Identifying components of the Shewanella phage LambdaSo lysis system.

Phage-induced lysis of Gram-negative bacterial hosts usually requires a set of phage lysis proteins, a holin, an endopeptidase, and a spanin system, to disrupt each of the three cell envelope layers. Genome annotations and previous studies identified a gene region in the Shewanella oneidensis prophage LambdaSo, which comprises potential holin- and endolysin-encoding genes but lacks an obvious spanin system. By a combination of candidate approaches, mutant screening, characterization, and microscopy, we found that LambdaSo uses a pinholin/signal-anchor-release (SAR) endolysin system to induce proton leakage and degradation of the cell wall. Between the corresponding genes, we found that two extensively nested open-reading frames encode a two-component spanin module Rz/Rz1. Unexpectedly, we identified another factor strictly required for LambdaSo-induced cell lysis, the phage protein Lcc6. Lcc6 is a transmembrane protein of 65 amino acid residues with hitherto unknown function, which acts at the level of holin in the cytoplasmic membrane to allow endolysin release. Thus, LambdaSo-mediated cell lysis requires at least four protein factors (pinholin, SAR endolysin, spanin, and Lcc6). The findings further extend the known repertoire of phage proteins involved in host lysis and phage egress. IMPORTANCE: Lysis of bacteria can have multiple consequences, such as the release of host DNA to foster robust biofilm. Phage-induced lysis of Gram-negative cells requires the disruption of three layers, the outer and inner membranes and the cell wall. In most cases, the lysis systems of phages infecting Gram-negative cells comprise holins to disrupt or depolarize the membrane, thereby releasing or activating endolysins, which then degrade the cell wall. This, in turn, allows the spanins to become active and fuse outer and inner membranes, completing cell envelope disruption and allowing phage egress. Here, we show that the presence of these three components may not be sufficient to allow cell lysis, implicating that also in known phages, further factors may be required.

An autonomous plasmid as an inovirus phage satellite.

Bacterial viruses (phages) are potent agents of lateral gene transfer and thus are important drivers of evolution. A group of mobile genetic elements, referred to as phage satellites, exploits phages to disseminate their own genetic material. Here, we isolated a novel member of the family Inoviridae, Shewanella phage Dolos, along with an autonomously replicating plasmid, pDolos. Dolos causes a chronic infection in its host Shewanella oneidensis by phage production with only minor effects on the host cell proliferation. When present, plasmid pDolos hijacks Dolos functions to be predominantly packaged into phage virions and released into the environment and, thus, acts as a phage satellite. pDolos can disseminate further genetic material encoding, e.g., resistances or fluorophores to host cells sensitive to Dolos infection. Given the rather simple requirements of a plasmid for takeover of an inovirus and the wide distribution of phages of this group, we speculate that similar phage-satellite systems are common among bacteria.IMPORTANCEPhage satellites are mobile genetic elements, which hijack phages to be transferred to other host cells. The vast majority of these phage satellites integrate within the host's chromosome, and they all carry remaining phage genes. Here, we identified a novel phage satellite, pDolos, which uses an inovirus for dissemination. pDolos (i) remains as an autonomously replicating plasmid within its host, (ii) does not carry recognizable phage genes, and (iii) is smaller than any other phage satellites identified so far. Thus, pDolos is the first member of a new class of phage satellites, which resemble natural versions of phagemids.

Dementia During the COVID-19 Pandemic: Experiences From Clinicians, Patients, and Caregivers in Switzerland.

Background: The COVID-19 pandemic had a significant impact on the Swiss health care system, affecting especially vulnerable people, such as patients suffering from dementia. The purpose of this study was to investigate the challenges experienced by dementia patients, their carers, and clinicians during the pandemic in Switzerland. Methods: An online survey was sent to all memory clinics in the German speaking part of Switzerland. Patients diagnosed with dementia and their carers were recruited for semi-structured telephone interviews at the memory clinic of the University Hospital Zurich. Results: A total of 28 clinicians, 17 carers, and seven patients participated in this study. According to the clinicians, all aspects of clinical work were affected by the pandemic. Carers did not perceive a significant role of the pandemic in the disease progression of the patients, despite many challenges faced. Patients described a high level of conscientiousness during the pandemic. Recommendations for future scenarios were provided from all groups. Conclusion: In order to increase the systemic resilience of the Swiss health care system, it is important to consider the experiences and recommendations of vulnerable groups and health care professionals for future public health measures and policies.

Implementation of Cognitive Behavioral Therapy in e-Mental Health Apps: Literature Review.

BACKGROUND: To address the matter of limited resources for treating individuals with mental disorders, e-mental health has gained interest in recent years. More specifically, mobile health (mHealth) apps have been suggested as electronic mental health interventions accompanied by cognitive behavioral therapy (CBT). OBJECTIVE: This study aims to identify the therapeutic aspects of CBT that have been implemented in existing mHealth apps and the technologies used. From these, we aim to derive research gaps that should be addressed in the future. METHODS: Three databases were screened for studies on mHealth apps in the context of mental disorders that implement techniques of CBT: PubMed, IEEE Xplore, and ACM Digital Library. The studies were independently selected by 2 reviewers, who then extracted data from the included studies. Data on CBT techniques and their technical implementation in mHealth apps were synthesized narratively. RESULTS: Of the 530 retrieved citations, 34 (6.4%) studies were included in this review. mHealth apps for CBT exploit two groups of technologies: technologies that implement CBT techniques for cognitive restructuring, behavioral activation, and problem solving (exposure is not yet realized in mHealth apps) and technologies that aim to increase user experience, adherence, and engagement. The synergy of these technologies enables patients to self-manage and self-monitor their mental state and access relevant information on their mental illness, which helps them cope with mental health problems and allows self-treatment. CONCLUSIONS: There are CBT techniques that can be implemented in mHealth apps. Additional research is needed on the efficacy of the mHealth interventions and their side effects, including inequalities because of the digital divide, addictive internet behavior, lack of trust in mHealth, anonymity issues, risks and biases for user groups and social contexts, and ethical implications. Further research is also required to integrate and test psychological theories to improve the impact of mHealth and adherence to the e-mental health interventions.

Elevated Expression of Toxin TisB Protects Persister Cells against Ciprofloxacin but Enhances Susceptibility to Mitomycin C.

Bacterial chromosomes harbor toxin-antitoxin (TA) systems, some of which are implicated in the formation of multidrug-tolerant persister cells. In Escherichia coli, toxin TisB from the tisB/istR-1 TA system depolarizes the inner membrane and causes ATP depletion, which presumably favors persister formation. Transcription of tisB is induced upon DNA damage due to activation of the SOS response by LexA degradation. Transcriptional activation of tisB is counteracted on the post-transcriptional level by structural features of tisB mRNA and RNA antitoxin IstR-1. Deletion of the regulatory RNA elements (mutant Δ1-41 ΔistR) uncouples TisB expression from LexA-dependent SOS induction and causes a 'high persistence' (hip) phenotype upon treatment with different antibiotics. Here, we demonstrate by the use of fluorescent reporters that TisB overexpression in mutant Δ1-41 ΔistR inhibits cellular processes, including the expression of SOS genes. The failure in SOS gene expression does not affect the hip phenotype upon treatment with the fluoroquinolone ciprofloxacin, likely because ATP depletion avoids strong DNA damage. By contrast, Δ1-41 ΔistR cells are highly susceptible to the DNA cross-linker mitomycin C, likely because the expression of SOS-dependent repair systems is impeded. Hence, the hip phenotype of the mutant is conditional and strongly depends on the DNA-damaging agent.

Glacial heterogeneity in Southern Ocean carbon storage abated by fast South Indian deglacial carbon release.

Past changes in ocean 14C disequilibria have been suggested to reflect the Southern Ocean control on global exogenic carbon cycling. Yet, the volumetric extent of the glacial carbon pool and the deglacial mechanisms contributing to release remineralized carbon, particularly from regions with enhanced mixing today, remain insufficiently constrained. Here, we reconstruct the deglacial ventilation history of the South Indian upwelling hotspot near Kerguelen Island, using high-resolution 14C-dating of smaller-than-conventional foraminiferal samples and multi-proxy deep-ocean oxygen estimates. We find marked regional differences in Southern Ocean overturning with distinct South Indian fingerprints on (early de-)glacial atmospheric CO2 change. The dissipation of this heterogeneity commenced 14.6 kyr ago, signaling the onset of modern-like, strong South Indian Ocean upwelling, likely promoted by rejuvenated Atlantic overturning. Our findings highlight the South Indian Ocean's capacity to influence atmospheric CO2 levels and amplify the impacts of inter-hemispheric climate variability on global carbon cycling within centuries and millennia.

Isolation and Characterization of Shewanella Phage Thanatos Infecting and Lysing Shewanella oneidensis and Promoting Nascent Biofilm Formation.

Species of the genus Shewanella are widespread in nature in various habitats, however, little is known about phages affecting Shewanella sp. Here, we report the isolation of phages from diverse freshwater environments that infect and lyse strains of Shewanella oneidensis and other Shewanella sp. Sequence analysis and microscopic imaging strongly indicate that these phages form a so far unclassified genus, now named Shewanella phage Thanatos, which can be positioned within the subfamily of Tevenvirinae (Duplodnaviria; Heunggongvirae; Uroviricota; Caudoviricetes; Caudovirales; Myoviridae; Tevenvirinae). We characterized one member of this group in more detail using S. oneidensis MR-1 as a host. Shewanella phage Thanatos-1 possesses a prolate icosahedral capsule of about 110 nm in height and 70 nm in width and a tail of about 95 nm in length. The dsDNA genome exhibits a GC content of about 34.5%, has a size of 160.6 kbp and encodes about 206 proteins (92 with an annotated putative function) and two tRNAs. Out of those 206, MS analyses identified about 155 phage proteins in PEG-precipitated samples of infected cells. Phage attachment likely requires the outer lipopolysaccharide of S. oneidensis, narrowing the phage's host range. Under the applied conditions, about 20 novel phage particles per cell were produced after a latent period of approximately 40 min, which are stable at a pH range from 4 to 12 and resist temperatures up to 55°C for at least 24 h. Addition of Thanatos to S. oneidensis results in partial dissolution of established biofilms, however, early exposure of planktonic cells to Thanatos significantly enhances biofilm formation. Taken together, we identified a novel genus of Myophages affecting S. oneidensis communities in different ways.

Virtopsy of a gravid Boa constrictor using computed tomography and magnetic resonance imaging.

This article presents radiologic examinations of a deeply sedated Boa constrictor with boid inclusion body disease (BIBD) as an adjunction to the subsequent necropsy. This method is known as virtopsy. The Boa constrictor in the present case was gravid. Computed tomography (CT) allowed for the detailed depiction of a fetal skeleton at the rear end of the adult snake. Furthermore, tiny gas formation was detected inside the cranium of the fetus, which was deemed a radiologic sign for decomposition. Magnetic resonance imaging (MRI) delineated the soft tissue at high resolution. This article illustrates the use of CT and MRI for the examination of a gravid Boa constrictor before necropsy and demonstrates the detection of "normal" postmortem findings leading to the confirmation of fetal death in situ.

Development, diagnosis and therapy of ketosis in non-gravid and non-lactating Guinea pigs.

BACKGROUND: Ketosis is a metabolic disorder often triggered by anorexia in animals fed on high energy diets. Although mostly described in pregnant female guinea pigs, under the name of pregnancy toxicosis; there is limited information on ketosis in males and non-pregnant females, often presented to clinics with anorexia or inappetence. The objective of this study was to observe progression of ketosis in guinea pigs, document the changes and evaluate diagnostic methods and a therapeutic approach. RESULTS: Twenty eight adult guinea pigs (Cavia porcellus), castrated males and intact females of obese and slim body condition were fasted for 3 days and refed afterwards. The slim animals served as control group for body condition. Either slim and fat animals were divided into two treatment groups: half of them received fluid replacements with glucose subcutaneously, the other half did not receive any injection and served as treatment control. Serum beta-hydroxybutyrate, and urine acetoacetate and acetone were measured during and after fasting. Serum ALT, bile acids and liver histology were also analyzed after 7 days of refeeding (and therapy). Females and obese guinea pigs showed a significantly higher increase in ketone bodies in serum and urine. Obese, female, or animals not receiving therapy needed more time to regulate ketone bodies to normal levels than slim animals, males or animals receiving therapy. Liver histology revealed increased hepatocyte degeneration and higher glycogen content in obese animals and animals receiving therapy, and additionally more glycogen content in males. Only minor hepatic fat accumulation was documented. Bile acids showed good correlation to histological liver changes whereas ALT did not. CONCLUSIONS: Female and obese animals react more intensively to fasting. As preventive management, animals should be kept in adequate body condition, fasting should be avoided, and anorexia should be treated immediately. In such a case, urinary dip sticks to detect ketone bodies are a useful diagnostic tool. Glucose therapy leads to faster cessation of ketogenesis and should be recommended in cases of ketosis. However, it needs to be adjusted to avoid hepatocyte glycogen overload and degeneration. Measuring bile acids presents a valuable indicator of liver damage.

How do technique and coordination change during learning of a whole-body task: Application to the upstart in gymnastics.

When learning swinging skills on a bar there has been conflicting advice in the research literature regarding whether to coach the "gold standard" technique to novices. The present study aimed to determine how technique (joint angle time histories) and (inter-limb) coordination changed as novice gymnasts learned a fundamental gymnastics skill (the upstart). It was hypothesised that both technique and coordination would become more like an expert as learning progressed. Eight novice gymnasts, unable to perform an upstart, underwent four months of training, with the number of successful upstarts out of 10 recorded at the start and then every month subsequently. In the first and last sessions motion capture was used to determine joint kinematics. Root mean squared differences for the joint angle time histories and continuous relative phase at the shoulder and hip were calculated between the novices and an expert gymnast. As training progressed technique and coordination became more like the expert gymnast. The more successful novices were better able to time their actions within the swing than the less successful novices. Gymnastics coaches teach towards a "gold standard" technique since being successful at the skill is not the only goal, as considerations for future skill development are made.

Measuring the Impact of Delayed Cerebral Ischemia on Neuropsychological Outcome After Aneurysmal Subarachnoid Hemorrhage-Protocol of a Swiss Nationwide Observational Study (MoCA-DCI Study).

BACKGROUND: The exact relationship between delayed cerebral ischemia (DCI) following aneurysmal subarachnoid hemorrhage (aSAH) and neuropsychological impairment remains unknown, as previous studies lacked a baseline examination after aneurysm occlusion but before the DCI-period. Neuropsychological evaluation of acutely ill patients is often applied in a busy intensive care unit (ICU), where distraction represents a bias to the obtained results. OBJECTIVE: To evaluate the relationship between DCI and neuropsychological outcome after aSAH by comparing the Montreal Cognitive Assessment (MoCA) results in aSAH patients with and without DCI at 3 mo with a baseline examination before the DCI-period (part 1). To determine the reliability of the MoCA, when applied in an ICU setting (part 2). METHODS: Prospective, multicenter, and observational study performed at all Swiss neurovascular centers. For part 1, n = 240 consecutive aSAH patients and for part 2, n = 50 patients with acute brain injury are recruited. EXPECTED OUTCOMES: Part 1: Effect size of the relationship between DCI and neuropsychological outcome (MoCA). Part 2: Reliability measures for the MoCA. DISCUSSION: The institutional review boards approved this study on July 4, 2017 under case number BASEC 2017-00103. After completion, the results will be offered to an international scientific journal for peer-reviewed publication. This study determines the exact impact of DCI on the neuropsychological outcome after aSAH, unbiased by confounding factors such as early brain injury or patient-specific characteristics. The study provides unique insights in the neuropsychological state of patients in the early period after aSAH.

Impact of food structure on the compatibility of heated WPI-pectin-complexes in meat dispersions.

Process-stable complexes composed of whey protein isolate (WPI) and sugar beet pectin have great potential as structuring agents or fat replacers in foods. The current study investigates the compatibility of heated WPI : pectin complexes in different meat matrices. Spreadable raw-fermented sausages and sliceable emulsion-type sausages were therefore manufactured containing biopolymer complexes with various WPI : pectin ratios r (2 : 1, 8 : 1). Macro- and microstructural properties of the meat dispersions were analyzed in terms of colour, texture, rheometry, sensory, and confocal laser scanning microscopy (CLSM) measurements. Textural and sensorial results demonstrated that the meat products became increasingly soft and yellowish as the biopolymer ratio r was increased regardless of the meat matrix, whereas pH and water activity values were not affected. CLSM images revealed that the meat protein network became disrupted and loose in the presence of pectin, which was attributed to a thermodynamic incompatibility effect. The results obtained from this study highlight that biopolymer complexes might be suitable fat mimetics, particularly for spreadable meat products.

Loading conditions in the spine, hip and knee during different executions of back extension exercises.

BACKGROUND: Back extension (BE) is a strength exercise for training the dorsal trunk and hip muscles. To optimise training recommendations that avoid overloading and possible injury, the aim of this study was to determine the loading conditions and the influence of different execution forms of BE on spine, hip and knee ranges of motion (RoMs), joint moments and muscle activity. METHODS: The kinematics, kinetics and muscle activity (EMG) of two execution types (BEh: dynamic hip, BEs: dynamic spine) and two versions (one-legged and two-legged) of BE were measured in 16 subjects. RoMs and external joint moments were calculated using an inverse dynamics approach and analysed with a linear mixed model. RESULTS: Although lumbar spine flexion was observed in both execution types, thoracic spine flexion predominantly occurred during BEs, whereas thoracic spine extension was observed during BEh. Larger maximal back and hip moments were observed for BEh than for BEs. The activity of the dorsal back and hip muscles, as observed using EMG, was increased for one-legged executions. CONCLUSION: To strengthen the hips and lower back, BEh seem to be more efficient due to the higher moments, with higher or similar RoMs in the hip and lower back. One-legged BEs seem to provide an effective training for the hamstrings and hip regions without subjecting the spine to excessive loading, possibly promoting this as an effective exercise during training and rehabilitation.

Mixing behaviour of WPI-pectin-complexes in meat dispersions: impact of biopolymer ratios.

Particulated complexes composed of oppositely charged biopolymers were incorporated into highly concentrated protein matrices as potential fat replacers and structuring agents. A multistep procedure was therefore utilized to generate process-stable complexes, which were subsequently embedded into emulsion-type sausages, whereas macro- and microstructural properties were then assessed. Firstly, stock WPI and sugar beet pectin solutions were mixed under neutral conditions (pH 7) at various biopolymer ratios r (2 : 1, 5 : 1, 8 : 1). Secondly, the pH of the biopolymer mixture was decreased to 3.5 to promote associative complexation. Thirdly, electrostatically attracted biopolymer particles were subjected to a heat treatment (ϑ = 85 °C, 20 min) to enhance their stability against superimposed stresses. Finally, fat-reduced emulsion-type sausages were fabricated containing stable WPI-pectin complexes. The results revealed that the heat treatment increased the pH-stability of the biopolymer complexes. In addition, textural and sensorial analysis demonstrated that the meat products became increasingly soft as the biopolymer ratio r increased. This effect was attributed to thermodynamic incompatibility between meat proteins and beet pectin. The results obtained from this study might have important implications for the fabrication of processed meat products with reduced fat levels.

A new monoclonal antibody (Cox mAB 31A2) detects VP1 protein of coxsackievirus B3 with high sensitivity and specificity.

Human enteroviruses, e.g. coxsackieviruses, induce a variety of severe acute and chronic forms of disease, including myocarditis, meningitis and diabetes mellitus type 1. To visualize enterovirus infection with a diagnostic intent, many studies have applied a commercially available antibody (anti-CVB5 VP1, clone 5-D8/1, Dako, Hamburg, Germany) that identifies VP1 of different enteroviral serotypes. Many antibodies, however, have been found to bind non-specifically to proteins of cardiomyocytes and in the interstitial space, resulting in non-specific staining in immunohistochemistry. In this paper we show that the anti-CVB5 VP1 antibody, recognizing VP1 of coxsackieviruses and widely used in diagnostics and research, shows strong cross-reactivity with cellular proteins in the heart (and pancreas) of humans and mice, which calls for a more specific antibody to be used for diagnostic purposes. We observed by Western blot analyses of lysates from human heart tissue samples and HeLa cells two cross-reactive bands when using clone 5-D8/1. Peptide mass fingerprinting (MALDI-TOF) identified these proteins as creatine kinase (B-type) and tubulin, confirming that this mAb detects cellular proteins in addition to viral VP1. In order to overcome the problems of false positive VP1 staining we generated a new highly specific and sensitive monoclonal antibody (Cox mAB 31A2) that recognizes VP1 from CVB3. The new antibody was characterized and was found to function well in immunohistochemistry, immunofluorescence staining, Western blotting, ELISA and FACS analyses.

Call for uniform neuropsychological assessment after aneurysmal subarachnoid hemorrhage: Swiss recommendations.

BACKGROUND: In a high proportion of patients with favorable outcome after aneurysmal subarachnoid hemorrhage (aSAH), neuropsychological deficits, depression, anxiety, and fatigue are responsible for the inability to return to their regular premorbid life and pursue their professional careers. These problems often remain unrecognized, as no recommendations concerning a standardized comprehensive assessment have yet found entry into clinical routines. METHODS: To establish a nationwide standard concerning a comprehensive assessment after aSAH, representatives of all neuropsychological and neurosurgical departments of those eight Swiss centers treating acute aSAH have agreed on a common protocol. In addition, a battery of questionnaires and neuropsychological tests was selected, optimally suited to the deficits found most prevalent in aSAH patients that was available in different languages and standardized. RESULTS: We propose a baseline inpatient neuropsychological screening using the Montreal Cognitive Assessment (MoCA) between days 14 and 28 after aSAH. In an outpatient setting at 3 and 12 months after bleeding, we recommend a neuropsychological examination, testing all relevant domains including attention, speed of information processing, executive functions, verbal and visual learning/memory, language, visuo-perceptual abilities, and premorbid intelligence. In addition, a detailed assessment capturing anxiety, depression, fatigue, symptoms of frontal lobe affection, and quality of life should be performed. CONCLUSIONS: This standardized neuropsychological assessment will lead to a more comprehensive assessment of the patient, facilitate the detection and subsequent treatment of previously unrecognized but relevant impairments, and help to determine the incidence, characteristics, modifiable risk factors, and the clinical course of these impairments after aSAH.

The Extension of the German CERAD Neuropsychological Assessment Battery with Tests Assessing Subcortical, Executive and Frontal Functions Improves Accuracy in Dementia Diagnosis.

BACKGROUND/AIMS: Alzheimer's disease (AD) is the most common form of dementia. Neuropsychological assessment of individuals with AD primarily focuses on tests of cortical functioning. However, in clinical practice, the underlying pathologies of dementia are unknown, and a focus on cortical functioning may neglect other domains of cognition, including subcortical and executive functioning. The current study aimed to improve the diagnostic discrimination ability of the Consortium to Establish a Registry for Alzheimer's Disease - Neuropsychological Assessment Battery (CERAD-NAB) by adding three tests of executive functioning and mental speed (Trail Making Tests A and B, S-Words). METHODS: Logistic regression analyses of 594 normal controls (NC), 326 patients with mild AD and 224 patients with other types of dementia (OD) were carried out, and the area under the curve values were compared to those of CERAD-NAB alone. RESULTS: All comparisons except AD-OD (65.5%) showed excellent classification rates (NC-AD: 92.7%; NC-OD: 89.0%; NC-all patients: 91.0%) and a superior diagnostic accuracy of the extended version. CONCLUSION: Our findings suggest that these three tests provide a sensible addition to the CERAD-NAB and can improve neuropsychological diagnosis of dementia.

Feruloyl-CoA 6'-Hydroxylase1-dependent coumarins mediate iron acquisition from alkaline substrates in Arabidopsis.

Although iron (Fe) is one of the most abundant elements in the earth's crust, its low solubility in soils restricts Fe uptake by plants. Most plant species acquire Fe by acidifying the rhizosphere and reducing ferric to ferrous Fe prior to membrane transport. However, it is unclear how these plants access Fe in the rhizosphere and cope with high soil pH. In a mutant screening, we identified 2-oxoglutarate-dependent dioxygenase Feruloyl-CoA 6'-Hydroxylase1 (F6'H1) to be essential for tolerance of Arabidopsis (Arabidopsis thaliana) to high pH-induced Fe deficiency. Under Fe deficiency, F6'H1 is required for the biosynthesis of fluorescent coumarins that are released into the rhizosphere, some of which possess Fe(III)-mobilizing capacity and prevent f6'h1 mutant plants from Fe deficiency-induced chlorosis. Scopoletin was the most prominent coumarin found in Fe-deficient root exudates but failed to mobilize Fe(III), while esculetin, i.e. 6,7-dihydroxycoumarin, occurred in lower amounts but was effective in Fe(III) mobilization. Our results indicate that Fe-deficient Arabidopsis plants release Fe(III)-chelating coumarins as part of the strategy I-type Fe acquisition machinery.

Establishing robust cognitive dimensions for characterization and differentiation of patients with Alzheimer's disease, mild cognitive impairment, frontotemporal dementia and depression.

OBJECTIVE: The diagnosis of mild cognitive impairment (MCI) and dementia requires detailed neuropsychological examinations. These examinations typically yield a large number of outcome variables, which may complicate the interpretation and communication of results. The purposes of this study were the following: (i) to reduce a large data set of interrelated neuropsychological variables to a smaller number of cognitive dimensions; (ii) to create a common metric for these dimensions (z-scores); and (iii) to study the ability of the cognitive dimensions to distinguish between groups of patients with different types of cognitive impairment. METHODS: We tested 1646 patients with different forms of dementia or with a major depression with a standard (n = 632) or, if cognitively less affected, a challenging neuropsychological battery (n = 1014). To identify the underlying cognitive dimensions of the two test batteries, maximum likelihood factor analyses with a promax rotation were conducted. To interpret the sum scores of the factors as standard scores, we divided them by the standard deviation of a cognitively healthy sample (n = 1145). RESULTS: The factor analyses yielded seven factors for each test battery. The cognitive dimensions in both test batteries distinguished patients with different forms of dementia (MCI, Alzheimer's dementia or frontotemporal dementia) and patients with major depression. Furthermore, patients with stable MCI could be separated from patients with progressing MCI. Discriminant analyses with an independent new sample of patients (n = 306) revealed that the new dimension scores distinguished new samples of patients with MCI from patients with Alzheimer's dementia with high accuracy. CONCLUSION: These findings suggest that these cognitive dimensions may benefit neuropsychological diagnostics.

Neuropsychological signs of Alzheimer's disease 8 years prior to diagnosis.

We investigated the earliest neuropsychological changes in Alzheimer's disease (AD) by comparing the baseline performance of 29 individuals who subsequently developed AD within an average of 7.91 ± 2.70 years with 29 pairwise-matched individuals who remained cognitively healthy (NC). We hypothesized that subtle, qualitative changes in cognition precede clinical AD by several years, and therefore examined subjective as well as standard quantitative measures of cognition, in addition to subjective estimates of mood and medical status. Participants were selected from the 825 members of the longitudinal BASEL study (BAsel Study on the ELderly), all of whom had been ApoE-genotyped and received comprehensive bi-annual neuropsychological assessments. Within 13 years, 29 were diagnosed with probable AD. Each individual who progressed to AD (AD-P) was pairwise matched to a NC participant based on age, education, demographic status, observation period, and, importantly, ApoE genotype. A regression analysis using the lasso technique identified which of 115 neuropsychological variables best discriminated baseline NC from baseline AD-P performance. This analysis yielded eleven neuropsychological variables that optimally discriminated the two groups (correct classification rate: 60.4%): 1) Intrusions and 2) response bias in verbal learning and memory tasks; 3) delayed figure recall; 4-6) three Wechsler Adult Intelligence Scale (WAIS) Block Design subtest variables; 7-8) number of errors and repetitions on letter fluency; and 9-11) self-report of memory problems, a feeling of sadness, and cardiac problems. These results suggest that the preclinical neuropsychological cascade to AD includes subtle but identifiable qualitative impairments in verbal and visual memory, visuospatial processing, error control, and subjective neuropsychological complaints.