Phase 2A Learnings Incorporated into RewinD-LB, a Phase 2B Clinical Trial of Neflamapimod in Dementia with Lewy Bodies.

BACKGROUND: In an exploratory 91-participant phase 2a clinical trial (AscenD-LB, NCT04001517) in dementia with Lewy bodies (DLB), neflamapimod showed improvement over placebo on multiple clinical endpoints. To confirm those results, a phase 2b clinical study (RewinD-LB, NCT05869669 ) that is similar to AscenD-LB has been initiated. OBJECTIVES: To optimize the choice of patient population, primary endpoint, and biomarker evaluations in RewinD-LB. DESIGN: Evaluation of the efficacy results from AscenD-LB, the main results of which, and a re-analysis after stratification for absence or presence of AD co-pathology (assessed by plasma ptau181), have been published. In addition, the MRI data from a prior phase 2a clinical trial in Early Alzheimer's disease (AD), were reviewed. SETTING: 22 clinical sites in the US and 2 in the Netherlands. PARTICIPANTS: Probable DLB by consensus criteria and abnormal dopamine uptake by DaTscan™ (Ioflupane I123 SPECT). INTERVENTION: Neflamapimod 40mg capsules or matching placebo capsules, twice-a-day (BID) or three-times-a-day (TID), for 16 weeks. MEASUREMENTS: 6-test Neuropsychological Test Battery (NTB) assessing attention and executive function, Clinical Dementia Rating Sum-of-Boxes (CDR-SB), Timed Up and Go (TUG), International Shopping List Test (ISLT). RESULTS: Within AscenD-LB, patients without evidence of AD co-pathology exhibited a neflamapimod treatment effect that was greater than that in the overall population and substantial (cohen's d effect size vs. placebo ≥ for CDR-SB, TUG, Attention and ISLT-recognition). In addition, the CDR-SB and TUG performed better than the cognitive tests to demonstrate neflamapimod treatment effect in comparison to placebo. Further, clinical trial simulations indicate with 160-patients (randomized 1:1), RewinD-LB conducted in patients without AD co-pathology has >95% (approaching 100%) statistical power to detect significant improvement over placebo on the CDR-SB. Preliminary evidence of positive treatment effects on beta functional connectivity by EEG and basal forebrain atrophy by MRI were obtained in AscenD-LB and the Early AD study, respectively. CONCLUSION: In addition to use of a single dose regimen of neflamapimod (40mg TID), key distinctions between phase 2b and phase 2a include RewinD-LB (1) excluding patients with AD co-pathology, (2) having CDR-SB as the primary endpoint, and (3) having MRI studies to evaluate effects on basal forebrain atrophy.

Network Hyperexcitability in Early Alzheimer's Disease: Is Functional Connectivity a Potential Biomarker?

Network hyperexcitability (NH) is an important feature of the pathophysiology of Alzheimer's disease. Functional connectivity (FC) of brain networks has been proposed as a potential biomarker for NH. Here we use a whole brain computational model and resting-state MEG recordings to investigate the relation between hyperexcitability and FC. Oscillatory brain activity was simulated with a Stuart Landau model on a network of 78 interconnected brain regions. FC was quantified with amplitude envelope correlation (AEC) and phase coherence (PC). MEG was recorded in 18 subjects with subjective cognitive decline (SCD) and 18 subjects with mild cognitive impairment (MCI). Functional connectivity was determined with the corrected AECc and phase lag index (PLI), in the 4-8 Hz and the 8-13 Hz bands. The excitation/inhibition balance in the model had a strong effect on both AEC and PC. This effect was different for AEC and PC, and was influenced by structural coupling strength and frequency band. Empirical FC matrices of SCD and MCI showed a good correlation with model FC for AEC, but less so for PC. For AEC the fit was best in the hyperexcitable range. We conclude that FC is sensitive to changes in E/I balance. The AEC was more sensitive than the PLI, and results were better for the thetaband than the alpha band. This conclusion was supported by fitting the model to empirical data. Our study justifies the use of functional connectivity measures as surrogate markers for E/I balance.

[Electroencephalography and connectivity in delirium]. / Eeg en innovatieve behandeling van verminderde hersenconnectiviteit bij delirium.

BACKGROUND: Delirium is associated with neurophysiological changes that can be identified with quantitative EEG analysis techniques (qEEG). AIM: To provide an overview of studies on neurophysiological changes in delirium using various qEEG analysis techniques. METHOD: Literature review. RESULTS: In delirium, there is an increase in delta and theta activity but a decrease in activity in the alpha frequency band. Additionally, there is a decrease in functional connectivity and efficiency of the brain network in the alpha frequency band. CONCLUSION: Delirium is characterized by diffuse slowing of the EEG, reduced functional connectivity, and decreased efficiency of the brain network. Improved functional connectivity could be a new approach to treat delirium.

[MRSA infection via a staff member with eczema]. / MRSA-besmetting via een medewerker met eczeem.

BACKGROUND: Transmission of MRSA from livestock to humans is rare, but it is advisable to remain alert. CASE STUDY: Following 2 hospital admissions within a month and a half, a 73-year-old patient was found to have become infected with MRSA. The MRSA type was livestock-related. Investigations into contact between the patient and staff revealed that 3 staff members were infected with the same bacteria; one of them had eczema on both hands. Her daughter, who worked intensively with horses, was revealed to be a carrier of the same type of MRSA. CONCLUSION: In order to prevent cross-contamination with MRSA it is essential to comply completely with hand hygiene requirements; this also applies to members of staff with skin infections such as eczema. Patient-related activities should be adapted if necessary. The company doctor plays an important role in this process.

Disrupted modular brain dynamics reflect cognitive dysfunction in Alzheimer's disease.

The relation between pathology and cognitive dysfunction in dementia is still poorly understood, although disturbed communication between different brain regions is almost certainly involved. In this study we combine magneto-encephalography (MEG) and network analysis to investigate the role of functional sub-networks (modules) in the brain with regard to cognitive failure in Alzheimer's disease. Whole-head resting-state (MEG) was performed in 18 Alzheimer patients (age 67 ± 9, 6 females, MMSE 23 ± 5) and 18 healthy controls (age 66 ± 9, 11 females, MMSE 29 ± 1). We constructed functional brain networks based on interregional synchronization measurements, and performed graph theoretical analysis with a focus on modular organization. The overall modular strength and the number of modules changed significantly in Alzheimer patients. The parietal cortex was the most highly connected network area, but showed the strongest intramodular losses. Nonetheless, weakening of intermodular connectivity was even more outspoken, and more strongly related to cognitive impairment. The results of this study demonstrate that particularly the loss of communication between different functional brain regions reflects cognitive decline in Alzheimer's disease. These findings imply the relevance of regarding dementia as a functional network disorder.

A marker associated with increased risk for severe liver disease in cystic fibrosis.

Genetic modifiers of liver disease in cystic fibrosis Bartlett et al. (2009) The Journal of the American Medical Association 302: 1076-1083.

A folate receptor defect that causes treatable neurological disorder in children.

Folate receptor alpha defect causes cerebral folate transport deficiency: a treatable neurodegenerative disorder associated with disturbed myelin metabolism Steinfeld et al. (2009) The American Journal of Human Genetics 85: 354-363.

Lipodystrophy and muscular dystrophy caused by PTRF mutations.

Human PTRF mutations cause secondary deficiency of caveolins resulting in muscular dystrophy with generalized lipodystrophy Hayashi et al. (2009) The Journal of Clinical Investigation 119: 2623-2633.

Cholesterol efflux via ATP-binding cassette transporter A1 (ABCA1) and cholesterol uptake via the LDL receptor influences cholesterol-induced impairment of beta cell function in mice.

AIMS/HYPOTHESIS: Cellular cholesterol accumulation is an emerging mechanism for beta cell dysfunction in type 2 diabetes. Absence of the cholesterol transporter ATP-binding cassette transporter A1 (ABCA1) results in increased islet cholesterol and impaired insulin secretion, indicating that impaired cholesterol efflux leads to beta cell dysfunction. In this study, we aimed to determine the role of the LDL receptor (LDLr) in islet cholesterol uptake and to assess the contributions of cholesterol uptake compared with efflux to islet cholesterol levels. METHODS: Islet cholesterol and beta cell function were assessed in mice lacking LDLr (Ldlr(-/-)), or apolipoprotein E (Apoe(-/-)), as well as in mice with beta-cell-specific deficiency of Abca1 crossed to Ldlr(-/-) mice. RESULTS: Hypercholesterolaemia resulted in increased islet cholesterol levels and decreased beta cell function in Apoe(-/-) mice but not in Ldlr(-/-) mice, suggesting that the LDL receptor is required for cholesterol uptake leading to cholesterol-induced beta cell dysfunction. Interestingly, when wild-type islets with functional LDL receptors were transplanted into diabetic, hypercholesterolaemic mice, islet graft function was normal compared with Ldlr(-/-) islets, suggesting that compensatory mechanisms can maintain islet cholesterol homeostasis in a hypercholesterolaemic environment. Indeed, transplanted wild-type islets had increased Abca1 expression. However, lack of the Ldlr did not protect Abca1(-/-) mice from islet cholesterol accumulation, suggesting that cholesterol efflux is the critical regulator of cholesterol levels in islets. CONCLUSIONS/INTERPRETATION: Our data indicate that islet cholesterol levels and beta cell function are strongly influenced by LDLr-mediated uptake of cholesterol into beta cells. Cholesterol efflux mediated by ABCA1, however, can compensate in hypercholesterolaemia to regulate islet cholesterol levels in vivo.

Graph theoretical analysis of magnetoencephalographic functional connectivity in Alzheimer's disease.

In this study we examined changes in the large-scale structure of resting-state brain networks in patients with Alzheimer's disease compared with non-demented controls, using concepts from graph theory. Magneto-encephalograms (MEG) were recorded in 18 Alzheimer's disease patients and 18 non-demented control subjects in a no-task, eyes-closed condition. For the main frequency bands, synchronization between all pairs of MEG channels was assessed using a phase lag index (PLI, a synchronization measure insensitive to volume conduction). PLI-weighted connectivity networks were calculated, and characterized by a mean clustering coefficient and path length. Alzheimer's disease patients showed a decrease of mean PLI in the lower alpha and beta band. In the lower alpha band, the clustering coefficient and path length were both decreased in Alzheimer's disease patients. Network changes in the lower alpha band were better explained by a 'Targeted Attack' model than by a 'Random Failure' model. Thus, Alzheimer's disease patients display a loss of resting-state functional connectivity in lower alpha and beta bands even when a measure insensitive to volume conduction effects is used. Moreover, the large-scale structure of lower alpha band functional networks in Alzheimer's disease is more random. The modelling results suggest that highly connected neural network 'hubs' may be especially at risk in Alzheimer's disease.

Effect of coexposure to methyl ethyl ketone (MEK) on n-hexane toxicokinetics in human volunteers.

In order to study the effects of methyl ethyl ketone (MEK) on the toxicokinetics of n-hexane and, in particular, the formation of 2,5-hexanedione from n-hexane in humans, volunteers were exposed to n-hexane (approx. 60 ppm, 2.4 microM in the inhaled air) with or without simultaneous inhalatory coexposure to MEK for 15.5 min. The concentration-time course of n-hexane (in exhaled alveolar air) and its neurotoxic metabolite, 2,5-hexanedione (in serum), were studied. The concentration-time courses obtained after exposure to n-hexane alone were compared with those obtained after coexposure to 200 or 300 ppm MEK in the same volunteer on the same day. No effect of MEK was observed on the concentration-time course of exhaled n-hexane. The concentration-time course of the metabolite, 2,5-hexanedione, revealed a decrease in the rate of formation of 2,5-hexanedione (about three-fold) after coexposure to MEK. Furthermore, the time to reach the peak concentration was increased from 18 to 30 min after the start of exposure. These changes in the concentration-time course of 2,5-hexanedione caused by MEK are most likely the result of inhibition of the biotransformation of one of the intermediate steps in the conversion of n-hexane to 2,5-hexanedione. These results indicate that the interaction of n-hexane and MEK leads to a decreased concentration of the neurotoxic metabolite 2,5-hexanedione (after short-term, acute exposure).

Determination of 2,5-hexanedione, a metabolite of n-hexane, in urine: evaluation and application of three analytical methods.

Three methods for the determination of 2,5-hexanedione (2,5-HD) in urine were compared in order to assess their applicability for toxicokinetic studies and biological monitoring of occupational exposure to n-hexane. Two of them were based on derivatization, followed by gas chromatography and electron-capture detection. Of these two, one is a modification of the other, already published, method. The third one involves direct extraction of 2,5-HD followed by gas chromatography and flame-ionization detection. To determine 2,5-HD in urine of workers occupationally exposed to n-hexane, the most straightforward method, direct extraction of 2,5-HD from urine, has been proven to be the most suitable. However, in case of very low concentrations of 2,5-HD in urine, or analysis of small samples of blood, e.g. in kinetic studies, it is necessary to use a more sensitive procedure. The sensitivity of the methods based on the derivatization of 2,5-HD followed by electron-capture detection, was, as expected, much higher in terms of analytical reliability. By using these methods, however, precautions are necessary to avoid a matrix effect.

Supercritical fluid extraction of polychlorinated biphenyls and pesticides from soil. Comparison with other extraction methods.

A comparison is made of supercritical fluid extraction (SFE) with two other techniques widely used for the extraction of polychlorinated biphenyls (PCBs) and organochlorine pesticides in soil. Extraction conditions for the SFE of PCBs and pesticides were first determined. An experimental approach was set up to determine the influence of different extraction parameters such as pressure, extraction time, static and dynamic extraction, restrictor type and collection solvent for off-line SFE. The use of carbon dioxide at 50 degrees C and 20 MPa, 10 min static followed by 20 min dynamic extraction with collection in iso-octane were been found to be the optimum conditions. Two types of soil, with a low and high content of organic carbon, respectively, spiked with 16 PCBs and organochlorine pesticides with a wide range of volatility and polarity at a level of 5 ng/g dry matter, were used as test materials. Conventional solvent extraction gives a good extraction yield for soil with a low content of organic carbon, but for peat soil the recoveries decrease dramatically to 30% for DDE, DDT and PCB 138 and 153. The recoveries with Soxhlet extraction are good, but an extra clean-up step before analysis is necessary. SFE gives good extraction yields for PCBs and organochlorine pesticides, varying between 85 and 105% with a reproducibility of 5% for each component for both types of soil. SFE is a fast, clean and reproducible method for the extraction of PCBs and organochlorine pesticides from these two soil matrices.

[Psychosocial aspects of the so-called short-bowel syndrome in children]. / Psychosociale aspecten van het zogenaamde korte-darmsyndroom bij kinderen.

In a retrospective study of 16 patients with (congenital) bowel pathology, aged 2 to 12, attention was paid to the psychosocial aspects of the short bowel syndrome. Parents were interviewed and parents' and teachers' reports of children's behavioural and emotional problems were obtained. Parents as well as children appeared to have reached a reasonable level of adjustment. Parents' emotions concerning the period of hospitalisation still appeared to be strikingly strong. Although most children did not show obvious psychopathology, problems were observed in the areas of behaviour and attention, interfering with optimal school functioning in the case of some children.

Mutagens in urine of non-smoking and smoking workers in an aircraft tyre retreading plant. Skin exposure as a causal factor?

In an aircraft type retreading plant environmental samples taken at several departments showed mutagenic properties. Thursday urine samples of non-smoking and smoking workers showed higher urinary mutagenicity than urine samples collected on Sundays, thus suggesting occupational exposure to mutagenic substances. A relation between urinary mutagenicity on Thursdays and skin contamination measured on Wednesdays was observed. The data suggest that intake through the skin plays an important role in the occupational exposure to mutagenic compounds of rubber workers.

Stimulating dental attendance in the Netherlands: comparison of three conceptual frameworks.

A field-experiment was done to study the differential effectiveness of three conceptual approaches to stimulate the demand for dental care. Persuasive messages were based on Ajzen & Fishbein's theory of reasoned action, on the health-belief model, and on the notion that knowledge of rights and obligations is a prerequisite for seeking dental care. All messages included an application form and a return envelope. Subjects were 269 members of Amsterdam health insurance companies. They had not received regular dental treatment and/or a certificate of dental fitness for at least 21/2 yr. Subjects received one of the three messages, an application form only (with a return envelope), or no message at all. Applying for treatment and acquiring a dental certificate were the behavioral measures. In all, 47.4% of insured who received message and/or application form applied for treatment. No control subjects applied. Fifteen months later 70% of the applicants had obtained a dental certificate. A differential effectiveness of the three messages was absent. Contrary to our expectations the condition of no message, application form only proved as effective as the message conditions. Results furthermore indicate that the main reason for not applying concerns fear of dental treatment. Whether or not the subject applied did not correlate with his knowledge of rights and obligations, sex, age, level of education, and occupational status.