Neuropsychological Function in Migraine Headaches: An Expanded Comprehensive Multidomain Meta-Analysis

BACKGROUND AND OBJECTIVES: A sizable literature has studied neuropsychologic function in persons with migraine (PwM), but despite this, few quantitative syntheses exist. These focused on circumscribed areas of the literature. In this study, we conducted an expanded comprehensive meta-analysis comparing performance on clinical measures of neuropsychological function both within and across domains, between samples of PwM and healthy controls (HCs). METHODS: For this Meta-analyses Of Observational Studies in Epidemiology-compliant meta-analysis, a unified search strategy was applied to OneSearch (a comprehensive collection of electronic databases) to identify peer-reviewed original research published across all years up until August 1, 2023. Using random-effects modeling, we examined aggregated effect sizes (Hedges' g), between-study heterogeneity (Cochran Q and I2), moderating variables (meta-regression and subgroup analyses), and publication bias (Egger regression intercept and Duval and Tweedie Trim-and-Fill procedure). Study bias was also coded using the NIH Study Quality Assessment Tools. RESULTS: Omnibus meta-analysis from the 58 studies included (PwM n = 5,452, HC n = 16,647; 612 effect sizes extracted) indicated lower overall cognitive performance in PwM vs HCs (g = -0.37; 95% CI -0.47 to -0.28; p < 0.001), and high between-study heterogeneity (Q = 311.25, I2 = 81.69). Significant domain-specific negative effects were observed in global cognition (g = -0.46, p < 0.001), executive function (g = -0.45, p < 0.001), processing speed (g = -0.42, p < 0.001), visuospatial/construction (g = -0.39, p = 0.006), simple/complex attention (g = -0.38, p < 0.001), learning/memory (g = -0.25, p < 0.001), and language (g = -0.24, p < 0.001). Orientation (p = 0.146), motor (p = 0.102), and intelligence (p = 0.899) were not significant. Moderator analyses indicated that age (particularly younger HCs), samples drawn from health care facility settings (e.g., tertiary headache centers) vs community-based populations, and higher attack duration were associated with larger (negative) effects and accounted for a significant proportion of between-study heterogeneity in effects. Notably, PwM without aura yielded stronger (negative) effects (omnibus g = -0.37) vs those with aura (omnibus g = -0.10), though aura status did not account for heterogeneity observed between studies. DISCUSSION: Relative to HCs, PwM demonstrate worse neurocognition, as detected by neuropsychological tests, especially on cognitive screeners and tests within executive functioning and processing speed domains. Effects were generally small to moderate in magnitude and evident only in clinic (vs community) samples. Aura was not meaningfully associated with neurocognitive impairment.

So how special is special K? A systematic review and meta-analysis of ketamine for PTSD RCTs.

Background: PTSD is a significant mental health problem worldwide. Current evidence-based interventions suffer various limitations. Ketamine is a novel agent that is hoped to be incrementally better than extant interventions.Objective: Several randomized control trials (RCTs) of ketamine interventions for PTSD have now been published. We sought to systematically review and meta-analyse results from these trials to evaluate preliminary evidence for ketamine's incremental benefit above-and-beyond control interventions in PTSD treatment.Results: Omnibus findings from 52 effect sizes extracted across six studies (n = 221) yielded a small advantage for ketamine over control conditions at reducing PTSD symptoms (g = 0.27, 95% CI = 0.03, 0.51). However, bias-correction estimates attenuated this effect (adjusted g = 0.20, 95%, CI = -0.08, 0.48). Bias estimates indicated smaller studies reported larger effect sizes favouring ketamine. The only consistent timepoint assessed across RCTs was 24-hours post-initial infusion. Effects at 24-hours post-initial infusion suggest ketamine has a small relative advantage over controls (g = 0.35, 95% CI = 0.06, 0.64). Post-hoc analyses at 24-hours post-initial infusion indicated that ketamine was significantly better than passive controls (g = 0.44, 95% CI = 0.03, 0.85), but not active controls (g = 0.24, 95% CI = -0.30, 0.78). Comparisons one-week into intervention suggested no meaningful group differences (g = 0.24, 95% CI = 0.00, 0.48). No significant differences were evident for RCTs that examined effects two-weeks post initial infusion (g = 0.17, 95% CI = -0.10, 0.44).Conclusions: Altogether, ketamine-for-PTSD RCTs reveal a nominal initial therapeutic advantage relative to controls. However, bias and heterogeneity appear problematic. While rapid acting effects were observed, all control agents (including saline) also evidenced rapid acting effects. We argue blind penetration to be a serious concern, and that placebo is the likely mechanism behind reported therapeutic effects.

We systematically reviewed and meta-analysed all randomized control trials of ketamine intervention for PTSD.While ketamine was associated with a reduction in symptoms, the effect was generally not stronger than control conditions.By two-weeks post-initial infusion, no meaningful differences are evident between ketamine and controls.

Arterial stiffness mediates the association between age and processing speed at low levels of microvascular function in humans across the adult lifespan.

The function of micro- and macrovessels within the peripheral vasculature has been identified as a target for the investigation of potential cardiovascular-based promoters of cognitive decline. However, little remains known regarding the interaction of the micro- and macrovasculature as it relates to cognitive function, especially in cognitively healthy individuals. Therefore, our purpose was to unravel peripheral factors that contribute to the association between age and processing speed. Ninety-nine individuals (51 men, 48 women) across the adult life span (19-81 yr) were used for analysis. Arterial stiffness was quantified as carotid-femoral pulse-wave velocity (cfPWV) and near-infrared spectroscopy assessed maximal tissue oxygenation (Sto2max) following a period of ischemia. Processing speed was evaluated with Trail Making Test (TMT) Parts A and B. Measures of central (cPP) and peripheral pulse pressure (pPP) were also collected. Moderated mediation analyses were conducted to determine contributions to the age and processing speed relation, and first-order partial correlations were used to assess associations while controlling for the linear effects of age. A P ≤ 0.05 was considered statistically significant. At low levels of Sto2max, there was a significant positive (b = 1.92; P = 0.005) effect of cfPWV on time to completion on TMT part A. In addition, cPP (P = 0.028) and pPP (P = 0.027) remained significantly related to part A when controlling for age. These results suggested that the peripheral microvasculature may be a valuable target for delaying cognitive decline, especially in currently cognitively healthy individuals. Furthermore, we reinforced current evidence that pulse pressure is a key endpoint for trials aimed at preventing or delaying the onset of cognitive decline.NEW & NOTEWORTHY Arterial stiffness partially mediates the association between age and processing speed in the presence of low microvascular function, as demarcated by maximum tissue oxygenation following ischemia. Central and peripheral pulse pressure remained associated with processing speed even after controlling for age. Our findings were derived from a sample that was determined to be cognitively healthy, which highlights the potential for these outcomes to be considered during trials aimed at the prevention of cognitive decline.

Longitudinal White and Gray Matter Response to Precision Medicine-Guided Intervention for Alzheimer's Disease.

BACKGROUND: Alzheimer's disease (AD) is a debilitating condition that is widely known to adversely affect gray matter (GM) and white matter (WM) tracts within the brain. Recently, precision medicine has shown promise in alleviating the clinical and gross morphological trajectories of patients with AD. However, regional morphological changes have not yet been adequately characterized. OBJECTIVE: Investigate regional morphological responses to a precision medicine-guided intervention with regards to white and gray matter in AD and mild cognitive impairment (MCI). METHODS: Clinical and neuroimaging data were compiled over a 9-month period from 25 individuals who were diagnosed with AD or MCI receiving individualized treatment plans. Structural T1-weighted MRI scans underwent segmentation and volumetric quantifications via Neuroreader. Longitudinal changes were calculated via annualized percent change of WM or GM ratios. RESULTS: Montreal Cognitive Assessment scores (p < 0.001) and various domains of the Computerized Neurocognitive Screening Vital Signs significantly improved from baseline to 9-month follow-up. There was regional variability in WM and GM atrophy or hypertrophy, but none of these observed changes were statistically significant after correction for multiple comparisons.

Examining Relationships between Cognitive Flexibility, Exercise Perceptions, and Cardiovascular Disease Risk Factors.

Adults do not engage in enough physical activity. Investigating cognitive and physiological factors related to improving this behavior-and reducing health risks-remains a public health priority. Our objective was to assess whether cognitive flexibility influenced perceptions and choice of exercise programs and whether flexibility was associated with cardiovascular disease (CVD) risk factors. Independent sample groups of college-aged adults (18-24 yrs) participated in two studies. Data were collected on individuals' degree of cognitive flexibility (both self-reported and objectively measured), perceptions and choice of exercise programs, and health status markers known to be associated with CVD (vascular function, muscular strength, and body composition). Vascular function was assessed with a near-infrared spectroscopy device, strength was defined as handgrip, and body composition was estimated via digital circumferences. Self-reported flexibility reliably predicted individuals' choice of exercise program and perceptions of effort required for success on an exercise program. The relationships among CVD risk factors and objectively measured cognitive flexibility were not significant, demonstrating that identifying a healthy individual's degree of performance-based cognitive flexibility does not predict health status. Furthermore, although greater self-reported trait flexibility (rigidity) is known to predict higher (lower) likelihood of physical activity, this finding should not be extrapolated to also assume that flexibility (rigidity), as measured by objective cognitive tests, is associated with reduced CVD risk in healthy adults. We posit a rationale for how understanding cognitive flexibility and rigidity can play an impactful role in improving adherence to exercise prescriptions targeted to reducing risks.

Precision Medicine Approach to Alzheimer's Disease: Rationale and Implications.

The neurodegenerative disease field has enjoyed extremely limited success in the development of effective therapeutics. One potential reason is the lack of disease models that yield accurate predictions and optimal therapeutic targets. Standard clinical trials have pre-determined a single treatment modality, which may be unrelated to the primary drivers of neurodegeneration. Recent proof-of-concept clinical trials using a precision medicine approach suggest a new model of Alzheimer's disease (AD) as a chronic innate encephalitis that creates a network insufficiency. Identifying and addressing the multiple potential contributors to cognitive decline for each patient may represent a more effective strategy. Here we review the rationale for a precision medicine approach in prevention and treatment of cognitive decline associated with AD. Results and implications from recent proof-of-concept clinical trials are presented. Randomized controlled trials, with much larger patient numbers, are likely to be significant to establishing precision medicine protocols as a standard of care for prevention and treatment of cognitive decline. Furthermore, combining this approach with the pharmaceutical approach offers the potential for enhanced outcomes. However, incorporating precision medicine approaches into everyday evaluation and care, as well as future clinical trials, would require fundamental changes in trial design, IRB considerations, funding considerations, laboratory evaluation, personalized treatment plans, treatment teams, and ultimately in reimbursement guidelines. Nonetheless, precision medicine approaches to AD, based on a novel model of AD pathophysiology, offer promise that has not been realized to date with monotherapeutic approaches.

A Randomized, Placebo-Controlled Clinical Trial of a Novel Dietary Supplement on Standardized CNS Vital Signs Cognitive Performance Parameters in Adults.

Objective: To test the effectiveness of a novel dietary supplement as a support for cognitive function in healthy younger and older adults Design: A double-blind, randomized, placebo-controlled trial of the dietary supplement, Braini® in two age cohorts with 60 participants: 31 healthy younger adults (18-30 years) and 29 healthy older adults (55-80 years). Intervention: A 28-day intervention of a dietary supplement (active or placebo) taken daily with cognitive assessment using CNS Vital Signs computer-based testing at day 0 and 28. Participants were asked to fill out a daily survey regarding compliance with supplement protocol, changes in health, adherence to the protocol, and reported side effects. CNS Vital Signs provides aged normed aggregated outcome measures for Processing Speed, Psychomotor Speed, Reaction Time, Cognitive Flexibility, Executive Function, and Motor Speed. Results: Significant improvements in performance were found for two CNS Vital Signs domains, Cognitive Flexibility (p = 0.048), and Executive Function (p = 0.025) in the treated younger adults (n = 12) compared with the placebo group (n = 19) at day 28 compared with baseline. The Shifting Attention Test Reaction Time (SAT-RT), a measure of shifting attention correct response reaction time, showed significant improvement at 28 days in those taking Braini in both younger (p = 0.004) and older adult cohorts (p = 0.05) with an average improvement over the control subjects of 44%. No serious side effects were reported. Conclusions: The dietary formulation, Braini, safely and significantly improved cognitive flexibility and executive function in younger adults and trended positively in older adults in this study that was stopped prematurely due to pandemic restrictions. Scores on SAT-RT significantly improved in both younger and older adults. Further studies are needed to confirm that Braini reliably improves cognitive function in additional CNS domains in healthy adults. Clinical Trial Registration: Clinicaltrials.gov under registration number: NCT04025255.

High speed ultraviolet digital image correlation (UV-DIC) for dynamic strains at extreme temperatures.

Digital Image Correlation (DIC) is a camera-based method of measuring full-field displacements and strains from the surface of a deforming object. It can be applied at any length scale (determined by the lenses) and any time scale (determined by the camera), and because it is non-contacting, it can also be used at temperatures much higher than can be withstood by bonded strain gauges. At extreme temperatures, materials emit light in the form of blackbody radiation, which can saturate the camera sensor. It has previously been shown that the emitted light can be effectively screened by using ultraviolet (UV) cameras, lenses, and filters; however, commercially available UV cameras are relatively slow, which limits the speed of combined UV-DIC measurements. In this study, a UV intensifier was paired with a high-speed camera, and its ability to perform UV-DIC at high temperature and high speed was investigated. The system was compared over three different experiments: (A) a quasi-static thermal expansion test at high temperature, (B) a vibration test at room temperature, and (C) the same vibration test repeated at high temperature. The system successfully performed DIC up to at least 1600 °C at frame rates of 5000 fps, which is more than 100 times faster than other examples of UV-DIC in the literature. In all cases, measurements made using the UV intensifier were much noisier than those made without the intensifier, but the intensifier enabled measurements at temperatures well above those which an unfiltered high-speed camera otherwise saturates.

An examination of the relationship among plasma brain derived neurotropic factor, peripheral vascular function, and body composition with cognition in midlife African Americans/Black individuals.

African American/Black individuals have been excluded from several lines of prominent neuroscience research, despite exhibiting disproportionately higher risk factors associated with the onset and magnitude of neurodegeneration. Therefore, the objective of the current investigation was to examine potential relationships among brain derived neurotropic factor (BDNF), peripheral vascular function, and body composition with cognition in a sample of midlife, African American/Black individuals. Midlife adults (men: n = 3, 60 ± 4 years; women: n = 9, 58 ± 5 years) were invited to complete two baseline visits separated by 4 weeks. Peripheral vascular function was determined by venous occlusion plethysmography, a dual-energy X-ray absorptiometry was used to determine body composition, and plasma was collected to quantify BDNF levels. The CNS Vital Signs computer-based test was used to provide scores on numerous cognitive domains. The principal results included that complex attention (r = 0.629) and processing speed (r = 0.734) were significantly (p < 0.05) related to the plasma BDNF values. However, there was no significant (p > 0.05) relationship between any vascular measure and any cognitive domain or BDNF value. Secondary findings included the relationship between lean mass and peak hyperemia (r = 0.758) as well as total hyperemia (r = 0.855). The major conclusion derived from these results was that there is rationale for future clinical trials to use interventions targeting increasing BDNF to potentially improve cognition. Additionally, these results strongly suggest that clinicians aiming to improve cognitive health via improvements in the known risk factor of vascular function should consider interventions capable of promoting the size and function of skeletal muscle, especially in the African American/Black population.

Rapid Characterization of Solid Tumors Using Resonant Sensors.

Cancer continues to be a significant cause of non-traumatic pediatric mortality. Diagnosis of pediatric solid tumors is paramount to prescribing the correct treatment regimen. Recent efforts have focused on non-invasive methods to obtain tumor tissues, but one of the challenges encountered is the ability to obtain an adequate amount of viable tissue. In this study, a wireless, inductor-capacitor (LC) sensor was employed to detect relative permittivity of pediatric tumor tissues. There is a comparison of resonant frequencies of tumor tissues between live versus dead tissues, the primary tumor tissue versus tissue from the organs of origin or metastasis, and treated versus untreated tumors. The results show significant shifts in resonant frequencies between the comparison groups. Dead tissues demonstrated a significant shift in resonant frequencies compared to alive tissues. There were significant differences between the resonant frequencies of normal tissues versus tumor tissues. Resonant frequencies were also significantly different between primary tumors compared to their respective metastases. These data indicate that there are potential clinical applications of LC technology in the detection and diagnosis of pediatric solid tumors.

Precision Medicine Approach to Alzheimer's Disease: Successful Pilot Project.

BACKGROUND: Effective therapeutics for Alzheimer's disease are needed. However, previous clinical trials have pre-determined a single treatment modality, such as a drug candidate or therapeutic procedure, which may be unrelated to the primary drivers of the neurodegenerative process. Therefore, increasing data set size to include the potential contributors to cognitive decline for each patient, and addressing the identified potential contributors, may represent a more effective strategy. OBJECTIVE: To determine whether a precision medicine approach to Alzheimer's disease and mild cognitive impairment is effective enough in a proof-of-concept trial to warrant a larger, randomized, controlled clinical trial. METHODS: Twenty-five patients with dementia or mild cognitive impairment, with Montreal Cognitive Assessment (MoCA) scores of 19 or higher, were evaluated for markers of inflammation, chronic infection, dysbiosis, insulin resistance, protein glycation, vascular disease, nocturnal hypoxemia, hormone insufficiency or dysregulation, nutrient deficiency, toxin or toxicant exposure, and other biochemical parameters associated with cognitive decline. Brain magnetic resonance imaging with volumetrics was performed at baseline and study conclusion. Patients were treated for nine months with a personalized, precision medicine protocol, and cognition was assessed at t = 0, 3, 6, and 9 months. RESULTS: All outcome measures revealed improvement: statistically significant improvement in MoCA scores, CNS Vital Signs Neurocognitive Index, and Alzheimer's Questionnaire Change score were documented. No serious adverse events were recorded. MRI volumetrics also improved. CONCLUSION: Based on the cognitive improvements observed in this study, a larger, randomized, controlled trial of the precision medicine therapeutic approach described herein is warranted.

Neurovascular Dysfunction in Diverse Communities With Health Disparities-Contributions to Dementia and Alzheimer's Disease.

Alzheimer's disease and related dementias (ADRD) are an expanding worldwide crisis. In the absence of scientific breakthroughs, the global prevalence of ADRD will continue to increase as more people are living longer. Racial or ethnic minority groups have an increased risk and incidence of ADRD and have often been neglected by the scientific research community. There is mounting evidence that vascular insults in the brain can initiate a series of biological events leading to neurodegeneration, cognitive impairment, and ADRD. We are a group of researchers interested in developing and expanding ADRD research, with an emphasis on vascular contributions to dementia, to serve our local diverse community. Toward this goal, the primary objective of this review was to investigate and better understand health disparities in Alabama and the contributions of the social determinants of health to those disparities, particularly in the context of vascular dysfunction in ADRD. Here, we explain the neurovascular dysfunction associated with Alzheimer's disease (AD) as well as the intrinsic and extrinsic risk factors contributing to dysfunction of the neurovascular unit (NVU). Next, we ascertain ethnoregional health disparities of individuals living in Alabama, as well as relevant vascular risk factors linked to AD. We also discuss current pharmaceutical and non-pharmaceutical treatment options for neurovascular dysfunction, mild cognitive impairment (MCI) and AD, including relevant studies and ongoing clinical trials. Overall, individuals in Alabama are adversely affected by social and structural determinants of health leading to health disparities, driven by rurality, ethnic minority status, and lower socioeconomic status (SES). In general, these communities have limited access to healthcare and healthy food and other amenities resulting in decreased opportunities for early diagnosis of and pharmaceutical treatments for ADRD. Although this review is focused on the current state of health disparities of ADRD patients in Alabama, future studies must include diversity of race, ethnicity, and region to best be able to treat all individuals affected by ADRD.

Neuropsychological Functioning in Primary Dystonia: Updated and Expanded Multidomain Meta-Analysis.

BACKGROUND: Primary dystonia is conventionally considered as a motor disorder, though an emerging literature reports associated cognitive dysfunction. OBJECTIVES: Here, we conducted meta-analyses on studies comparing clinical measures of cognition in persons with primary dystonia and healthy controls (HCs). METHODS: We searched PubMed, Embase, Cochrane Library, Scopus, and PsycINFO (January 2000-October 2020). Analyses were modeled under random effects. We used Hedge's g as a bias-corrected estimate of effect size, where negative values indicate lower performance in dystonia versus controls. Between-study heterogeneity and bias were primarily assessed with Cochran's Q, I2 , and Egger's regression. RESULTS: From 866 initial results, 20 studies met criteria for analysis (dystonia n = 739, controls n = 643; 254 effect sizes extracted). Meta-analysis showed a significant combined effect size of primary dystonia across all studies (g = -0.56, P < 0.001), with low heterogeneity (Q = 25.26, P = 0.15, I2  = 24.78). Within-domain effects of primary dystonia were motor speed = -0.84, nonmotor speed = -0.83, global cognition = -0.65, language = -0.54, executive functioning = -0.53, learning/memory = -0.46, visuospatial/construction = -0.44, and simple/complex attention = -0.37 (P-values <0.01). High heterogeneity was observed in the motor/nonmotor speed and learning/memory domains. There was no evidence of publication bias. Moderator analyses were mostly negative but possibly underpowered. Blepharospasm samples showed worse performance than other focal/cervical dystonias. Those with inherited (ie, genetic) disease etiology demonstrated worse performance than acquired. CONCLUSIONS: Dystonia patients consistently demonstrated lower performances on neuropsychological tests versus HCs. Effect sizes were generally moderate in strength, clustering around -0.50 SD units. Within the speed domain, results suggested cognitive slowing beyond effects from motor symptoms. Overall, findings indicate dystonia patients experience multidomain cognitive difficulties, as detected by neuropsychological tests. © 2022 International Parkinson and Movement Disorder Society.

Normative and Maladaptive Personality Traits and Self-Reported Executive Functioning.

Research on self-reported executive functioning (EF) and personality has largely focused on normative personality traits. While previous research has demonstrated that maladaptive personality traits are associated with performance-based EF, the literature examining the relationship between these traits and self-reported EF is limited. The current study examined the relationship between multiple domains of self-reported EF (Barkley Deficits in Executive Functioning Scale) and both normative (The International Personality Item Pool-NEO-120 Item [IPIP-120]) and maladaptive (Personality Inventory for DSM-5-Short Form [PID-5-SF]) personality traits in an undergraduate student sample (n = 354). Similar to past research, relationships were largest across EF domains for both measures related to neuroticism (i.e., IPIP-120 neuroticism and PID-5-SF negative affectivity) and conscientiousness (i.e., IPIP-120 conscientiousness and PID-5-SF disinhibition). Normative personality traits generally accounted for greater variance in EF when examined alone and were also generally associated with greater incremental validity when compared with maladaptive personality traits. However, multiple regression analyses indicated that maladaptive personality traits added unique predictive variance above and beyond normative personality traits in their association with multiple domains of EF. These results highlight the utility of assessing both normative and maladaptive personality traits as well as multiple domains of EF to more fully understand the relationship between personality and EF.

Examining an Alternative Scoring Procedure for a Clinical Working Memory Measure.

The Digit Span test is a widely used working memory measure. However, when using standardized scoring procedures, previous studies have demonstrated inconsistent relationships between Digit Span subtests and working memory measures frequently used in cognitive psychology experiments. Partial scoring involves awarding credit for all digits recalled in the correct serial location, whereas traditional scoring involves only awarding credit for a trial if all digits are recalled in the correct serial location. The current study compared the traditional all-or-nothing scoring method and the partial scoring method on Digit Span with other working memory measures and with measures of general fluid intelligence. The results showed that when differences were found, partial scoring was associated with stronger relationships with Digit Span Backwards but weaker relationships with Digit Span Forward and Sequencing compared with traditional scoring. These results support previous findings identifying differences between the Digit Span subtests and the utility of examining traditional scoring procedures.

Great balls of fire: activation and signalling of inflammatory caspases.

Innate immune responses are tightly regulated by various pathways to control infections and maintain homeostasis. One of these pathways, the inflammasome pathway, activates a family of cysteine proteases called inflammatory caspases. They orchestrate an immune response by cleaving specific cellular substrates. Canonical inflammasomes activate caspase-1, whereas non-canonical inflammasomes activate caspase-4 and -5 in humans and caspase-11 in mice. Caspases are highly specific enzymes that select their substrates through diverse mechanisms. During inflammation, caspase activity is responsible for the secretion of inflammatory cytokines and the execution of a form of lytic and inflammatory cell death called pyroptosis. This review aims to bring together our current knowledge of the biochemical processes behind inflammatory caspase activation, substrate specificity, and substrate signalling.

Mapping of a Regulatory Site of the Escherichia coli ADP-Glucose Pyrophosphorylase.

The enzyme ADP-glucose pyrophosphorylase (ADP-Glc PPase) controls the biosynthesis of glycogen in bacteria and starch in plants. It is regulated by various activators in different organisms according to their metabolic characteristics. In Escherichia coli, the major allosteric activator is fructose 1,6-bisphosphate (FBP). Other potent activator analogs include 1,6-hexanediol bisphosphate (HBP) and pyridoxal 5'-phosphate (PLP). Recently, a crystal structure with FBP bound was reported (PDB ID: 5L6S). However, it is possible that the FBP site found is not directly responsible for the activation of the enzyme. We hypothesized FBP activates by binding one of its phosphate groups to another site ("P1") in which a sulfate molecule was observed. In the E. coli enzyme, Arg40, Arg52, and Arg386 are part of this "P1" pocket and tightly complex this sulfate, which is also present in the crystal structures of ADP-Glc PPases from Agrobacterium tumefaciens and Solanum tuberosum. To test this hypothesis, we modeled alternative binding conformations of FBP, HBP, and PLP into "P1." In addition, we performed a scanning mutagenesis of Arg residues near potential phosphate binding sites ("P1," "P2," "P3"). We found that Arg40 and Arg52 are essential for FBP and PLP binding and activation. In addition, mutation of Arg386 to Ala decreased the apparent affinity for the activators more than 35-fold. We propose that the activator binds at this "P1" pocket, as well as "P2." Arg40 and Arg52 are highly conserved residues and they may be a common feature to complex the phosphate moiety of different sugar phosphate activators in the ADP-Glc PPase family.

A Laboratory Word Memory Test Analogue Differentiates Intentional Feigning from True Responding Using the P300 Event-Related Potential.

Symptom exaggeration and feigned cognitive impairment occur commonly in forensic and medicolegal evaluations. As a result, methods to detect feigned cognitive impairment are an indispensable component of neuropsychological assessments. This study reports the results of two neurophysiological experiments using a forced-choice recognition task built from the stimuli of the Word Memory Test and Medical Symptom Validity Test as well as a new linguistically informed stimulus set. Participant volunteers were instructed either to do their best or to feign cognitive impairment consistent with a mild traumatic brain injury while their brain activity was monitored using event-related potentials (ERP). Experiment 1 varied instructions across individuals, whereas Experiment 2 varied instructions within individuals. The target brain component was a positive deflection indicating stimulus recognition that occurs approximately 300 ms after exposure to a stimulus (i.e., the P300). Multimodal comparison (P300 amplitude to behavioral accuracy) allowed the detection of feigned cognitive impairment. Results indicate that, for correct responses, P300s were equivalent for the simulated malingering and good effort conditions. However, for incorrect responses, feigned impairment produced reliable but significantly reduced P300 amplitudes. Although the P300 is an automatic index of recognition-even when knowledge is hidden-its amplitude appears capable of modulation by feigning strategies. Implications of this finding are discussed for research and clinical applications.