years of age, mother’s education was another independent determinant of children’s memory performance. There was a progressive increase in the odds of children having lower memory performance at 4–5?years of age as the mother’s education decreased.

Conclusion: Primary prevention of overweight and management of cognitive functions may be important strategies to improve the cognitive development of children in the future.