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.

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.

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.

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.

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.

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.

The BDNF Val66Met polymorphism moderates the relationship between cognitive reserve and executive function.

The concept of cognitive reserve (CR) has been proposed to account for observed discrepancies between pathology and its clinical manifestation due to underlying differences in brain structure and function. In 433 healthy older adults participating in the Tasmanian Healthy Brain Project, we investigated whether common polymorphic variations in apolipoprotein E (APOE) or brain-derived neurotrophic factor (BDNF) influenced the association between CR contributors and cognitive function in older adults. We show that BDNF Val66Met moderates the association between CR and executive function. CR accounted for 8.5% of the variance in executive function in BDNF Val homozygotes, but CR was a nonsignificant predictor in BDNF Met carriers. APOE polymorphisms were not linked to the influence of CR on cognitive function. This result implicates BDNF in having an important role in capacity for building or accessing CR.

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.

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.

Nutritional access routes following oesophagectomy--a systematic review.

Nutritional support in patients undergoing oesophagectomy is of paramount importance in this usually malnourished patient group, but encountering significant clinical practice variation between units. Our aim was therefore to assess the strength of evidence behind nutritional support routes post-oesophagectomy. The Cochrane Library and Controlled Trials Registry, MEDLINE (Ovid) (1966-April 2009), PubMed, EMBASE (1966-April 2009), CINAHL, Web of knowledge and SCOPUS databases, were electronically searched for the highest level of evidence, with English language as a limit. Reference follow-up was also used. Studies were critically reviewed based on The NHS Public Health Resource Unit Critical Appraisal Skills Programme Tools. Five randomised control trials (RCTs) and one case-control trial, with 344 patients, were included in the review. There was a significant variation in the routes assessed (including intravenous fluid therapy, peripheral and central line nutrition, feeding jejunostomy, nasojejunal and nasoduodenal tubes) and the methodological quality of each study, with small patient numbers. No route was found to be superior over another in the RCTs. In the case-control trial, the combination of enteral parenteral nutrition led to shorter hospital stay compared with parenteral feeding alone. Nasojejunal and nasoduodenal tubes are associated with a significant rate of dislodgement. There is absence of strong direct evidence supporting a single feeding access route in oesophagectomy patients. Clinical decisions should be made based on available evidence from other types of gastrointestinal surgery, currently favouring enteral nutrition. If enteral feeding is chosen, feeding jejunostomy may be superior to nasojejunal or duodenal tubes.

Association of metallothionein-III with oligodendroglial cytoplasmic inclusions in multiple system atrophy.

Multiple system atrophy (MSA) is an adult-onset neurodegenerative disease characterised by Parkinsonian and autonomic symptoms and by widespread intracytoplasmic inclusion bodies in oligodendrocytes. These glial cytoplasmic inclusions (GCIs) are comprised of 9-10 nm filaments rich in the protein alpha-synuclein, also found in neuronal inclusion bodies associated with Parkinson's disease. Metallothioneins (MTs) are a class of low-molecular weight (6-7 kDa), cysteine-rich metal-binding proteins the expression of which is induced by heavy metals, glucocorticoids, cytokines and oxidative stress. Recent studies have shown a role for the ubiquitously expressed MT-I/II isoforms in the brain following a variety of stresses, whereas, the function of the brain-specific MT isoform, MT-III, is less clear. MT-III and MT-I/II immunostaining of post-mortem tissue in MSA and normal control human brains showed that the number of MT-III-positive cells is significantly increased in MSA in visual cortex, whereas MT-I/II isoforms showed no significant difference in the distribution of immunopositive cells in MSA compared to normal tissue. GCIs were immunopositive for MT-III, but were immunonegative for the MT-I/II isoforms. Immunofluorescence double labelling showed the co-localisation of alpha-synuclein and MT-III in GCIs in MSA tissue. In isolated GCIs, transmission electron microscopy demonstrated MT-III immunogold labelling of the amorphous material surrounding alpha-synuclein filaments in GCIs. High-molecular weight MT-III species in addition to MT-III monomer were detected in GCIs by Western analysis of the detergent-solubilised proteins of purified GCIs. These results show that MT-III, but not MT-I/II, is a specific component of GCIs, present in abnormal aggregated forms external to the alpha-synuclein filaments.

Neuron-glia interactions underlie ALS-like axonal cytoskeletal pathology.

Amyotrophic lateral sclerosis (ALS) is a devastating disorder involving loss of movement due to degeneration of motor neurons. Studies suggest that in ALS axonal dysfunction precedes the death of motor neurons. Pathologically, ALS is characterized by neurofilamentous swellings (spheroids) within the axons of motor neurons. However, the causes of this axonopathy and possible resulting axonal dysfunction are not known. Using a novel model of cultured mouse motor neurons, we have determined that these neurons are susceptible to proximal axonopathy, which is related to the glial environment. This axonopathy showed remarkable similarity, both morphologically and neurochemically, to spheroids that develop over months in SOD1(G93A) transgenic mice. Focal ubiquitination, as well as perturbations of neurofilaments and microtubules, occurred in the axonal spheroid-like swellings in vitro, and visualization of mitochondrial dynamics demonstrated that axonopathy resulted in impaired axonal transport. These data provide strong evidence for the involvement of non-neuronal cells in axonal dysfunction in ALS. This cell culture model may be of benefit for the development of therapeutic interventions directed at axonal preservation.

Individualised assessment of response to clopidogrel in patients presenting with acute coronary syndromes: a role for short thrombelastography?

INTRODUCTION: There is considerable interindividual variation in response to the antiplatelet agent clopidogrel. Hyporesponse predicts negative outcomes in patients presenting with a variety of ischemic cardiac conditions and following intracoronary stent placement. Many tests of clopidogrel activity are time consuming and complex. Short thromboelastography (s-TEG) allows rapid measurement of platelet clopidogrel response. AIMS: We initiated this study to investigate the utility of s-TEG in assessing the response to clopidogrel in patients presenting with acute coronary syndromes (ACS) and to compare these results with established clopidogrel monitoring techniques. METHODS: Patients admitted with unstable angina (UA) or Non ST elevation myocardial infarction (NSTEMI) undergoing coronary angiography were recruited. After routine loading with clopidogrel, all patients were tested with s-TEG and Accumetrics Verify-Now rapid platelet function analyzer (VN-RPFA). We used the modified TEG technique of measuring area under the curve at 15 min (AUC15), which allows a rapid estimation of antiplatelet response. Vasodilator-stimulated phosphoprotein phosphorylation (VASP) was also tested in a subgroup of patients. Clinical follow-up was obtained at 1 year. s-TEG results were correlated with VN-RPFA and VASP findings. RESULTS: A total of 49 patients (33 male, mean age 63) were recruited and tested with s-TEG and VN-RPFA and a total of 39 patients were also assessed with VASP. s-TEG readings correlated well with VN-RPFA (r(2)= 0.54, P < 0.0001) and VASP (r(2)= 0.26, P= 0.001). CONCLUSION: s-TEG provides timely results which compare to current tests of clopidogrel activity. This technique can also be used to measure a variety of other clotting parameters and as such could develop into a valuable near patient test for the interventional cardiologist.

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.

Excitotoxicity mediated by non-NMDA receptors causes distal axonopathy in long-term cultured spinal motor neurons.

Excitotoxicity has been implicated as a potential cause of neuronal degeneration in amyotrophic lateral sclerosis (ALS). It has not been clear how excitotoxic injury leads to the hallmark pathological changes of ALS, such as the abnormal accumulation of filamentous proteins in axons. We have investigated the effects of overactivation of excitatory receptors in rodent neurons maintained in long-term culture. Excitotoxicity, mediated principally via non-N-methyl-D-aspartate (NMDA) receptors, caused axonal swelling and accumulation of cytoskeletal proteins in the distal segments of the axons of cultured spinal, but not cortical, neurons. Axonopathy only occurred in spinal neurons maintained for 3 weeks in vitro, indicating that susceptibility to axonal pathology may be related to relative maturity of the neuron. Excitotoxic axonopathy was associated with the aberrant colocalization of phosphorylated and dephosphorylated neurofilament proteins, indicating that disruption to the regulation of phosphorylation of neurofilaments may lead to their abnormal accumulation. These data provide a strong link between excitotoxicity and the selective pattern of axonopathy of lower motor neurons that underlies neuronal dysfunction in ALS.

Cellular dynamics underlying regeneration of damaged axons differs from initial axon development.

While long-distance regeneration may be limited in mammalian species, it is becoming apparent that damaged mature neurons retain some capacity for attempted regeneration and that the adult CNS is not entirely inhibitory to axon growth. Our investigations show that there are critical intrinsic features of postinjury axonal regeneration that differ from initial axon development, and that these distinct differences may account for the limited and inappropriate regenerative response that currently characterizes the mature CNS. We compared the neurochemical and dynamic characteristics of developing axons to relatively mature regenerating axons, utilizing an in vitro model of axonal transection to long-term cultured rat cortical neurons. Immunolabelling studies revealed that regenerating and developing axons have a similar localization of cytoskeletal proteins, but the tips of regenerating axons, although morphologically similar, were smaller with reduced fillopodial extension, relative to developmental growth cones. Live imaging demonstrated that regenerating axons exhibited significantly less outgrowth than developmental neurites. Furthermore, growth cones of regenerating axons had a significant reduction in pausing, considered vital for interstitial branching and pathfinding, than did developmental growth cones. In addition, unlike developing axons, the regenerating axons were unresponsive to the growth factors BDNF and GDNF. Thus, although similar in their cytoskeletal composition, the growth cones of regenerative sprouts differed from their developmental counterparts in their size, their dynamic behaviour and their ability to respond to critical growth factors. These intrinsic differences may account for the inability of post-traumatic locally sprouting axons to make accurate pathway decisions and successfully respond to trauma.

Metallothionein expression by NG2 glial cells following CNS injury.

Metallothionein (MT) expression is rapidly up-regulated following CNS injury, and there is a strong correlation between the presence or absence of MTand improved or impaired (respectively) recovery from such trauma.We now report that a distinct subset of NG2-positive, GFAP-negative glial cells bordering the injury tract express MT following focal injury to the adult rat neocortex. To confirm the ability of these NG2 glial cells to express MT, we have isolated and cultured them and identified that they can express MT following stimulation with zinc. To investigate the functional importance of MT expression by NG2 glial cells, we plated cortical neurons onto these cells and found that expression of MT enhanced the permissivity of NG2 glial cells to neurite outgrowth. Our data suggest that expression of MT by NG2 glial cells may contribute to the overall permissiveness of these cells to axon regeneration.