Cholecystokinin B receptor agonists alleviates anterograde amnesia in cholecystokinin-deficient and aged Alzheimer's disease mice.

BACKGROUND: As one major symptom of Alzheimer's disease (AD), anterograde amnesia describes patients with an inability in new memory formation. The crucial role of the entorhinal cortex in forming new memories has been well established, and the neuropeptide cholecystokinin (CCK) is reported to be released from the entorhinal cortex to enable neocortical associated memory and long-term potentiation. Though several studies reveal that the entorhinal cortex and CCK are related to AD, it is less well studied. It is unclear whether CCK is a good biomarker or further a great drug candidate for AD. METHODS: mRNA expressions of CCK and CCK-B receptor (CCKBR) were examined in two mouse models, 3xTg AD and CCK knock-out (CCK-/-) mice. Animals' cognition was investigated with Morris water maze, novel object recognition test and neuroplasticity with in-vitro electrophysiological recording. Drugs were given intraperitoneally to animals to investigate the rescue effects on cognitive deficits, or applied to brain slices directly to explore the influence in inducement of long-term potentiation. RESULTS: Aged 3xTg AD mice exhibited reduced CCK mRNA expression in the entorhinal cortex but reduced CCKBR expression in the neocortex and hippocampus, and impaired cognition and neuroplasticity comparable with CCK-/- mice. Importantly, the animals displayed improved performance and enhanced long-term potentiation after the treatment of CCKBR agonists. CONCLUSIONS: Here we provide more evidence to support the role of CCK in learning and memory and its potential to treat AD. We elaborated on the rescue effect of a promising novel drug, HT-267, on aged 3xTg AD mice. Although the physiological etiology of CCK in AD still needs to be further investigated, this study sheds light on a potential pharmaceutical candidate for AD and dementia.

The Safety and Efficacy of Remimazolam Compared to Dexmedetomidine for Awake Tracheal Intubation by Flexible Bronchoscopy: A Randomized, Double-Blind, Controlled Trial.

Background: Remimazolam is a novel ultra-short-acting benzodiazepine sedative that has the potential to be an alternative for procedural sedation due to its rapid sedation and recovery, no accumulation effect, stable hemodynamics, minimal respiratory depression, anterograde amnesia effect, and specific antagonist. Here, we aimed to compare the safety and efficacy of remimazolam with dexmedetomidine for awake tracheal intubation by flexible bronchoscopy (ATI-FB). Methods: Ninety patients scheduled for ATI-FB were randomly divided into three groups, each consisting of 30 cases: dexmedetomidine 0.6 µg/kg + sufentanil (group DS), remimazolam 0.073 mg/kg + sufentanil (group R1S), or remimazolam 0.093 mg/kg + sufentanil (group R2S). The primary outcome was the success rate of sedation. Secondary outcomes were MOAA/S scores, hemodynamic and respiratory parameters, intubation conditions, intubation time, tracheal intubation amnesia, and adverse events. Results: The success rates of sedation in groups R2S and DS were higher than that in group R1S (93.3%, 86.7%, respectively, vs 58.6%; P = 0.002), and intubation conditions were better than those in group R1S (P < 0.05). Group R2S had shorter intubation times than groups R1S and DS (P = 0.003), and a higher incidence of tracheal intubation amnesia than group DS (P = 0.006). No patient in the three groups developed hypoxemia or hypotension, and there were no significant differences in oligopnea, PetCO2, or bradycardia (P > 0.05). Conclusion: In conclusion, both DS and R2S had higher success rates of sedation, better intubation conditions, and minor respiratory depression, but R2S, with its shorter intubation time, higher incidence of anterograde amnesia, and ability to be antagonized by specific antagonists, may be a good alternative sedation regimen for patients undergoing ATI-FB.

Pure amnestic seizure: A clinico-intracranial EEG study.

OBJECTIVE: Enduring anterograde amnesia is caused by lesions in bilateral mesial temporal lobes. However, whether transient dysfunction of bilateral mesial temporal regions induces reversible amnesia has not been proven. We investigated this association in patients with epilepsy and analyzed the electroclinical correlation during pure amnestic seizures (PAS). PAS are defined as seizures with anterograde amnesia as the only ictal manifestation, accompanied by preserved responsiveness and other cognitive functions. METHODS: We retrospectively searched our intracranial EEG database to find PAS. Pure ictal amnesia was confirmed by immediate and comprehensive ictal examinations. RESULTS: Among 401 patients who underwent intracranial EEG recording, three patients with temporal lobe epilepsy (TLE) manifesting PAS were identified. The patients talked and behaved normally during seizure but did not remember the episodes afterwards. Ictal discharges were confined to bilateral mesial temporal regions, with no or mild involvement of surrounding structures. Spread of low-voltage fast activities to bilateral mesial temporal regions corresponded to onset of ictal anterograde amnesia. Two patients underwent unilateral mesial temporal resection and became seizure-free with improvement in cognitive functions. SIGNIFICANCE: PAS is a rare ictal semiology in TLE. Bilateral mesial temporal regions that play a critical role in memory encoding are presumably the symptomatogenic zones for PAS.

A case of severe anterograde amnesia in the era of smartphone technology.

A.V. is a young herpes simplex encephalitis (HSE) survivor who suffered extensive bilateral damage to the medial temporal lobe (MTL) leading to a severe and pervasive form of anterograde amnesia. Structural Magnetic Resonance Imaging (MRI) revealed lesions that encompass the hippocampus and amygdala in both hemispheres and that extend more laterally in the right temporal lobe. At the same time, detailed neuropsychological testing showed that the disparity between A.V.'s preserved intellectual functioning (Full Scale IQ: 115) and severe memory deficit (Delayed Memory Index: 42) is one of the largest on record. Despite this deficit, A.V. has regained a higher level of functioning and autonomy compared to previously documented amnesic cases with major bilateral MTL lesions. As a millennial, one advantage which A.V. has over prior amnesic cases is fluency with digital technology - particularly the smartphone. The analysis of his phone and specific app usage showed a pattern that is consistent with the strategy to offload cognitive tasks that would normally be supported by the MTL. A.V.'s behavior is significant in terms of rehabilitation and may have broader implications at the societal level and for public health given the ubiquity of smartphone technology and its potential to become integrated with neural mnemonic functions.

Epigenetic Processes of DNA Methylation Are Selectively Involved in the Mechanisms of Retrograde and Anteograde Amnesia.

The participation of DNA methylation processes in the mechanisms of anterograde and retrograde amnesia caused by impaired reconsolidation of conditioned food aversion memory by NMDA glutamate receptor antagonists or serotonin receptor antagonists, respectively, were studied on grape snails. Anterograde amnesia was characterized by impaired formation of long-term memory during repeated learning. Administration of a DNA methyltransferase (DNMT) inhibitor to amnestic animals resulted in accelerated formation of long-term memory during 1 day of repetitive training vs 3 days during initial training. In serotonin-dependent retrograde amnesia, repeated learning without DNMT inhibitor administration or after inhibitor injections led to the formation of long-term memory. The dynamics of memory formation was similar in both cases and did not differ from that during the initial training: the memory was formed within 3 days of training. Thus, epigenetic processes of DNA methylation are selectively involved in the mechanisms of anterograde amnesia, but do not participate in the mechanisms of retrograde amnesia.

The relationship between semantic and episodic memory: evidence from a case of severe anterograde amnesia.

It is increasingly being recognized that new declarative, consciously accessible information can be learned in anterograde amnesia, but it is not clear whether this learning is supported by episodic or semantic memory. We report a case of a 55-year-old man who experienced severe amnesia after limited damage to the medial temporal lobe following neurosurgical complications. His general cognitive performance and knowledge of new French words and public events that occurred before and after the onset of amnesia were assessed. Performance remained satisfactory on post-morbid vocabulary and public events, with a drop in performance observed for very recent public events only, while knowledge of very recent vocabulary was comparable to that of the control subjects. The implications of these findings for our understanding of the underlying learning mechanisms are discussed. This is the first report of acquisition of consciously accessible postmorbid knowledge of public events in a patient with severe amnesia.

Alcohol-induced blackouts among college student drinkers: A multilevel analysis.

OBJECTIVE: To identify factors (manner of drinking, combined alcohol and other substance use, physiology) that are associated with alcohol-induced blackouts (AIBs) over and above estimated blood alcohol concentration (eBAC). METHODS: Students (N = 462, 51.7 % female, 87.7 % White, Mage = 20.1) were assessed across 6 weekends via e-surveys (80-97 % response rate). eBAC was calculated using standard number of drinks, drinking duration, sex, and weight. Three-level multilevel models (days, weeks, persons) were conducted to test for main effects, controlling for eBAC. RESULTS: Protective behavioral strategies (PBS) were associated with decreased odds of AIBs on the daily (OR = 0.64, 95 % CI: 0.53, 0.77), weekly (OR = 0.84, 95 % CI: 0.72, 0.98), and person-levels (OR = 0.62, 95 % CI: 0.51, 0.74). Combined cannabis with alcohol was associated with increased odds of AIBs on the weekly (OR = 2.13, 95 % CI 1.13, 4.07) and person-levels (OR = 3.56, 95 % CI 1.60, 7.93). People who more frequently played drinking games (OR = 1.41, 95 % CI: 1.12, 1.77), pregamed (OR = 1.55, 95 % CI: 1.19, 2.03), and showed higher tolerance (OR = 1.22, 95 % CI: 1.08, 1.37) showed increased risk of AIBs, over and above eBAC levels. CONCLUSION: We identified a number of daily-, weekly-, and person-level factors that uniquely contribute to the prediction of AIBs even at equivalent eBACs. Many of these factors were behavioral, suggesting that they may serve as malleable prevention targets for AIBs in college student drinkers.

Associations between blackout drinking and self-reported everyday cognition among young adults.

INTRODUCTION: Blackout drinking, or alcohol-induced memory loss during at least some part of a drinking occasion, is common among young adults and associated with negative alcohol-related consequences. One potential unique effect of blackout drinking episodes could be prolonged, general difficulties forming new memories through impairments in encoding, storage, or retrieval. The current study examined preliminary associations between blackout drinking and self-reported everyday cognitive functioning (i.e., memory lapses, non-memory cognitive difficulties, cognitive concerns) among a sample of young adults. We also examined the moderating role of key factors linked to blackout drinking: gender and frequent simultaneous alcohol and cannabis use. METHODS: Participants (N = 479; 53% women) were aged 18-30 who reported past-year blackout drinking. Participants completed an online survey through Qualtrics Panels. RESULTS: More frequent blackout experiences were found to be significantly related to more memory lapses, more non-memory cognitive difficulties, and more cognitive concerns even after controlling for typical alcohol use behavior. Men and individuals reporting frequent simultaneous use indicated stronger relationships between blackout drinking frequency and cognitive outcomes. DISCUSSION AND CONCLUSIONS: Findings add to the growing body of literature supporting the uniquely hazardous effects of blackout drinking and identify individuals at heightened risk of harms. Given that associations between blackout drinking frequency and everyday cognitive functioning were identified even among a young adult sample suggests that blackout drinking may be a risky behavior that links to poorer cognitive functioning.

Prevalence and correlates of alcohol-induced blackout in a diverse sample of veterans.

BACKGROUND: Alcohol-induced blackouts have been associated concurrently and prospectively with alcohol-related harm. Although rates of heavy drinking among military samples tend to be comparable or higher than rates among civilian samples, the prevalence and correlates of blackout in the military population are understudied. METHODS: Veterans (N = 241, 29% female, 39% Black) reported on their alcohol consumption and mental health as part of a larger health-related study among veterans. In this secondary analysis, we tested theoretically and empirically informed predictors (gender, drinking quantity, and other drug use) and consequences [depression, posttraumatic stress disorder (PTSD)] of alcohol-induced blackout. Given the diversity of the sample, potential roles of racial/ethnic discrimination and drinking to cope in alcohol-induced blackout were also tested. RESULTS: Past-year prevalence of alcohol-induced blackout was 53% among veterans who drank alcohol and 68% among those who screened positive for hazardous drinking. Everyday experience of racial discrimination was the strongest concurrent predictor of alcohol-induced blackout. Drinking quantity and use of other drugs were significant correlates only in bivariate models. Controlling for gender, race, drinking quantity, other drug use, and discrimination, blackout frequency was significantly associated with symptoms of depression, but not symptoms of PTSD. Both blackout and racial discrimination were associated with drinking to cope. CONCLUSIONS: The prevalence and correlates of alcohol-induced blackout among veterans are largely consistent with those documented in civilian and young adult populations. Among racially diverse groups, racial discrimination may be more strongly associated with mental health symptoms than alcohol consumption or acute alcohol consequences such as blackout.

DNA methylation inhibition participates in the anterograde amnesia key mechanism through the suppression of the transcription of genes involved in memory formation in grape snails.

The study of the amnesia mechanisms is of both theoretical and practical importance. The mechanisms of anterograde amnesia are the least studied, due to the lack of an experimental model that allows studying this amnesia type molecular and cellular mechanisms. Previously, we found that conditional food aversion memory reconsolidation impairment in snails by NMDA glutamate receptor antagonists led to the amnesia induction, in the late stages of which (>10 days) repeated training did not cause long-term memory formation. In the same animals, long-term memory aversion to a new food type was formed. We characterized this amnesia as specific anterograde amnesia. In the present work we studied the role of epigenetic DNA methylation processes as well as protein and mRNA synthesis in the mechanisms of anterograde amnesia and memory recovery. DNMT methyltransferase inhibitors (iDNMT: zebularine, RG108 (N-Phthalyl-1-tryptophan), and 5-AZA (5-Aza-2'-deoxycytidine)) were used to alter DNA methylation. It was found that in amnesic animals the iDNMT administration before or after shortened repeated training led to the rapid long-term conditional food aversion formation (Ebbinghaus saving effect). This result suggests that amnestic animals retain a latent memory, which is the basis for accelerated memory formation during repeated training. Protein synthesis inhibitors administration (cycloheximide) before or immediately after repeated training or administration of RNA synthesis inhibitor (actinomycin D) after repeated training prevented memory formation under iDNMT action. The earlier protein synthesis inhibitor effect suggests that the proteins required for memory formation are translated from the pre-existing, translationally repressed mRNAs. Thus, we have shown for the first time that the anterograde amnesia key mechanism is DNMT-dependent suppression of the transcription of genes involved in memory mechanisms. Inhibition of DNMT during repeated training reversed these genes expression blockade, opening access to them by transcription factors synthesized during training from the pre-existing mRNAs.

Life-long deficits in social adaptation and the frontal lobes: New evidence, seventy-five years after Ackerly and Benton's landmark case report of JP.

The case of JP, reported by Ackerly and Benton in 1948 with a detailed follow-up by Ackerly in 1964, stands as the index case of developmental prefrontal damage and its impact on social adaptation. Although the 1948 case report included findings from a 1933 pneumoencephalogram and exploratory craniotomy, a definitive cause was never established for JP's prefrontal damage. Etiologies were never determined for the left-sided seizures that occurred when JP was age four, nor for the progressive anterograde amnesia that JP developed in middle age. Given Ackerly's thoroughness and long-term follow-up of his patient, it was hoped that a brain cutting would have been done, though no report of a post-mortem examination was published. The lead author of this paper (SB) set out to discover what had happened to JP after Ackerly's 1964 report and whether a brain cutting had in fact occurred. Using a variety of investigative approaches, it was discovered that a post-mortem brain examination had taken place. Those present at the brain cutting were identified, and the still-living witnesses to the brain cutting were interviewed. Previously unpublished, relevant materials were uncovered from archival sources. A film of the brain cutting, as well as photos, were located. A film of Ackerly interviewing JP prior to JP's death at age sixty-four also was found. The authors studied autopsy findings in the newly discovered video and still images. These findings were judged consistent with massive perinatal hemorrhagic damage to both frontal lobes. JP's left-sided seizures were likely due to activation of a focus from his congenital brain damage. The anterograde amnesia that was documented when JP was twenty-five and that was noted to worsen when he was forty-nine remains unexplained but may have been related to slowly progressive hydrocephalus. This paper expands what is known about the case of JP, making it the only report of a person with congenital frontal injury followed for their entire life including post-mortem brain examination.

Isolated bilateral fornix anterior columns infarction with acute amnesia and fiber tracts damage, a case report.

Isolated fornix anterior column infarction has rarely been described and is difficult to assess accurately using conventional magnetic resonance imaging (MRI). We report the case of a 75-year-old female who experienced acute anterograde amnesia. MRI performed within 24 h after amnesia onset showed an isolated infarction of the bilateral anterior columns of the fornix on diffusion-weighted imaging (DWI). Her symptoms persisted for up to 50 days, and diffusion tensor imaging (DTI) showed disruption of the fiber tracts of the fornix. when acute amnesia syndrome onset, fornix anterior column infarction should be considered, and optimized DWI and DTI methods are needed to study the fornix in vivo in future research.

Insomnia as a moderator of alcohol use and blackout: Potential role in acute physiological consequences.

BACKGROUND: Alcohol-induced blackout is associated concurrently and prospectively with alcohol-related harm, including emergency room visits and sexual coercion. Although sleep has not been linked empirically to blackout, symptoms of insomnia have also been linked to memory impairment, in which case insomnia symptoms may compound alcohol's negative effects on memory. This study tested insomnia symptoms as a moderator of the association between heavy drinking and alcohol-induced blackout. METHODS: Heavy-drinking young adults in college (N = 461, 69% female) completed assessments online from remote locations. Hierarchical linear regression was used to test a moderation model predicting blackout frequency. Logistic regression was used to test post hoc hypotheses. RESULTS: In contrast to our main hypothesis, heavy drinking was more weakly (not more strongly) associated with blackout in the context of more severe insomnia. Post hoc analyses tested insomnia symptoms as a unique moderator of the association between heavy drinking and likelihood of acute physiological consequences of alcohol use (blackout, passing out, nausea/throwing up, and hangover). Insomnia severity at least marginally moderated the association between heavy drinking and 4 out of 5 physiological consequences of alcohol use, and only moderated the association between drinking and 1 of 19 remaining consequences. CONCLUSIONS: Symptoms of insomnia are associated with alcohol-related harm, but may buffer associations between drinking and acute physiological consequences of alcohol. Additional research is needed to determine if alcohol heightens sensitivity to the acute physiological effects of alcohol, in which case less alcohol may be required for young adults with insomnia to experience these effects.

A mixed-methods approach to improve the measurement of alcohol-induced blackouts: ABOM-2.

BACKGROUND: Alcohol-induced blackouts describe memory loss resulting from alcohol consumption. Approximately half of college students report experiencing a blackout in their lifetime. Blackouts are associated with an increased risk for negative consequences, including serious injury. Research has documented two types of blackouts, en bloc (EB) and fragmentary (FB). However, research is limited by the lack of a validated measure that differentiates between these two forms of blackout. This study used a mixed-methods approach to improve the assessment of FB and EB among young adults. Specifically, we sought to improve the existing Alcohol-Induced Blackout Measure (ABOM), which was derived from a relatively small pool of items that did not distinguish FB from EB. METHODS: Study 1 used three rounds of cognitive interviewing with U.S. college students (N = 31) to refine existing assessment items. Nineteen refined blackout items were retained for Study 2. Study 2 used face validity, factor analysis, item response theory, and external validation analyses to test the two-factor blackout model among U.S. heavy-drinking college students (N = 474) and to develop and validate a new blackout measure (ABOM-2). RESULTS: Iterative factor analyses demonstrated that the items were well represented by correlated EB and FB factors, consistent with our hypothesis. External validation analyses demonstrated convergent and discriminant validity. These analyses also provided preliminary evidence for the two factors having differential predictive validity (e.g., FB correlated with enhancement drinking motives, while EB correlated with coping and conformity motives). CONCLUSIONS: The Alcohol-Induced Blackout Measure-2 (ABOM-2) improves the measurement of blackout experiences among college students. Its use could facilitate the examination of EB and FB as differential predictors of alcohol-related outcomes in future studies.

Use of protective behavioral strategies and blackout experience among mandated college students.

OBJECTIVE: Alcohol-induced blackouts are experienced by approximately half of college students who drink. People who use protective behavioral strategies (PBS) tend to experience fewer alcohol-related consequences of drinking, but the relationship between PBS and blackouts is unknown. This study examines the associations among the use of protective behavioral strategies and blacking out. METHODS: Participants were 484 college students, aged 18-22 (56% male, 51% first-year), who were mandated to complete alcohol education following an alcohol violation. Before the intervention, participants completed questionnaires that included questions about past month peak consumption, alcohol-related consequences, marijuana use frequency, and frequency of PBS use. Logistic regression analyses were conducted to evaluate how use of PBS was related to the odds of experiencing a blackout, controlling for consumption and other risk factors. RESULTS: Participants endorsing greater overall use of PBS had decreased odds of having experienced a blackout. However, this association depended on the type of PBS being used. Participants endorsing greater use of PBS regarding manner of drinking and stopping/limiting drinking had decreased odds of having experienced a blackout, but those who endorsed greater use of PBS relating to serious harm reduction did not. CONCLUSIONS: This study adds nuance to the idea that PBS protect against adverse alcohol-related consequences. Only PBS that serve to limit or slow consumption appear to be protective against experiencing blackouts. Research on specific associations between types of PBS and consequences may lead to improved outcomes in interventions that incorporate PBS.

The Role of DNA Methylation and Activity of Neurotransmitter Receptors in the Mechanisms of Specific Anterograde Amnesia and Memory Recovery.

Impairment of reconsolidation of conditioned food aversion memory led to the development of a specific anterograde amnesia: repeated training of amnestic snails did not induce long-term memory formation. DNA demethylation caused by injections of DNA methyltransferase inhibitor (DNAMT) during repeated training led to long-term memory formation. Injections of an NMDA glutamate receptor antagonist or a serotonin receptor antagonist prevented memory formation induced by administration of DNAMT inhibitor and repeated training. We hypothesize that methylation-dependent repression of neuronal genes underlies anterograde amnesia. Demethylation eliminated the blockade of these genes and created conditions for long-term memory formation, the induction mechanisms of which involve neurotransmitter receptors.

Stiff Person Syndrome and Encephalitis with GAD Antibodies with Severe Anterograde Amnesia in an Adolescent: A Case Study and Literature Review.

Antiglutamic acid decarboxylase (GAD65) encephalitis is rare and few pediatric cases have been reported, with variable clinical presentations. A 14-year-old female adolescent was managed in our department. She had been treated for several months for drug-resistant temporal lobe epilepsy and gradually presented major anterograde amnesia with confusion. Upon her arrival at the University Hospital Centre, she showed a classical form of stiff person syndrome. The brain magnetic resonance imaging showed bitemporal hyperintensities and hypertrophy of the amygdala. The blood and cerebrospinal fluid were positive for GAD65 antibodies. At 2 years of immunosuppressive treatment and rehabilitation, the course showed partial improvement of the memory and neuropsychiatric impairment, and epilepsy that continued to be active. GAD65 antibodies are associated with various neurological syndromes, and this presentation combining limbic encephalitis and stiff person syndrome is the first pediatric form published to date; there are also few cases described in adults.