The Test Your Memory for Mild Cognitive Impairment (TYM-MCI)

BACKGROUND: To validate a short cognitive test: the Test Your Memory for Mild Cognitive Impairment (TYM-MCI) in the diagnosis of patients with amnestic mild cognitive impairment or mild Alzheimer’s disease (aMCI/AD). METHODS: Two hundred and two patients with mild memory problems were recruited. All had ‘passed’ the Mini-Mental State Examination (MMSE). Patients completed the TYM-MCI, the Test Your Memory test (TYM), MMSE and revised Addenbrooke’s Cognitive Examination (ACE-R), had a neurological examination, clinical diagnostics and multidisciplinary team review. RESULTS: As a single test, the TYM-MCI performed as well as the ACE-R in the distinction of patients with aMCI/AD from patients with subjective memory impairment with a sensitivity of 0.79 and specificity of 0.91. Used in combination with the ACE-R, it provided additional value and identified almost all cases of aMCI/AD. The TYM-MCI correctly classified most patients who had equivocal ACE-R scores. Integrated discriminant improvement analysis showed that the TYM-MCI added value to the conventional memory assessment. Patients initially diagnosed as unknown or with subjective memory impairment who were later rediagnosed with aMCI/AD scored poorly on their original TYM-MCI. CONCLUSION: The TYM-MCI is a powerful short cognitive test that examines verbal and visual recall and is a valuable addition to the assessment of patients with aMCI/AD. It is simple and cheap to administer and requires minimal staff time and training.JBR was supported by the Wellcome Trust (103838)

Ultraviolet singularities in classical brane theory

We construct for the first time an energy-momentum tensor for the electromagnetic field of a p-brane in arbitrary dimensions, entailing finite energy-momentum integrals. The construction relies on distribution theory and is based on a Lorentz-invariant regularization, followed by the subtraction of divergent and finite counterterms supported on the brane. The resulting energy-momentum tensor turns out to be uniquely determined. We perform the construction explicitly for a generic flat brane. For a brane in arbitrary motion our approach provides a new paradigm for the derivation of the, otherwise divergent, self-force of the brane. The so derived self-force is automatically finite and guarantees, by construction, energy-momentum conservation.Comment: 41 pages, no figures, minor change

Noradrenergic-dependent functions are associated with age-related locus coeruleus signal intensity differences.

The locus coeruleus (LC), the origin of noradrenergic modulation of cognitive and behavioral function, may play an important role healthy ageing and in neurodegenerative conditions. We investigated the functional significance of age-related differences in mean normalized LC signal intensity values (LC-CR) in magnetization-transfer (MT) images from the Cambridge Centre for Ageing and Neuroscience (Cam-CAN) cohort - an open-access, population-based dataset. Using structural equation modelling, we tested the pre-registered hypothesis that putatively noradrenergic (NA)-dependent functions would be more strongly associated with LC-CR in older versus younger adults. A unidimensional model (within which LC-CR related to a single factor representing all cognitive and behavioral measures) was a better fit with the data than the a priori two-factor model (within which LC-CR related to separate NA-dependent and NA-independent factors). Our findings support the concept that age-related reduction of LC structural integrity is associated with impaired cognitive and behavioral function

Carboxyhaemoglobin levels and their determinants in older British men

Background: Although there has been concern about the levels of carbon monoxide exposure, particularly among older people, little is known about COHb levels and their determinants in the general population. We examined these issues in a study of older British men.Methods: Cross-sectional study of 4252 men aged 60-79 years selected from one socially representative general practice in each of 24 British towns and who attended for examination between 1998 and 2000. Blood samples were measured for COHb and information on social, household and individual factors assessed by questionnaire. Analyses were based on 3603 men measured in or close to (< 10 miles) their place of residence.Results: The COHb distribution was positively skewed. Geometric mean COHb level was 0.46% and the median 0.50%; 9.2% of men had a COHb level of 2.5% or more and 0.1% of subjects had a level of 7.5% or more. Factors which were independently related to mean COHb level included season (highest in autumn and winter), region (highest in Northern England), gas cooking (slight increase) and central heating (slight decrease) and active smoking, the strongest determinant. Mean COHb levels were more than ten times greater in men smoking more than 20 cigarettes a day (3.29%) compared with non-smokers (0.32%); almost all subjects with COHb levels of 2.5% and above were smokers (93%). Pipe and cigar smoking was associated with more modest increases in COHb level. Passive cigarette smoking exposure had no independent association with COHb after adjustment for other factors. Active smoking accounted for 41% of variance in COHb level and all factors together for 47%.Conclusion: An appreciable proportion of men have COHb levels of 2.5% or more at which symptomatic effects may occur, though very high levels are uncommon. The results confirm that smoking (particularly cigarette smoking) is the dominant influence on COHb levels

Immunisation with Recombinant PfEMP1 Domains Elicits Functional Rosette-Inhibiting and Phagocytosis-Inducing Antibodies to Plasmodium falciparum

BACKGROUND: Rosetting is a Plasmodium falciparum virulence factor implicated in the pathogenesis of life-threatening malaria. Rosetting occurs when parasite-derived P. falciparum Erythrocyte Membrane Protein One (PfEMP1) on the surface of infected erythrocytes binds to human receptors on uninfected erythrocytes. PfEMP1 is a possible target for a vaccine to induce antibodies to inhibit rosetting and prevent severe malaria. METHODOLOGY/FINDINGS: We examined the vaccine potential of the six extracellular domains of a rosette-mediating PfEMP1 variant (ITvar9/R29var1 from the R29 parasite strain) by immunizing rabbits with recombinant proteins expressed in E. coli. Antibodies raised to each domain were tested for surface fluorescence with live infected erythrocytes, rosette inhibition and phagocytosis-induction. Antibodies to all PfEMP1 domains recognized the surface of live infected erythrocytes down to low concentrations (0.02-1.56 µg/ml of total IgG). Antibodies to all PfEMP1 domains except for the second Duffy-Binding-Like region inhibited rosetting (50% inhibitory concentration 0.04-4 µg/ml) and were able to opsonize and induce phagocytosis of infected erythrocytes at low concentrations (1.56-6.25 µg/ml). Antibodies to the N-terminal region (NTS-DBL1α) were the most effective in all assays. All antibodies were specific for the R29 parasite strain, and showed no functional activity against five other rosetting strains. CONCLUSIONS/SIGNIFICANCE: These results are encouraging for vaccine development as they show that potent antibodies can be generated to recombinant PfEMP1 domains that will inhibit rosetting and induce phagocytosis of infected erythrocytes. However, further work is needed on rosetting mechanisms and cross-reactivity in field isolates to define a set of PfEMP1 variants that could induce functional antibodies against a broad range of P. falciparum rosetting parasites

The Test Your Memory for Mild Cognitive Impairment (TYM-MCI)

BACKGROUND: To validate a short cognitive test: the Test Your Memory for Mild Cognitive Impairment (TYM-MCI) in the diagnosis of patients with amnestic mild cognitive impairment or mild Alzheimer’s disease (aMCI/AD). METHODS: Two hundred and two patients with mild memory problems were recruited. All had ‘passed’ the Mini-Mental State Examination (MMSE). Patients completed the TYM-MCI, the Test Your Memory test (TYM), MMSE and revised Addenbrooke’s Cognitive Examination (ACE-R), had a neurological examination, clinical diagnostics and multidisciplinary team review. RESULTS: As a single test, the TYM-MCI performed as well as the ACE-R in the distinction of patients with aMCI/AD from patients with subjective memory impairment with a sensitivity of 0.79 and specificity of 0.91. Used in combination with the ACE-R, it provided additional value and identified almost all cases of aMCI/AD. The TYM-MCI correctly classified most patients who had equivocal ACE-R scores. Integrated discriminant improvement analysis showed that the TYM-MCI added value to the conventional memory assessment. Patients initially diagnosed as unknown or with subjective memory impairment who were later rediagnosed with aMCI/AD scored poorly on their original TYM-MCI. CONCLUSION: The TYM-MCI is a powerful short cognitive test that examines verbal and visual recall and is a valuable addition to the assessment of patients with aMCI/AD. It is simple and cheap to administer and requires minimal staff time and training.JBR was supported by the Wellcome Trust (103838)

Predictability of evolutionary trajectories in fitness landscapes

Experimental studies on enzyme evolution show that only a small fraction of all possible mutation trajectories are accessible to evolution. However, these experiments deal with individual enzymes and explore a tiny part of the fitness landscape. We report an exhaustive analysis of fitness landscapes constructed with an off-lattice model of protein folding where fitness is equated with robustness to misfolding. This model mimics the essential features of the interactions between amino acids, is consistent with the key paradigms of protein folding and reproduces the universal distribution of evolutionary rates among orthologous proteins. We introduce mean path divergence as a quantitative measure of the degree to which the starting and ending points determine the path of evolution in fitness landscapes. Global measures of landscape roughness are good predictors of path divergence in all studied landscapes: the mean path divergence is greater in smooth landscapes than in rough ones. The model-derived and experimental landscapes are significantly smoother than random landscapes and resemble additive landscapes perturbed with moderate amounts of noise; thus, these landscapes are substantially robust to mutation. The model landscapes show a deficit of suboptimal peaks even compared with noisy additive landscapes with similar overall roughness. We suggest that smoothness and the substantial deficit of peaks in the fitness landscapes of protein evolution are fundamental consequences of the physics of protein folding.Comment: 14 pages, 7 figure

Self-Affirmation Improves Problem-Solving under Stress

High levels of acute and chronic stress are known to impair problem-solving and creativity on a broad range of tasks. Despite this evidence, we know little about protective factors for mitigating the deleterious effects of stress on problem-solving. Building on previous research showing that self-affirmation can buffer stress, we tested whether an experimental manipulation of self-affirmation improves problem-solving performance in chronically stressed participants. Eighty undergraduates indicated their perceived chronic stress over the previous month and were randomly assigned to either a self-affirmation or control condition. They then completed 30 difficult remote associate problem-solving items under time pressure in front of an evaluator. Results showed that self-affirmation improved problem-solving performance in underperforming chronically stressed individuals. This research suggests a novel means for boosting problem-solving under stress and may have important implications for understanding how self-affirmation boosts academic achievement in school settings. © 2013 Creswell et al

Characterization of 3 PET Tracers for Quantification of Mitochondrial and Synaptic Function in Healthy Human Brain: {18}^F-BCPP-EF, {11}^C-SA-4503, and {11}^C-UCB-J

Mitochondrial complex 1 is involved in maintaining brain bioenergetics; σ-1 receptor responds to neuronal stress; and synaptic vesicle protein 2A reflects synaptic integrity. Expression of each of these proteins is altered in neurodegenerative diseases. Here, we characterize the kinetic behavior of 3 PET radioligands—{18}^F-BCPP-EF, {11}^C-SA-4503, and {11}^C-UCB-J for the measurement of mitochondrial complex 1, σ-1 receptor, and synaptic vesicle protein 2A, respectively, and determine appropriate analysis workflows for their application in future studies of the in vivo molecular pathology of these diseases. METHODS: Twelve human subjects underwent dynamic PET scans with each radioligand, including associated arterial blood sampling. A range of kinetic models was investigated to identify an optimal kinetic analysis method for each radioligand and a suitable acquisition duration. RESULTS: All 3 radioligands readily entered the brain and yielded heterogeneous uptake consistent with the known distribution of the targets. The optimal models determined for the regional estimates of volume of distribution were multilinear analysis 1 (MA1) and the 2-tissue-compartment model for {18}^F-BCPP-EF, MA1 for 11}^C-SA-4503, and both MA1 and the 1-tissue-compartment model for {11}^C-UCB-J, respectively, provided good estimates of regional volume of distribution values. An effect of age was observed on {18}^F-BCPP-EF and {11}^C-UCB-J signal in the caudate. CONCLUSION: These ligands can be assessed for their potential to stratify patients or monitor the progression of molecular neuropathology in neurodegenerative diseases