Reducing false positive diagnoses in mild cognitive impairment: the importance of comprehensive neuropsychological assessment.

BACKGROUND AND PURPOSE: Longitudinal studies of mild cognitive impairment (MCI) report that a sizeable proportion of MCI cases revert to normal levels of functioning over time. The rate of recovery from MCI indicates that existing MCI diagnostic criteria result in an unacceptably high rate of false positive diagnoses and lack adequate sensitivity and specificity. METHODS: The aim of the present study was to identify a set of neuropsychological measures able to differentiate between true positive cases of MCI from those who were unimpaired at 11 months' follow-up. RESULTS: A discriminant function analysis identified that a combination of measures of complex sustained attention, semantic memory, working memory, episodic memory and selective attention correctly classified outcome in more than 80% of cases. The rate of false positive diagnoses (5.93%) was considerably lower than is evident in previously published MCI studies. CONCLUSIONS: The results of the present study indicate that the rate of false positive MCI diagnoses can be significantly reduced through the use of sensitive and specific neuropsychological measures of memory and non-memory functions.

Are tomorrow's doctors prepared to prevent dementia? A cross-sectional study of Tasmanian medical students' knowledge of dementia risk factors.

Tomorrow's doctors are unprepared to prevent dementia. This cross-sectional study invited medical students enrolled in the University of Tasmania 5-year medical degree (MBBS) to participate in an online questionnaire during 2019. This study measured students' recall of risk factors, prompted and unprompted, for dementia and cardiovascular disease (CVD), and Dementia Knowledge Assessment Scale (DKAS) score. Data were collected via an online survey comprising the DKAS, and risk factor questions adapted from the Alzheimer's Research UK National Monitor Survey, with questions on CVD risk factors added for comparison. Medical students (n = 82) proffered fewer unprompted risk factors for dementia than for CVD and were less proficient at recognizing dementia risk factors from a prompted list. Knowledge of vascular risk factors for dementia was particularly limited. Their broader dementia knowledge was generally adequate and DKAS scores were at the level of a qualified doctor by final year. Whilst medical students' general knowledge of dementia was satisfactory, their knowledge of modifiable risk factors of dementia was limited. If replicated elsewhere, this raises concerns about whether the future medical workforce is equipped to take a necessary lead role in managing dementia risk reduction. As dementia incidence rises worldwide, and 40% cases are attributable to modifiable risk factors, educational programs may need to urgently address these deficiencies.

Cortical axon sub-population maintains density, but not turnover, of en passant boutons in the aged APP/PS1 amyloidosis model.

Synaptic dysfunction is one of the key mechanisms associated with cognitive deficits observed in Alzheimer's disease (AD), yet little is known about the presynaptic axonal boutons in AD. Focusing on cortical en passant boutons (EPBs) along axons located in the motor, sensory and prefrontal regions of the cerebral cortex in the APP/PS1 mouse model of AD, we investigated structural properties of EPBs over the lifespan and in response to a midlife environmental enrichment (EE) intervention. At 3, 12, and 18-22 months and following 6 months of midlife EE, we found that EPBs showed remarkable resilience in preserving overall synaptic output, as evidenced by the maintained density of EPBs along the axon shaft across all experimental conditions. Using cranial window imaging to monitor synaptic changes in real time, we report that despite maintaining a stable synaptic density, the dynamic fraction (gains and losses) of EPBs was significantlyreduced at 10-13 months of age in APP/PS1 axons compared to age matched controls.

A review of the (60)Co internal dosimetry at Devonport Royal Dockyard.

The physico-chemical properties of (60)Co contaminants arising from the UK Naval Nuclear Propulsion Programme (NNPP) pressurised water reactor (PWR) plants have been investigated in order to review individual monitoring requirements at Devonport Royal Dockyard (DRD). This has been achieved through laboratory tests on NNPP primary component samples and interpretation of direct bioassay measurements using internal dosimetry modelling software. Interpretation of lung measurements was completed for two inhalation events involving material originating from a PWR plant and post-primary circuit decontamination. Initial estimates of intake and dose were calculated using International Commission on Radiological Protection default parameter values. However, a good fit could only be achieved by fitting the data to alternative absorption parameters where 90-95% of the material dissolved and absorbed rapidly at a rate of 1 day(-1). As a consequence of this review, a number of improvements have been made to monitoring arrangements at DRD. A minimum of three direct measurements are now taken during the 0-30 day period after an intake, the capability of the Canberra Accuscan has been enhanced and dissolution tests are being carried out by the Health Protection Agency (HPA) on samples taken from PWR plants.

Nonlinear generalized functions on manifolds.

In this work, we adopt a new approach to the construction of a global theory of algebras of generalized functions on manifolds based on the concept of smoothing operators. This produces a generalization of previous theories in a form which is suitable for applications to differential geometry. The generalized Lie derivative is introduced and shown to extend the Lie derivative of Schwartz distributions. A new feature of this theory is the ability to define a covariant derivative of generalized scalar fields which extends the covariant derivative of distributions at the level of association. We end by sketching some applications of the theory. This work also lays the foundations for a nonlinear theory of distributional geometry that is developed in a subsequent paper that is based on Colombeau algebras of tensor distributions on manifolds.

A nonlinear theory of distributional geometry.

This paper builds on the theory of nonlinear generalized functions begun in Nigsch & Vickers (Nigsch, Vickers 2021 Proc. R. Soc. A 20200640 (doi:10.1098/rspa.2020.0640)) and extends this to a diffeomorphism-invariant nonlinear theory of generalized tensor fields with the sheaf property. The generalized Lie derivative is introduced and shown to commute with the embedding of distributional tensor fields and the generalized covariant derivative commutes with the embedding at the level of association. The concept of a generalized metric is introduced and used to develop a non-smooth theory of differential geometry. It is shown that the embedding of a continuous metric results in a generalized metric with well-defined connection and curvature and that for C 2 metrics the embedding preserves the curvature at the level of association. Finally, we consider an example of a conical metric outside the Geroch-Traschen class and show that the curvature is associated to a delta function.

Associations of Later-Life Education, the BDNF Val66Met Polymorphism and Cognitive Change in Older Adults.

In 358 participants of the Tasmanian Healthy Brain Project, we quantified the cognitive consequences of engaging in varying loads of university-level education in later life, and investigated whether or not BDNF Val66Met affected outcomes. Assessment of neuropsychological, health, and psychosocial function was undertaken at baseline, 12-month, and 24-month follow-up. Education load was positively associated with change in language processing performance, but this effect did not reach statistical significance (P = 0.064). The BDNF Val66Met polymorphism significantly moderated the extent to which education load was associated with improved language processing (P = 0.026), with education load having a significant positive relationship with cognitive change in BDNF Met carriers but not in BDNF Val homozygotes. In older adults who carry BDNF Met, engaging in university-level education improves language processing performance in a load-dependent manner.

Association between the serotonin transporter gene polymorphism and verbal learning in older adults is moderated by gender.

The S allele of the functional 5-HTTLPR polymorphism has previously been associated with reductions in memory function. Given the change in function of the serotonergic system in older adults, and the functional consequences of memory decline in this age group, further investigation into the impact of 5-HTTLPR in healthy older adults is required. This investigation examined the effect of 5-HTTLPR variants (S carriers versus L/L homozygotes) on verbal and visual episodic memory in 438 healthy older adults participating in the Tasmanian Healthy Brain Project (age range 50-79 years, M=60.35, s.d.=6.75). Direct effects of 5-HTTLPR on memory processes, in addition to indirect effects through interaction with age and gender, were assessed. Although no direct effects of 5-HTTLPR on memory processes were identified, our results indicated that gender significantly moderated the impact that 5-HTTLPR variants exerted on the relationship between age and verbal episodic memory function as assessed by the Rey Auditory Verbal Learning Test. No significant direct or indirect effects were identified in relation to visual memory performance. Overall, this investigation found evidence to suggest that 5-HTTLPR genotype affects the association of age and verbal episodic memory for males and females differently, with the predicted negative effect of S carriage present in males but not females. Such findings indicate a gender-dependent role for 5-HTTLPR in the verbal episodic memory system of healthy older adults.

Quiet eye training aids the long-term learning of throwing and catching in children: Preliminary evidence for a predictive control strategy.

Quiet eye training (QET) may be a more effective method for teaching children to catch than traditional training (TT) methods, but it is unclear if the benefits accrued persist in the long term. Thirty children were randomly allocated into a QET or TT group and, while wearing a mobile eye tracker, underwent baseline testing, training and two retention tests over a period of eight weeks, using a validated throw and catch task. During training, movement-related information was provided to both groups, while the QET group received additional instruction to increase the duration of their targeting fixation (QE1) on the wall prior to the throw, and pursuit tracking (QE2) period on the ball prior to catching. In both immediate (R1) and delayed (R2, six weeks later) retention tests, the QET group had a significantly longer QE1 duration and an earlier and longer QE2 duration, compared to the TT group, who revealed no improvements. A performance advantage was also found for the QET compared to the TT group at both R1 and R2, revealing the relatively robust nature of the visuomotor alterations. Regression analyses suggested that only the duration of QE1 predicted variance in catch success post-training, pointing to the importance of a pre-programming visuomotor strategy for successful throw and catch performance.

Cellular and synaptic localization of NMDA and non-NMDA receptor subunits in neocortex: organizational features related to cortical circuitry, function and disease.

Excitatory amino acid (EAA) receptors are an important component of neocortical circuitry as a result of their role as the principal mediators of excitatory synaptic activity, as well as their involvement in use-dependent modifications of synaptic efficacy, excitoxicity and cell death. The diversity in the effects generated by EAA-receptor activation can be attributed to multiple receptor subtypes, each of which is composed of multimeric assemblies of functionally distinct receptor subunits. The use of subunit-specific antibodies and molecular probes now makes it feasible to localize individual receptor subunits anatomically with a high level of cellular and synaptic resolution. Initial studies of the distribution of immunocytochemically localized EAA-receptor subunits suggest that particular subunit combinations exhibit a differential cellular, laminar and regional distribution in the neocortex. While such patterns might indicate that the functional heterogeneity of EAA-receptor-linked circuits, and the cell types in which they operate, are based partly on differential subunit parcellation, a definitive integration of these anatomical details into current schemes of cortical circuitry and organization awaits many further studies. Ideally, such studies should link a high level of molecular precision regarding subunit localization with synaptic details of identified connections and neurochemical features of neocortical cells.

Localization of glutamate receptors in developing cortical neurons in culture and relationship to susceptibility to excitotoxicity.

Overactivation of glutamate receptors leading to excitotoxicity has been implicated in the neurodegenerative alterations of a range of central nervous system (CNS) disorders. We have investigated the cell-type-specific changes in glutamate receptor localization in developing cortical neurons in culture, as well as the relationship between glutamate receptor subunit distribution with synapse formation and susceptibility to excitotoxicity. Glutamate receptor subunit clustering was present prior to the formation of synapses. However, different receptor types showed distinctive temporal patterns of subunit clustering, localization to spines, and apposition to presynaptic terminals. N-methyl-D-aspartate (NMDA) receptor subunit immunolabelling was present in puncta along dendrites prior to the formation of synapses, with relatively little localization to spines. Vulnerability to NMDA receptor-mediated excitotoxicity occurred before receptor subunits became localized in apposition to presynaptic terminals. Clustering of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors occurred concurrently with development of vulnerability to excitotoxicity and was related to localization of AMPA receptors at synapses and in spines. Different AMPA receptor subunits demonstrated cell-type-specific localization as well as distribution to spines, dendrites, and extrasynaptic subunit clusters. A subclass of neurons demonstrated substantial perineuronal synaptic innervation, and these neurons expressed relatively high levels of GluR1 and/or GluR4 at receptor puncta, indicating the presence of calcium-permeable AMPA receptors and suggesting alternative synaptic signalling mechanisms and vulnerability to excitotoxicity. These data demonstrate the relationship between glutamate receptor subunit expression and localization with synaptogenesis and development of neuronal susceptibility to excitotoxicity. These data also suggest that excitotoxicity can be mediated through extrasynaptic receptor subunit complexes along dendrites.

Gaze behaviors of goaltenders under spatial-temporal constraints.

It is still not known what underlies successful performance in goaltending. Some studies have reported that advanced cues from the shooter's body (hip, kicking leg or support leg) are most important (Savelsbergh, G. J. P., Williams, A. M., Van der Kamp, J., & Ward, P. (2002). Visual search, anticipation and expertise in soccer goalkeepers. Journal of Sports Sciences, 20, 279-287; Savelsbergh, G. J. P., Williams, A. M., Van der Kamp, J., & Ward, P. (2005). Anticipation and visual search behaviour in expert soccer goalkeepers. Ergonomics, 48, 1686-1697; Williams, A. M., & Burwitz, L. (1993). Advanced cue utilization in soccer. In T. Reilly, J. Clarys, & A. Stibbe (Eds.), Science and football II (pp. 239-243). London, England: E&FN Spon), while others have found that the early tracking of the object prior to and during flight is most critical (Bard, C., & Fleury, M. (1981). Considering eye movement as a predictor of attainment. In: I. M. Cockerill, & W. M. MacGillvary (Eds.), Vision and Sport (pp. 28-41). Cheltenham, England: Stanley Thornes (Publishers) Ltd.). These results are similar to those found in a number of interceptive timing studies (Land, M. F., & McLeod, P. (2000). From eye movements to actions: How batsmen hit the ball. Nature Neuroscience, 3, 1340-1345; Ripoll and Fleurance, 1988; Vickers, J. N., & Adolphe, R. M. (1997). Gaze behaviour during a ball tracking and aiming skill. International Journal of Sports Vision, 4, 18-27). The coupled gaze and motor behavior of elite goaltenders were determined while responding to wrist shots taken from 5 m and 10 m on ice. The results showed that the goalies faced shots that were significantly different in phase durations due to distance (5 versus 10 m), but this was not a factor in making saves. Instead, the ability to stop the puck was dependent on the location, onset and duration of the final fixation/tracking gaze (or quiet eye) prior to initiating the saving action. The relative onset of quiet eye was significantly (p<.001) earlier (8.6%) and the duration was longer on saves (M=80.5%; 952.3 ms) compared to goals (onset 18.86%; M=70.1%, 826.1 ms). The quiet eye was located on the puck/stick during the preparation and execution of the shot in 70.53% of all trials, or on the ice in front of the release point of the puck (25.68%) and rarely on the body of the shooter (2.1%). The results are discussed within the context of current research on goaltending with specific emphasis on the timing of critical cues and the effect of tasks constraints.

The cause of neuronal degeneration in Alzheimer's disease.

Alzheimer's disease is associated with a specific pattern of pathological changes in the brain that result in neurodegeneration and the progressive development of dementia. Pathological hallmarks common to the disease include beta-amyloid plaques, dystrophic neurites associated with plaques and neurofibrillary tangles within nerve cell bodies. The exact relationship between these pathological features has been elusive, although it is clear that beta-amyloid plaques precede neurofibrillary tangles in neocortical areas. Examination of the brains of individuals in the preclinical stage of the disease have shown that the earliest form of neuronal pathology associated with beta-amyloid plaques resembles the cellular changes that follow structural injury to axons. Thus, the development of beta-amyloid plaques in the brain may cause physical damage to axons, and the abnormally prolonged stimulation of the neuronal response to this kind of injury ultimately results in the profound cytoskeletal alterations that underlie neurofibrillary pathology and neurodegeneration. Therapeutically, inhibition of the neuronal reaction to physical trauma may be a useful neuroprotective strategy in the earliest stages of Alzheimer's disease.

Response of congenitally athymic (nude) mice to infection with Mycobacterium bovis (strain BCG).

Mice homozygous for the mutation "nude" (nu/nu) are athymic and lack thymus-dependent lymphocytes. Heterozygote (nu/+) controls, which are phenotypically and immunologically normal, and (nu/nu) mice were infected with 1.0 times 10-6 colony-forming units of Phipps strain BCG. In the spleens of nu/+ mice, there was a progressive increase in number of BCG up to the second week, followed by a gradual decline. However, in the nu/nu mice, BCG growth was gradual and continuous until termination of the experiment at 5 weeks. In the lung, significant differences were not noted until after the second week, at which time the nude mice showed a rapid increase (of more than 2 log10) in the number of BCG. However, the number of BCG was not significantly greater in the livers of either group. Changes in the normal histology of the lung included a massive influx of monocytes during the first 2 weeks which peaked at day 21. In the lungs of the nu/+ mice by day 28, there was considerable granuloma formation consisting of monocytes and small lymphocytes. However, in the lungs of nu/nu animals, the granulomas were made up primarily of monocytes with a lack of small lymphocytes. Acid-fast stains confirmed the presence of large numbers of organisms in the macrophages of nu/nu mice, with gradual destruction of these phagocytic cells.

Alterations in neurofilaments and the transformation of the cytoskeleton in axons may provide insight into the aberrant neuronal changes of Alzheimer's disease.

Neurofilaments are major protein constituents of the brain, but are particularly abundant in specific subpopulations of neurons and likely have a key role in the regulation of axonal calibre. Neurofilament proteins may also be involved in the transformation of the neuronal cytoskeleton leading to substantial tau pathology in axons damaged by Aß, subsequently leading to neurofibrillary pathology in their cell bodies of origin. An understanding of neurofilamentous changes in axons and subsequent tau pathology may provide insight into how Aß pathology may stimulate an aberrant plasticity-related response of damaged neurons, leading to the progressive and degenerative changes in the neuronal cytoskeleton that result in synapse loss and neuronal degeneration.

Cerebrospinal fluid monoamine and adrenal correlates of aggression in free-ranging rhesus monkeys.

Clinical and preclinical studies involving several different mammalian species and research paradigms suggest a negative correlation between aggression and central serotonin activity. To test the generalizability of laboratory findings in rhesus monkeys that show a negative correlation between cerebrospinal fluid 5-hydroxyindoleacetic acid concentrations and aggression, we obtained cisternal cerebrospinal fluid and blood plasma samples from monkeys living in naturalistic conditions. During a semiannual trapping, 28 juvenile and adolescent male rhesus monkeys were chosen from a population of 4200 provisioned, free-ranging rhesus monkeys living on Morgan Island, a sea island located off the coast of South Carolina. Based on direct observations of participation or avoidance of aggressive behavior and examinations of apparent fight wounds, 18 monkeys were selected for cerebrospinal fluid taps and blood samples. The remaining 10 monkeys were selected at random. Descriptions of aggressive behavior and the number of old scars and recent wounds were carefully transcribed, and a photograph showing wounds and scars was obtained for each animal. Using the transcriptions and photographs, researchers experienced in rhesus monkey behavior, but blind to the subjects' monoamine and hormone concentrations, were asked to rank the monkeys from the most to the least aggressive. The results showed a significant negative correlation between high rankings for aggression and cerebrospinal fluid 5-hydroxyindoleacetic acid concentrations. There was evidence that aggression was associated with stress, in that cerebrospinal fluid, norepinephrine, and plasma corticotropin and cortisol concentrations were positively correlated with high rankings of aggression.

Excessive mortality in young free-ranging male nonhuman primates with low cerebrospinal fluid 5-hydroxyindoleacetic acid concentrations.

BACKGROUND: The purpose of this study was to assess the impact of central serotonin turnover rate on survival to adulthood among nonhuman primates living in a large, free-ranging colony. METHODS: The rate of mortality was ascertained over a 4-year period after obtaining blood and cisternal cerebrospinal fluid (CSF) samples from 49 free-ranging, 2-year-old prepubertal male rhesus monkeys. Cerebrospinal fluid was assayed for 5-hydroxyindoleacetic acid (5-HIAA), norepinephrine, 3-methoxy-4-hydroxyphenylgycol, and homovanillic acid. Blood plasma was assayed for adrenocorticotropic hormone, cortisol, and testosterone. Following the sampling of body fluids, records of scars and wounds and aggressive encounters were used to rank the subjects from low to high in aggressiveness. Direct observations of aggressive behavior were collected from 27 of the subjects over a 3-month period. RESULTS: Four years later, 6 of the 49 subjects were known to be dead and an additional 5 had been missing for more than 2 years and were presumed dead. The CSF 5-HIAA concentrations were predictive of which subjects died, with 46% of the subjects with low CSF 5-HIAA concentrations dead or presumed dead. None of the subjects from the highest CSF 5-HIAA concentration quartile were dead or missing. Indeed, 91% of the dead subjects came from the 2 lowest quartiles of CSF 5-HIAA concentrations. Direct observations of aggressive behavior showed that dead or missing subjects had initiated escalated aggression, a measure of unrestrained aggression that has a high probability of trauma or injury, at a higher rate than subjects that were known to be alive. The cause of death could be ascertained for 6 of the 11 missing subjects. The 4 subjects that were known to die as a consequence of aggressive encounters came from the lowest quartile of CSF 5-HIAA concentrations and had been rated as more aggressive during their initial capture. Subjects captured more than once possessed lower CSF 5-HIAA concentrations, were rated as more aggressive, and were more likely to suffer early death than those captured only once. CONCLUSION: These findings suggest that low CSF 5-HIAA concentrations quantified early in life is a powerful biological predictor of future excessive aggression, risk taking, and premature death among nonhuman primate males.

Metallothionein biology in the ageing and neurodegenerative brain.

In recent years metallothionein (MT) biology has moved from investigation of its ability to protect against environmental heavy metals to a wider appreciation of its role in responding to cellular stress, whether as a consequence of normal function, or following injury and disease. This is exemplified by recent investigation of MT in the mammalian brain where plausible roles for MT action have been described, including zinc metabolism, free radical scavenging, and protection and regeneration following neurological injury. Along with other laboratories we have used several models of central nervous system (CNS) injury to investigate possible parallels between injury-dependent changes in MT expression and those observed in the ageing and/or degenerating brain. Therefore, this brief review aims to summarise existing information on MT expression during CNS ageing, and to examine the possible involvement of this protein in the course of human neurodegenerative disease, as exemplified by Alzheimer's disease.

Quiet eye training facilitates visuomotor coordination in children with developmental coordination disorder.

INTRODUCTION: Quiet eye training (QET) has been shown to be more effective than traditional training (TT) methods for teaching a throw and catch task to typically developing 8-10 yr old children. The current study aimed to apply the technique to children with developmental coordination disorder (DCD). METHOD: 30 children with DCD were randomly allocated into TT or QET intervention groups. The TT group were taught how to control their arm movements during the throw and catch phases, while the QET group were also taught to fixate a target location on the wall prior to the throw (quiet eye1; QE1), followed by tracking the ball prior to the catch (quiet eye2; QE2). Performance, gaze and motion analysis data were collected at pre/post-training and 6-week retention. RESULTS: The QET group significantly increased QE durations from pre-training to delayed retention (QE1 = +247 ms, QE2 = +19%) whereas the TT group experienced a reduction (QE1 = -74 ms, QE2 = -4%). QET participants showed significant improvement in the quality of their catch attempts and increased elbow flexion at catch compared to the TT group (QET = -28°, TT = -1°). CONCLUSION: QET changed DCD children's ability to focus on a target on the wall prior to the throw, followed by better anticipation and pursuit tracking on the ball, which in turn led to improved catching technique. QET may be an effective adjunct to traditional instructions, for therapists teaching visuomotor skills to children with DCD.