Lecanemab: Appropriate Use Recommendations.

Lecanemab (Leqembi®) is approved in the United States for the treatment of Alzheimer's disease (AD) to be initiated in early AD (mild cognitive impairment [MCI] due to AD or mild AD dementia) with confirmed brain amyloid pathology. Appropriate Use Recommendations (AURs) are intended to help guide the introduction of new therapies into real-world clinical practice. Community dwelling patients with AD differ from those participating in clinical trials. Administration of lecanemab at clinical trial sites by individuals experienced with monoclonal antibody therapy also differs from the community clinic-based administration of lecanemab. These AURs use clinical trial data as well as research and care information regarding AD to help clinicians administer lecanemab with optimal safety and opportunity for effectiveness. Safety and efficacy of lecanemab are known only for patients like those participating in the phase 2 and phase 3 lecanemab trials, and these AURs adhere closely to the inclusion and exclusion criteria of the trials. Adverse events may occur with lecanemab including amyloid related imaging abnormalities (ARIA) and infusion reactions. Monitoring guidelines for these events are detailed in this AUR. Most ARIA with lecanemab is asymptomatic, but a few cases are serious or, very rarely, fatal. Microhemorrhages and rare macrohemorrhages may occur in patients receiving lecanemab. Anticoagulation increases the risk of hemorrhage, and the AUR recommends that patients requiring anticoagulants not receive lecanemab until more data regarding this interaction are available. Patients who are apolipoprotein E ε4 (APOE4) gene carriers, especially APOE4 homozygotes, are at higher risk for ARIA, and the AUR recommends APOE genotyping to better inform risk discussions with patients who are lecanemab candidates. Clinician and institutional preparedness are mandatory for use of lecanemab, and protocols for management of serious events should be developed and implemented. Communication between clinicians and therapy candidates or those on therapy is a key element of good clinical practice for the use of lecanemab. Patients and their care partners must understand the potential benefits, the potential harms, and the monitoring requirements for treatment with this agent. Culture-specific communication and building of trust between clinicians and patients are the foundation for successful use of lecanemab.

Blood Biomarkers from Research Use to Clinical Practice: What Must Be Done? A Report from the EU/US CTAD Task Force.

Timely and accurate diagnosis of Alzheimer's disease (AD) in clinical practice remains challenging. PET and CSF biomarkers are the most widely used biomarkers to aid diagnosis in clinical research but present limitations for clinical practice (i.e., cost, accessibility). Emerging blood-based markers have the potential to be accurate, cost-effective, and easily accessible for widespread clinical use, and could facilitate timely diagnosis. The EU/US CTAD Task Force met in May 2022 in a virtual meeting to discuss pathways to implementation of blood-based markers in clinical practice. Specifically, the CTAD Task Force assessed: the state-of-art for blood-based markers, the current use of blood-based markers in clinical trials, the potential use of blood-based markers in clinical practice, the current challenges with blood-based markers, and the next steps needed for broader adoption in clinical practice.

Aducanumab: Appropriate Use Recommendations Update.

Aducanumab (Aduhelm) is approved in the United States for the treatment of patients with mild cognitive impairment due to Alzheimer's disease or mild AD dementia. Aducanumab Appropriate Use Recommendations (AURs) have been published and have helped guide best practices for use of aducanumab. As real-world use has occurred and more information has accrued, the AURs require refinement. We update the AURs to better inform appropriate patient selection and improve shared decision-making, safety monitoring, and risk mitigation in treated patients. Based on evolving experience we emphasize the importance of detecting past medical conditions that may predispose to amyloid related imaging abnormalities (ARIA) or may increase the likelihood of ARIA complications including autoimmune or inflammatory conditions, seizures, or disorders associated with extensive white matter pathology. The apolipoprotein E ε4 (APOE4) genotype is strongly associated with ARIA and exhibits a gene dose effect. We recommend that clinicians perform APOE genotyping to better inform patient care decisions, discussions regarding risk, and clinician vigilance concerning ARIA. As most ARIA occurs during the titration period of aducanumab, we suggest performing MRI before the 5th, 7th, 9th, and 12th infusions to improve detection. Uncommonly, ARIA may be recurrent or serious; we suggest additional parameters for treatment discontinuation taking these observations into account. It is important to continue to learn from the real-world use of aducanumab and the AURs will continue to evolve as new information becomes available. This AUR update does not address efficacy, price, or insurance coverage and is provided to assist clinicians to establish best practices for use of aducanumab in the treatment of patients with mild cognitive impairment and mild Alzheimer's dementia.

Aducanumab: Appropriate Use Recommendations.

Aducanumab has been approved by the US Food and Drug Administration for treatment of Alzheimer's disease (AD). Clinicians require guidance on the appropriate use of this new therapy. An Expert Panel was assembled to construct Appropriate Use Recommendations based on the participant populations, conduct of the pivotal trials of aducanumab, updated Prescribing Information, and expert consensus. Aducanumab is an amyloid-targeting monoclonal antibody delivered by monthly intravenous infusions. The pivotal trials included patients with early AD (mild cognitive impairment due to AD and mild AD dementia) who had confirmed brain amyloid using amyloid positron tomography. The Expert Panel recommends that use of aducanumab be restricted to this population in which efficacy and safety have been studied. Aducanumab is titrated to a dose of 10 mg/kg over a 6-month period. The Expert Panel recommends that the aducanumab be titrated to the highest dose to maximize the opportunity for efficacy. Aducanumab can substantially increase the incidence of amyloid-related imaging abnormalities (ARIA) with brain effusion or hemorrhage. Dose interruption or treatment discontinuation is recommended for symptomatic ARIA and for moderate-severe ARIA. The Expert Panel recommends MRIs prior to initiating therapy, during the titration of the drug, and at any time the patient has symptoms suggestive of ARIA. Recommendations are made for measures less cumbersome than those used in trials for the assessment of effectiveness in the practice setting. The Expert Panel emphasized the critical importance of engaging in a process of patient-centered informed decision-making that includes comprehensive discussions and clear communication with the patient and care partner regarding the requirements for therapy, the expected outcome of therapy, potential risks and side effects, and the required safety monitoring, as well as uncertainties regarding individual responses and benefits.

Practical recommendations for timely, accurate diagnosis of symptomatic Alzheimer's disease (MCI and dementia) in primary care: a review and synthesis.

The critical role of primary care clinicians (PCCs) in Alzheimer's disease (AD) prevention, diagnosis and management must evolve as new treatment paradigms and disease-modifying therapies (DMTs) emerge. Our understanding of AD has grown substantially: no longer conceptualized as a late-in-life syndrome of cognitive and functional impairments, we now recognize that AD pathology builds silently for decades before cognitive impairment is detectable. Clinically, AD first manifests subtly as mild cognitive impairment (MCI) due to AD before progressing to dementia. Emerging optimism for improved outcomes in AD stems from a focus on preventive interventions in midlife and timely, biomarker-confirmed diagnosis at early signs of cognitive deficits (i.e. MCI due to AD and mild AD dementia). A timely AD diagnosis is particularly important for optimizing patient care and enabling the appropriate use of anticipated DMTs. An accelerating challenge for PCCs and AD specialists will be to respond to innovations in diagnostics and therapy for AD in a system that is not currently well positioned to do so. To overcome these challenges, PCCs and AD specialists must collaborate closely to navigate and optimize dynamically evolving AD care in the face of new opportunities. In the spirit of this collaboration, we summarize here some prominent and influential models that inform our current understanding of AD. We also advocate for timely and accurate (i.e. biomarker-defined) diagnosis of early AD. In doing so, we consider evolving issues related to prevention, detecting emerging cognitive impairment and the role of biomarkers in the clinic.

Sleep electroencephalography and brain maturation: developmental trajectories and the relation with cognitive functioning.

Sleep has a crucial role in brain functioning and cognition, and several sleep electroencephalography (EEG) hallmarks are associated with intellectual abilities, neural plasticity, and learning processes. Starting from this evidence, a growing interest has been raised regarding the involvement of the sleep EEG in brain maturation and cognitive functioning during typical development (TD). The aim of this review is to provide a general framework about the maturational changes and the functional role of the human sleep EEG during TD from birth to late adolescence (≤22 years). The reviewed findings show large developmental modifications in several sleep EEG hallmarks (slow wave activity, sleep spindles, theta activity, and cyclic alternating pattern) during TD, and many studies support the notion of an active role of sleep slow wave activity in supporting brain maturation. Moreover, we focus on the possible relation between sleep microstructure, intelligence, and several memory domains (declarative, emotional, procedural), showing that sleep EEG oscillations seem involved in intellectual abilities and learning processes during TD, although results are often conflicting and divergent from findings in adults. Starting from the present literature, we propose that larger methodological uniformity, greater attention to the topographical and maturational aspects of the sleep EEG oscillations and their mutual interactions, and a higher number of longitudinal studies will be essential to clarify the role of the sleep EEG in cognitive functioning during TD.

Narcolepsy and emotional experience: a review of the literature.

Narcolepsy is a chronic sleep disorder characterized by excessive daytime sleepiness, cataplexy, hypnagogic hallucinations, and sleep paralysis. This disease affects significantly the overall patient functioning, interfering with social, work, and affective life. Some symptoms of narcolepsy depend on emotional stimuli; for instance, cataplectic attacks can be triggered by emotional inputs such as laughing, joking, a pleasant surprise, and also anger. Neurophysiological and neurochemical findings suggest the involvement of emotional brain circuits in the physiopathology of cataplexy, which seems to depending on the dysfunctional interplay between the hypothalamus and the amygdala associated with an alteration of hypocretin levels. Furthermore, behavioral studies suggest an impairment of emotions processing in narcolepsy-cataplexy (NC), like a probable coping strategy to avoid or reduce the frequency of cataplexy attacks. Consistently, NC patients seem to use coping strategies even during their sleep, avoiding unpleasant mental sleep activity through lucid dreaming. Interestingly, NC patients, even during sleep, have a different emotional experience than healthy subjects, with more vivid, bizarre, and frightening dreams. Notwithstanding this evidence, the relationship between emotion and narcolepsy is poorly investigated. This review aims to provide a synthesis of behavioral, neurophysiological, and neurochemical evidence to discuss the complex relationship between NC and emotional experience and to direct future research.

Oncologic doses of zoledronic acid induce site specific suppression of bone modelling in rice rats.

OBJECTIVES: To examine the effect of zoledronic acid (ZOL) on cortical bone modelling and healing of extraction sockets in the jaw bones of a rodent model. We hypothesized ZOL suppresses both the bone formation in the modelling mode in the jaw bones and alters the extraction site healing. MATERIAL & METHODS: Rice rats were administered saline solution and two dose regimens of ZOL: 0.1 mg/kg, twice a week, for 4 weeks (n=17, saline=8 & ZOL=9) and a higher dose of 0.4 mg/kg, weekly, for 9 weeks (n=30, saline=15 & ZOL=15). Two pairs of fluorochrome bone labels were administered. Extraction of maxillary teeth was performed in maxilla. Mineral apposition rate, mineralizing surface and bone formation rate (BFR) were quantified on periodontal (PDL), alveolar and basal bone surfaces, and in the trabecular bone of proximal tibia. Bone volume (BV) was evaluated at extraction sockets. Multivariate Gaussian models were used to account for repeated measurements, and analyzes were conducted in SAS V9.3. RESULTS: ZOL suppressed bone modelling (BFR/BS) at the PDL surfaces in the mandible (P<.05), but its effect was not significant at the periosteal surfaces of both jaws. BV for the healing sockets of ZOL treated animals was not significantly different (P=.07) compared to the saline group. ZOL suppressive effect was higher in the tibia compared to the jaws. CONCLUSION: ZOL severely suppresses coupled remodelling in the tibia, and the suppression of bone formation in the modelling mode in the jaws demonstrates the site specific effects of ZOL in rice rats.

Electrical stimulation of the frontal cortex enhances slow-frequency EEG activity and sleepiness.

Our aim was to enhance the spontaneous slow-frequency EEG activity during the resting state using oscillating transcranial direct currents (tDCS) with a stimulation frequency that resembles the spontaneous oscillations of sleep onset. Accordingly, in this preliminary study, we assessed EEG after-effects of a frontal oscillatory tDCS with different frequency (0.8 vs. 5 Hz) and polarity (anodal, cathodal, and sham). Two single-blind experiments compared the after effects on the resting EEG of oscillatory tDCS [Exp. 1=0.8 Hz, 10 subjects (26.2 ± 2.5 years); Exp. 2=5 Hz, 10 subjects (27.4 ± 2.4 years)] by manipulating its polarity. EEG signals recorded (28 scalp derivations) before and after stimulation [slow oscillations (0.5-1 Hz), delta (1-4 Hz), theta (5-7 Hz), alpha (8-12 Hz), beta 1 (13-15 Hz) and beta 2 (16-24 Hz)] were compared between conditions as a function of polarity (anodal vs. cathodal vs. sham) and frequency of stimulation (0.8 vs. 5 Hz). We found a significant relative enhancement of the delta activity after the anodal tDCS at 5 Hz compared to that at 0.8 Hz. This increase, even though not reaching the statistical significance compared to sham, is concomitant to a significant increase of subjective sleepiness, as assessed by a visual analog scale. These two phenomena are linearly related with a regional specificity, correlations being restricted to cortical areas perifocal to the stimulation site. We have shown that a frontal oscillating anodal tDCS at 5 Hz results in an effective change of both subjective sleepiness and spontaneous slow-frequency EEG activity. These changes are critically associated to both stimulation polarity (anodal) and frequency (5 Hz). However, evidence of frequency-dependence seems more unequivocal than evidence of polarity-dependence.

Relationship of fMRI activation to clinical trial memory measures in Alzheimer disease.

BACKGROUND: Functional MRI (fMRI) has shown promise as a tool to characterize altered brain function in Alzheimer disease (AD) and for use in proof of concept clinical trials. FMRI studies of subjects with AD have demonstrated altered hippocampal and neocortical activation while encoding novel stimuli compared to older controls. However, the relationship between fMRI activation and performance on standardized clinical trial memory measures has not been fully investigated. OBJECTIVE: To determine whether patterns of activation during an associative-memory fMRI paradigm correlate with performance on memory measures used in AD clinical trials. METHODS: Twenty-nine subjects with AD underwent neuropsychological testing, including the AD Assessment Scale (ADAS-Cog), and an associative-encoding fMRI paradigm. Scores were entered as regressors in SPM2 analyses of the differential fMRI activation to novel-vs-repeated (NvR) stimuli. To account for cerebral atrophy, native-space structure-function analyses were performed with subjects' high-resolution structural images. RESULTS: Performance on the ADAS-Cog verbal memory component, and the ADAS-Cog total score, correlated with NvR activation in left superior temporal (p = 0.0003; r = -0.51) and left prefrontal (p = 0.00001; r = -0.63) cortices. In a subgroup with more extensive neuropsychological testing (n = 14), performance on the Free and Cued Selective Reminding Test was correlated with activation in these same regions. fMRI activation remained correlated with performance even when accounting for atrophy. CONCLUSIONS: The relationship between functional MRI (fMRI) activation and standardized memory measures supports the potential use of fMRI to investigate regional mechanisms of treatment response in clinical trials of novel therapies for Alzheimer disease. .

Human granulocytic ehrlichiosis presenting as facial diplegia in a 42-year-old woman.

Neurologic manifestations of human ehrlichiosis are unusual and have been described almost exclusively in human monocytic ehrlichiosis associated with Ehrlichia chaffeensis. We report here a case of a previously healthy 42-year-old woman who developed bilateral facial nerve palsies in association with infection by the agent of human granulocytic ehrlichiosis (aoHGE). The diagnosis was made by specific polymerase chain reaction amplification of aoHGE sequences from samples of the patient's blood and cerebrospinal fluid (CSF), as well as propagation of aoHGE in culture of HL60 cells inoculated with the patient's CSF. To our knowledge, this is the first report directly demonstrating the presence of aoHGE in CSF, and it underscores the importance of considering HGE in patients presenting with a nonspecific febrile illness and unexplained neurologic manifestations. HGE should also be considered in the differential diagnosis of bilateral facial palsy-a rare occurrence.

Spontaneous esophageal perforation: atypical presentation.

A case of spontaneous esophageal perforation occurring in a healthy esophagus without any predisposing factor is reported. The problem of delayed diagnosis has been discussed.

MILORD: Multi-media Interaction with Large Object-oriented Radiological and clinical Databases.

The MILORD project concerns the storage, communication, and processing of large multi-media clinical information in an integrated environment. Advanced information technologies are exploited: new knowledge representation languages and tools, friendly human-computer interaction, 3D graphical processing and displaying of medical images, high performance parallel architectures, large-scale distributed data storage, federated environments for clinical cooperation. The project is developing an environment for designing and handling medical workstations. New turn-key marketable systems are expected after the end of the project. From its first version, the system is installed and under evaluation in large hospitals.

A single-pool model for intracellular calcium oscillations and waves in the Xenopus laevis oocyte.

We construct a minimal model of cytosolic free Ca2+ oscillations based on Ca2+ release via the inositol 1,4,5-trisphosphate (IP3) receptor/Ca2+ channel (IP3R) of a single intracellular Ca2+ pool. The model relies on experimental evidence that the cytosolic free calcium concentration ([Ca2+]c) modulates the IP3R in a biphasic manner, with Ca2+ release inhibited by low and high [Ca2+]c and facilitated by intermediate [Ca2+]c, and that channel inactivation occurs on a slower time scale than activation. The model produces [Ca2+]c oscillations at constant [IP3] and reproduces a number of crucial experiments. The two-dimensional spatial model with IP3 dynamics, cytosolic diffusion of IP3 (Dp = 300 microns 2 s-1), and cytosolic diffusion of Ca2+ (Dc = 20 microns 2 s-1) produces circular, planar, and spiral waves of Ca2+ with speeds of 7-15 microns.s-1, which annihilate upon collision. Increasing extracellular [Ca2+] influx increases wave speed and baseline [Ca2+]c. A [Ca2+]c-dependent Ca2+ diffusion coefficient does not alter the qualitative behavior of the model. An important model prediction is that channel inactivation must occur on a slower time scale than activation in order for waves to propagate. The model serves to capture the essential macroscopic mechanisms that are involved in the production of intracellular Ca2+ oscillations and traveling waves in the Xenopus laevis oocyte.

[Computerized prototype of a screening test for the assessment of psychomotor development in childhood]. / Prototipo automatizzato di un test di screening per la valutazione dello sviluppo psicomotorio dell'infanzia.

The aim of Denver's screening test is to study the psychomotor development of normal or supposed normal children aged from 0 to 6 years and to suggest further investigation when an abnormal development is noticed. The test is divided into 4 sections: social behavior, fine motility, language, gross motility. The results are valid only if the test is done in a standardized manner. The aim of this paper is to describe the computerized prototype of the Denver test in use at the Divisional Pediatric Ambulatory of "A. Gemelli" University Policlinic in Rome. This test is used in the context of an automatized ambulatory management system called ARPIA, capable of interacting and guiding "non expert" user. The program performs the following functions: 1) General instructions for the execution and interpretation of the test. The original instructions of the test (1975 version) have been used. 2) Input, modification, exclusion of questions. The archive is organized in the following manner: questions are divided in the above four sections, according to the child, undergoing the test, age limit; the questions regarding information that can be asked directly to the parents or the display of a picture that better explains the test are marked. During the test the questions may be modified using a menu with a certain number of options to facilitate the use of the system. The questions to eliminate from the test may be appropriately marked and removed. The text is not physically deleted from the archive. The inverse operation of inclusion of a formerly removed question may be performed too.(ABSTRACT TRUNCATED AT 250 WORDS)

[Implementation of a computerized pharmacological database for pediatric use]. / Realizzazione di un archivio farmacologico computerizzato ad uso pediatrico.

The authors present a pharmacological database to support teaching and care activity carried out in the Divisional Paediatric Ambulatory of the Catholic University of Rome. This database is included in a integrated system, ARPIA (Ambulatory and Research in Pediatric by Information Assistance), devoted to manage ambulatory paediatric data. ARPIA has been implemented by using a relational DBMS, very cheap and highly diffused on personal computers. The database specifies: active ingredient and code number related to it, clinical uses, doses, contra-indications and precautions, adverse effects, besides the possible wrapping available on the market. All this is showed on a single for that appears on the screen and allows a fast reading of the most important elements characterizing every drug. The search of the included drugs can be made on the basis of three different detailed lists: active ingredient, proprietary preparation and clinical use. It is, besides, possible to have a complete report about the drugs requested by the user. This system allows the user, without modifying the program, to interact with the included data modifying each element of the form. In the system there is also a fast consultation handbook containing for every active ingredient, the complete list of italian proprietary medicines. This system aims to give a better knowledge of the most commonly used drugs, not only limited to the paediatrician but also to the ambulatory health staff; an improvement of the therapy furthering, a more effective use of several pharmacological agents and first of all a training device not only to specialists but also to students.

Functionality of the ARPIA ambulatory information system.

Although database-based medical information systems are becoming popular, experiments done by researchers tell us that physicians still do not fully accept them. Key factors for changing physicians' practice habits are the availability of more powerful methods and tools for interactive data acquisition and retrieval. Problems involving human engineering usually require the identification of and experimentation with many novel approaches before the most suitable answer is discovered. ARPIA is an ambulatory information system experimenting on the effectiveness and acceptability (by medical users) of new intelligent and friendly interaction techniques and tools. In particular, it tests a novel flexible dialogue-based man-machine interface offering physical and logical data 'independence' during retrieval operations. Other features of the system are: a fast and robust data acquisition environment; a text- and picture-based data presentation and report generation facility; finally, a set of modules offering the ambulatory staff effective assistance in some extra complex interactive tasks. A user-oriented description of the main functionality of ARPIA is given; users' feedback summarizing almost 2 years of usage of the system is also reported.

[The laboratory in monitoring high-risk pregnancy]. / Il laboratorio nel monitoraggio della gravidanza a rischio.

108 cases of high-risk pregnancy are object of our investigation (gestosis, feto-placental insufficiency, chronic nephropathy, rhesus immunization). HCG, plasma estriol, HPL and beta1-SP1-glycoprotein have been studied. The simultaneous determination of the four hormones makes it possible to establish the degree of the pregnancy risk, eventual fetal suffering and the hormonal course of pregnancy.