Traumatic encephalopathy syndrome (TES) has overlapping clinical symptoms with Alzheimer disease (AD). AD pathology commonly co-occurs with chronic traumatic encephalopathy (CTE) pathology. There are ...currently no validated CTE biomarkers. AD-specific biomarkers such as plasma P-tau181 and P-tau217 may help to identify patients with TES who have AD pathology.
We measured plasma P-tau181 and P-tau217 (Meso Scale Discovery electrochemiluminescence) in patients with TES, mild cognitive impairment/dementia with biomarker-confirmed AD ("AD"), and healthy controls ("HC"). Patients underwent amyloid-beta (Aβ)-PET and a subset underwent tau-PET using 18FFlortaucipir. We compared plasma P-tau levels controlling for age and sex and also performed AUC analyses to evaluate the accuracy of group differentiation. In patients with TES, we evaluated associations between plasma P-tau, years of repetitive head impact exposure, and tau-PET. Four TES patients with autopsy-confirmed CTE were described qualitatively.
The sample included 131 participants (TES, N = 18; AD, N = 65; HC, N = 48). Aβ(+) patients with TES (N = 10), but not Aβ(-) TES, had significantly higher plasma P-tau levels than HC (P-tau181:
< 0.001,
= 1.34; P-tau217:
< 0.001,
= 1.59). There was a trend for Aβ(+) TES having higher plasma P-tau than Aβ(-) TES (P-tau181:
= 0.06,
= 1.06; P-tau217:
= 0.09,
= 0.93). AUC analyses showed good classification of Aβ(+) TES from HC for P-tau181 (AUC = 0.87 0.71-1.00) and P-tau217 (AUC = 0.93 0.86-1.00). Plasma P-tau217 showed fair differentiation of Aβ(+) TES from Aβ(-) TES (AUC = 0.79 0.54-1.00,
= 0.04), whereas classification accuracy of P-tau181 was slightly lower and not statistically significant (AUC = 0.71 0.46-0.96,
= 0.13). Patients with AD had higher tau-PET tracer uptake than Aβ(+) TES and were well differentiated using P-tau181 (AUC = 0.81 0.68-0.94) and P-tau217 (AUC = 0.86 0.73-0.98). Plasma P-tau correlated with the tau-PET signal in Aβ(+) TES but not in Aβ(-) TES, and there was no association between plasma P-tau and years of repetitive head impact exposure. TES patients with severe CTE and no AD at autopsy had low P-tau181 and P-tau217 levels.
Measuring P-tau181 and P-tau217 in plasma may be a feasible and scalable fluid biomarker for identifying AD pathology in TES. Low plasma P-tau levels may be used to increase clinical suspicion of CTE over AD as a primary pathology in TES. Currently, there is no support for P-tau181 or P-tau217 as in vivo biomarkers of CTE tau. Larger studies of patients with pathologically confirmed CTE are needed.
This study provides Class III evidence that (1) among patients with TES and abnormal Aβ-PET scans, elevated plasma P-tau can differentiate between affected individuals and HCs; (2) low plasma P-tau may help identify patients with TES who do not have Alzheimer; and (3) plasma P-tau181 and P-tau217 are not useful biomarkers of patients with TES who do not have AD.
Renewable energy is the cornerstone of preventing dangerous climate change whilst maintaining a robust energy supply. Tidal energy will arguably play a critical role in the renewable energy portfolio ...as it is both predictable and reliable, and can be put in place across the globe. However, installation may impact the local and regional ecology via changes in tidal dynamics, sediment transport pathways or bathymetric changes. In order to mitigate these effects, tidal energy devices need to be modelled, to predict hydrodynamic changes. Robust mesh generation is a fundamental component required for developing simulations with high accuracy. However, mesh generation for coastal domains can be an elaborate procedure. Here, we describe an approach combining mesh generators with Geographical Information Systems. We demonstrate robustness and efficiency by constructing a mesh with which to examine the potential environmental impact of a tidal turbine farm installation in the Orkney Islands. The mesh is then used with two well-validated ocean models, to compare their flow predictions with and without a turbine array. The results demonstrate that it is possible to create an easy-to-use tool to generate high-quality meshes for combined coastal engineering, here tidal turbines, and coastal ocean simulations.
•An unstructured mesh generation framework for coastal ocean modelling is presented.•We detail the interfacing of GIS with a mesh-generator and online data repositories.•An application in a study of tidal ow in the Pentland Firth is presented.•The framework facilitated identical mesh and bathymetry in two ocean models.
The kinematic complexity and the favorable position of M51 on the sky make this galaxy an ideal target to test different theories of spiral arm dynamics. Using a tilted-ring analysis supported by ...several other archival data sets, we update the estimation of M51's position angle (P.A. = (173 + or - 3)degrees) and inclination (i = (22 + or - 5)degrees). Harmonic decomposition of the high-resolution (~40 pc) CO velocity field shows the first kinematic evidence of an m = 3 wave in the inner disk of M51 with a corotation at R sub(CR, )m=3 = 1.1 + or - 0.1 kpc and a pattern speed of Omega sub(p, m=3) approximately 140 km s super(-1) kpc super(-1). Our joint analysis of HI and CO velocity fields at low and high spatial resolution reveals that the atomic and molecular gas phases respond differently to the spiral perturbation due to their different vertical distribution and emission morphology.
ABSTRACT The cloud-scale density, velocity dispersion, and gravitational boundedness of the interstellar medium (ISM) vary within and among galaxies. In turbulent models, these properties play key ...roles in the ability of gas to form stars. New high-fidelity, high-resolution surveys offer the prospect to measure these quantities across galaxies. We present a simple approach to make such measurements and to test hypotheses that link small-scale gas structure to star formation and galactic environment. Our calculations capture the key physics of the Larson scaling relations, and we show good correspondence between our approach and a traditional "cloud properties" treatment. However, we argue that our method is preferable in many cases because of its simple, reproducible characterization of all emission. Using, low-J 12CO data from recent surveys, we characterize the molecular ISM at 60 pc resolution in the Antennae, the Large Magellanic Cloud (LMC), M31, M33, M51, and M74. We report the distributions of surface density, velocity dispersion, and gravitational boundedness at 60 pc scales and show galaxy-to-galaxy and intragalaxy variations in each. The distribution of flux as a function of surface density appears roughly lognormal with a 1 width of ∼0.3 dex, though the center of this distribution varies from galaxy to galaxy. The 60 pc resolution line width and molecular gas surface density correlate well, which is a fundamental behavior expected for virialized or free-falling gas. Varying the measurement scale for the LMC and M31, we show that the molecular ISM has higher surface densities, lower line widths, and more self-gravity at smaller scales.
Measuring plasma glial fibrillary acidic protein (GFAP) alongside cortical amyloid-β (Aβ) may shed light on astrocytic changes in aging and Alzheimer's disease (AD).
To examine associations between ...plasma GFAP and cortical Aβ deposition in older adults across the typical aging-to-AD dementia spectrum.
We studied two independent samples from UCSF (Cohort 1, N = 50; Cohort 2, N = 37) covering the spectra of clinical severity (CDR Sum of Boxes; CDR-SB) and Aβ-PET burden. Aβ-PET was completed with either florbetapir or Pittsburgh Compound B and standardized uptake value ratios were converted to the Centiloid (CL) scale for analyses. All participants with CDR-SB > 0 were Aβ-PET positive, while clinically normal participants (CDR-SB = 0) were a mix of Aβ-PET positive and negative. Regression analyses evaluated main effect and interaction associations between plasma GFAP, Aβ-PET, and clinical severity.
In both cohorts, plasma GFAP increased linearly with Aβ-PET CLs in clinically normal older adults. In Cohort 2, which included participants with more severe clinical dysfunction and Aβ-PET burden, the association between Aβ and GFAP became curvilinear (inverted U-shape; quadratic model R2 change = 0.165, p = 0.009), and Aβ-PET interacted with CDR-SB (R2 change = 0.164, p = 0.007): older adults with intermediate functional impairment (CDR-SB = 0.5-4.0) showed a weak (negative) association between Aβ-PET CLs and plasma GFAP, while older adults with dementia (CDR-SB > 4.0) showed a strong, negative association of higher Aβ-PET CLs with lower plasma GFAP.
The relationship between astrocytic integrity and cortical Aβ may be highly dynamic, with linear, positive associations early in disease that diverge in more severe disease stages.
Accurate safety information in published clinical trials guides the assessment of risk-benefit, as well as the design of future clinical trials. Comprehensive reporting of adverse events, toxicity, ...and discontinuations from acute spinal cord injury clinical trials is an essential step in this process. Here, we sought to assess the degree of "satisfactoriness" of reporting in past clinical trials in spinal cord injury. A review of citations from MEDLINE and EMBASE identified eligible clinical trials in acute (within 30 days) spinal cord injury. English language studies, published between 1980 and 2020, with sensory, motor, or autonomic neurological assessments as the primary outcome measure were eligible for inclusion. Criteria were then established to qualify the safety reporting as satisfactory (i.e., distinguished severe/life-threatening events), partially satisfactory, or unsatisfactory (i.e., only mentioned in general statements, or reported but without distinguishing severe events). A total of 40 trials were included. Satisfactory reporting for clinical adverse events was observed in 30% of trials; partially satisfactory was achieved by 10% of the trials, and the remaining 60% were unsatisfactory. The majority of trials were determined to be unsatisfactory for the reporting of laboratory-defined toxicity (82.5%); only 17.5% were satisfactory. Discontinuations were satisfactorily reported for the majority of trials (80%), with the remaining partially satisfactory (5%) or unsatisfactory (15%). Reporting of safety in clinical trials for acute spinal cord injury is suboptimal. Due to the complexities of acute spinal cord injury (e.g., polytrauma, multiple systems affected), tailored and specific standards for tracking adverse events and safety reporting should be established.
Accurately predicting the underlying neuropathological diagnosis in patients with behavioural variant frontotemporal dementia (bvFTD) poses a daunting challenge for clinicians but will be critical ...for the success of disease-modifying therapies. We sought to improve pathological prediction by exploring clinicopathological correlations in a large bvFTD cohort. Among 438 patients in whom bvFTD was either the top or an alternative possible clinical diagnosis, 117 had available autopsy data, including 98 with a primary pathological diagnosis of frontotemporal lobar degeneration (FTLD), 15 with Alzheimer's disease, and four with amyotrophic lateral sclerosis who lacked neurodegenerative disease-related pathology outside of the motor system. Patients with FTLD were distributed between FTLD-tau (34 patients: 10 corticobasal degeneration, nine progressive supranuclear palsy, eight Pick's disease, three frontotemporal dementia with parkinsonism associated with chromosome 17, three unclassifiable tauopathy, and one argyrophilic grain disease); FTLD-TDP (55 patients: nine type A including one with motor neuron disease, 27 type B including 21 with motor neuron disease, eight type C with right temporal lobe presentations, and 11 unclassifiable including eight with motor neuron disease), FTLD-FUS (eight patients), and one patient with FTLD-ubiquitin proteasome system positive inclusions (FTLD-UPS) that stained negatively for tau, TDP-43, and FUS. Alzheimer's disease was uncommon (6%) among patients whose only top diagnosis during follow-up was bvFTD. Seventy-nine per cent of FTLD-tau, 86% of FTLD-TDP, and 88% of FTLD-FUS met at least 'possible' bvFTD diagnostic criteria at first presentation. The frequency of the six core bvFTD diagnostic features was similar in FTLD-tau and FTLD-TDP, suggesting that these features alone cannot be used to separate patients by major molecular class. Voxel-based morphometry revealed that nearly all pathological subgroups and even individual patients share atrophy in anterior cingulate, frontoinsula, striatum, and amygdala, indicating that degeneration of these regions is intimately linked to the behavioural syndrome produced by these diverse aetiologies. In addition to these unifying features, symptom profiles also differed among pathological subtypes, suggesting distinct anatomical vulnerabilities and informing a clinician's prediction of pathological diagnosis. Data-driven classification into one of the 10 most common pathological diagnoses was most accurate (up to 60.2%) when using a combination of known predictive factors (genetic mutations, motor features, or striking atrophy patterns) and the results of a discriminant function analysis that incorporated clinical, neuroimaging, and neuropsychological data.
Dementia cases may reach 100 million by 2050. Interventions are sought to curb or prevent cognitive decline. Exercise yields cognitive benefits, but few older adults exercise. Virtual ...reality-enhanced exercise or "exergames" may elicit greater participation.
To test the following hypotheses: (1) stationary cycling with virtual reality tours ("cybercycle") will enhance executive function and clinical status more than traditional exercise; (2) exercise effort will explain improvement; and (3) brain-derived neurotrophic growth factor (BDNF) will increase.
Multi-site cluster randomized clinical trial (RCT) of the impact of 3 months of cybercycling versus traditional exercise, on cognitive function in older adults. Data were collected in 2008-2010; analyses were conducted in 2010-2011.
102 older adults from eight retirement communities enrolled; 79 were randomized and 63 completed.
A recumbent stationary ergometer was utilized; virtual reality tours and competitors were enabled on the cybercycle.
Executive function (Color Trails Difference, Stroop C, Digits Backward); clinical status (mild cognitive impairment; MCI); exercise effort/fitness; and plasma BDNF.
Intent-to-treat analyses, controlling for age, education, and cluster randomization, revealed a significant group X time interaction for composite executive function (p=0.002). Cybercycling yielded a medium effect over traditional exercise (d=0.50). Cybercyclists had a 23% relative risk reduction in clinical progression to MCI. Exercise effort and fitness were comparable, suggesting another underlying mechanism. A significant group X time interaction for BDNF (p=0.05) indicated enhanced neuroplasticity among cybercyclists.
Cybercycling older adults achieved better cognitive function than traditional exercisers, for the same effort, suggesting that simultaneous cognitive and physical exercise has greater potential for preventing cognitive decline.
This study is registered at Clinicaltrials.gov NCT01167400.
Focal anterior temporal lobe degeneration often preferentially affects the left or right hemisphere. While patients with left-predominant anterior temporal lobe atrophy show severe anomia and verbal ...semantic deficits and meet criteria for semantic variant primary progressive aphasia and semantic dementia, patients with early right anterior temporal lobe atrophy are more difficult to diagnose as their symptoms are less well understood. Focal right anterior temporal lobe atrophy is associated with prominent emotional and behavioural changes, and patients often meet, or go on to meet, criteria for behavioural variant frontotemporal dementia. Uncertainty around early symptoms and absence of an overarching clinico-anatomical framework continue to hinder proper diagnosis and care of patients with right anterior temporal lobe disease. Here, we examine a large, well-characterized, longitudinal cohort of patients with right anterior temporal lobe-predominant degeneration and propose new criteria and nosology. We identified individuals from our database with a clinical diagnosis of behavioural variant frontotemporal dementia or semantic variant primary progressive aphasia and a structural MRI (n = 478). On the basis of neuroimaging criteria, we defined three patient groups: right anterior temporal lobe-predominant atrophy with relative sparing of the frontal lobes (n = 46), frontal-predominant atrophy with relative sparing of the right anterior temporal lobe (n = 79) and left-predominant anterior temporal lobe-predominant atrophy with relative sparing of the frontal lobes (n = 75). We compared the clinical, neuropsychological, genetic and pathological profiles of these groups. In the right anterior temporal lobe-predominant group, the earliest symptoms were loss of empathy (27%), person-specific semantic impairment (23%) and complex compulsions and rigid thought process (18%). On testing, this group exhibited greater impairments in Emotional Theory of Mind, recognition of famous people (from names and faces) and facial affect naming (despite preserved face perception) than the frontal- and left-predominant anterior temporal lobe-predominant groups. The clinical symptoms in the first 3 years of the disease alone were highly sensitive (81%) and specific (84%) differentiating right anterior temporal lobe-predominant from frontal-predominant groups. Frontotemporal lobar degeneration-transactive response DNA binding protein (84%) was the most common pathology of the right anterior temporal lobe-predominant group. Right anterior temporal lobe-predominant degeneration is characterized by early loss of empathy and person-specific knowledge, deficits that are caused by progressive decline in semantic memory for concepts of socioemotional relevance. Guided by our results, we outline new diagnostic criteria and propose the name, 'semantic behavioural variant frontotemporal dementia', which highlights the underlying cognitive mechanism and the predominant symptomatology. These diagnostic criteria will facilitate early identification and care of patients with early, focal right anterior temporal lobe degeneration as well as in vivo prediction of frontotemporal lobar degeneration-transactive response DNA binding protein pathology.
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