Plasma tau phosphorylated at threonine 217 (p-tau217) and plasma tau phosphorylated at threonine 181 (p-tau181) are associated with Alzheimer's disease tau pathology. We compared the diagnostic value ...of both biomarkers in cognitively unimpaired participants and patients with a clinical diagnosis of mild cognitive impairment, Alzheimer's disease syndromes, or frontotemporal lobar degeneration (FTLD) syndromes.
In this retrospective multicohort diagnostic performance study, we analysed plasma samples, obtained from patients aged 18–99 years old who had been diagnosed with Alzheimer's disease syndromes (Alzheimer's disease dementia, logopenic variant primary progressive aphasia, or posterior cortical atrophy), FTLD syndromes (corticobasal syndrome, progressive supranuclear palsy, behavioural variant frontotemporal dementia, non-fluent variant primary progressive aphasia, or semantic variant primary progressive aphasia), or mild cognitive impairment; the participants were from the University of California San Francisco (UCSF) Memory and Aging Center, San Francisco, CA, USA, and the Advancing Research and Treatment for Frontotemporal Lobar Degeneration Consortium (ARTFL; 17 sites in the USA and two in Canada). Participants from both cohorts were carefully characterised, including assessments of CSF p-tau181, amyloid-PET or tau-PET (or both), and clinical and cognitive evaluations. Plasma p-tau181 and p-tau217 were measured using electrochemiluminescence-based assays, which differed only in the biotinylated antibody epitope specificity. Receiver operating characteristic analyses were used to determine diagnostic accuracy of both plasma markers using clinical diagnosis, neuropathological findings, and amyloid-PET and tau-PET measures as gold standards. Difference between two area under the curve (AUC) analyses were tested with the Delong test.
Data were collected from 593 participants (443 from UCSF and 150 from ARTFL, mean age 64 years SD 13, 294 50% women) between July 1 and Nov 30, 2020. Plasma p-tau217 and p-tau181 were correlated (r=0·90, p<0·0001). Both p-tau217 and p-tau181 concentrations were increased in people with Alzheimer's disease syndromes (n=75, mean age 65 years SD 10) relative to cognitively unimpaired controls (n=118, mean age 61 years SD 18; AUC=0·98 95% CI 0·95–1·00 for p-tau217, AUC=0·97 0·94–0·99 for p-tau181; pdiff=0·31) and in pathology-confirmed Alzheimer's disease (n=15, mean age 73 years SD 12) versus pathologically confirmed FTLD (n=68, mean age 67 years SD 8; AUC=0·96 0·92–1·00 for p-tau217, AUC=0·91 0·82–1·00 for p-tau181; pdiff=0·22). P-tau217 outperformed p-tau181 in differentiating patients with Alzheimer's disease syndromes (n=75) from those with FTLD syndromes (n=274, mean age 67 years SD 9; AUC=0·93 0·91–0·96 for p-tau217, AUC=0·91 0·88–0·94 for p-tau181; pdiff=0·01). P-tau217 was a stronger indicator of amyloid-PET positivity (n=146, AUC=0·91 0·88–0·94) than was p-tau181 (n=214, AUC=0·89 0·86–0·93; pdiff=0·049). Tau-PET binding in the temporal cortex was more strongly associated with p-tau217 than p-tau181 (r=0·80 vs r=0·72; pdiff<0·0001, n=230).
Both p-tau217 and p-tau181 had excellent diagnostic performance for differentiating patients with Alzheimer's disease syndromes from other neurodegenerative disorders. There was some evidence in favour of p-tau217 compared with p-tau181 for differential diagnosis of Alzheimer's disease syndromes versus FTLD syndromes, as an indication of amyloid-PET-positivity, and for stronger correlations with tau-PET signal. Pending replication in independent, diverse, and older cohorts, plasma p-tau217 and p-tau181 could be useful screening tools to identify individuals with underlying amyloid and Alzheimer's disease tau pathology.
US National Institutes of Health, State of California Department of Health Services, Rainwater Charitable Foundation, Michael J Fox foundation, Association for Frontotemporal Degeneration, Alzheimer's Association.
ObjectivesOver 1 million people attend emergency departments in England and Wales with a head injury annually, with up to 50% of these patients under the age of 15.1 Although most have minor ...injuries, head injuries can signify underlying safeguarding concerns. RCPCH 2018 guidance described paediatric emergency departments (PEDs) as a potential first point of contact for children who have been subjected to abuse or neglect and the active role clinicians must play in the early recognition of these individuals.2 This study aims to review the assessment of paediatric head injuries, and consideration of safeguarding concerns, in a PED in a large district general hospital, comparing the differences between paediatricians and emergency physicians.MethodsRetrospective cross-sectional study at a single PED (01/01/22 – 31/12/22). Infants up to two years of age attending with a head injury were included. All PED attendances coded as ‘head injury’ were selected for screening. Data was collected on attendance details, examination findings, consideration of non-accidental injury and whether verbal and written discharge advice was given, as per NICE head injury recommendations.3 Data was extracted from medical electronic and paper records and analysed using Microsoft Excel. A chi-square test was used to determine significance.Results383 patients were identified as having attended the department with a head injury, with 345 patients having accessible documentation (e.g., did not self-discharge or were streamed to primary care). Paediatricians were significantly more likely than emergency physicians to perform a head-to-toe examination of the child (83% vs 51%; p<0.0001), expose the child to examine the skin (90% vs 69%; p=0.000356), and document the time of the injury (98% vs 87%; p=0.005877). Emergency physicians were significantly more likely to given written and verbal head injury advice (47% vs 79%; p<0.0001).ConclusionIt is perhaps unsurprising that more time-intensive assessments of safeguarding concerns in children with head injury (head-to-toe, exposure of skin) are less commonly utilised in clinical practice in busy PEDs. This data suggests further education is needed for emergency physicians for consideration of safeguarding concerns when approaching an infant with a head injury. Despite being significantly more likely to perform these assessments, this should also be considered for paediatricians given that 17% did not perform a head-to-toe examination.References‘Context – head injury: assessment and early management: guidance.’ NICE, 18 May 2023, nice.org.uk/guidance/ng232/chapter/Context‘Facing the future: standards for children in emergency care settings.’ RCPCH, June 2018, rcpch.ac.uk/sites/default/files/2018- 06/FTFEC%20Digital%20updated%20final.pdf‘Recommendations – head injury: assessment and early management: guidance.’ NICE, 18 May 2023, https://www.nice.org.uk/guidance/ng232/chapter/Recommendations
When plants die, neighbours escape competition. Living conspecifics could disproportionately benefit because they are freed from negative intraspecific processes; however, if the negative effects of ...past conspecific neighbours persist, other species might be advantaged, and diversity might be maintained through legacy effects. We examined legacy effects in a mapped forest by modelling the survival of 37,212 trees of 23 species using four neighbourhood properties: living conspecific, living heterospecific, legacy conspecific (dead conspecifics) and legacy heterospecific densities. Legacy conspecific effects proved nearly four times stronger than living conspecific effects; changes in annual survival associated with legacy conspecific density were 1.5% greater than living conspecific effects. Over 90% of species were negatively impacted by legacy conspecific density, compared to 47% by living conspecific density. Our results emphasize that legacies of trees alter community dynamics, revealing that prior research may have underestimated the strength of density dependent interactions by not considering legacy effects.
The presence of dead conspecific neighbours significantly decreased tree survival. Negative legacy conspecific effects proved nearly four times stronger than living conspecific density effects. The legacies of past trees alter community dynamics, and past work may have underestimated the strength of density dependence by not considering legacy effects.
Factors that control tree seedling dynamics are critical determinants of forest diversity. We examined the role of density-dependent mortality and abiotic factors in the differential establishment ...and survival of tree seedlings at three, large, mapped forest plots in Indiana, Virginia, and Wisconsin, USA. We tested whether seedling densities and seedling survival are related to local biotic and abiotic factors with generalized linear mixed models. Spatial point pattern analyses were utilized to determine if the distribution patterns of seedlings and saplings are consistent with a pattern generated by negative density-dependent mortality with respect to conspecific trees. Initial sampled seedling density for nearly a third of species showed a positive correlation with increasing conspecific basal area, indicating dispersal limitation, but few had any association with abiotic variables. By contrast, survival of seedlings over one year significantly declined with increasing conspecific basal area. Point pattern analyses indicated that nearly one-third of tree species had significantly over-dispersed point patterns of conspecific seedlings and saplings relative to adult densities; the majority of other species exhibited random spatial arrangements. Our results demonstrate-that negative conspecific density-dependent mortality of seedlings could generate the spatial patterns observed at later life stages. By differentially favoring seedlings of other species, this process may contribute to the maintenance of tree diversity in temperate forests, just as others have demonstrated for tropical forests.
We investigated plasma proteomic markers of astrocytopathy, brain degeneration, plasticity, and inflammation in sporadic early-onset versus late-onset Alzheimer's disease (EOAD and LOAD).
Plasma was ...analyzed using ultra-sensitive immuno-based assays from 33 EOAD, 30 LOAD, and 36 functionally normal older adults.
Principle component analyses identified 3 factors: trophic (BDNF, VEGF, TGFβ), degenerative (GFAP, NfL), and inflammatory (TNFα, IL-6, IP-10, IL-10). Trophic factor was elevated in both AD groups and associated with cognition and gray matter volumes. Degenerative factor was elevated in EOAD, with higher levels associated with worse functioning in this group. Biomarkers of inflammation were not significantly different between groups and were only associated with age.
Plasma proteomic biomarkers provide novel means of investigating molecular processes in vivo and their contributions to clinical outcomes. We present initial investigations of several of these fluid biomarkers, capturing aspects of astrocytopathy, neuronal injury, cellular plasticity, and inflammation in EOAD versus LOAD.
•Plasma biomarkers offer a noninvasive means of studying pathological differences in Alzheimer's disease (AD).•Plasma markers of neuronal injury, astrocytic activation, systemic inflammation, and cellular plasticity were quantified in EOAD and LOAD.•Markers of neuronal injury and astrocytic activation were elevated in AD groups in comparison with controls, with larger effect sizes in EOAD.•Markers of cellular plasticity were elevated in AD and especially associated with functional decline in EOAD.•Systemic inflammation correlated with age across groups, reflecting the well-described phenomenon of age-associated sterile chronic inflammation.
Although trait information has been widely used to explore underlying mechanisms of forest community structure, most studies have focused on local patterns of phylogenetic or functional alpha ...diversity. Investigations of functional beta diversity, on the other hand, have not been conducted at local scales in a spatially explicit way. In this study, we provide a powerful methodology based on recent advances in spatial point pattern analysis using fully mapped data of large and small trees in two large temperate forest plots. This approach allowed us to assess the relative importance of different ecological processes and mechanisms for explaining patterns of local phylogenetic and functional beta diversity. For both forests and size classes, we found a clear hierarchy of scales: habitat filtering accounted for patterns of phylogenetic and functional beta diversity at larger distances (150-250 m), dispersal limitation accounted for the observed decline in beta diversity at distances below 150 m, and species interactions explained small departures from functional and phylogenetic beta diversity at the immediate plant-neighborhood scale (below 20 m). Thus, both habitat filtering and dispersal limitation influenced the observed patterns in phylogenetic and functional beta diversity at local scales. This result contrasts with a previous study from the same forests, where dispersal limitation alone approximated the observed species beta diversity for distances up to 250 m. In addition, species interactions were relatively unimportant for predicting phylogenetic and functional beta diversity. Our analysis suggests that phylogenetic and functional beta diversity can provide insights into the mechanisms of local community assembly that are missed by studies focusing exclusively on species beta diversity.
The study of biodiversity has tended to focus primarily on relatively information-poor measures of species diversity. Recently, many studies of local diversity (alpha diversity) have begun to use ...measures of functional and phylogenetic alpha diversity. Investigations into the phylogenetic and functional dissimilarity (beta diversity) of communities have been far less numerous, but these dissimilarity measures have the potential to infer the mechanisms underlying community assembly and dynamics. Here, we relate levels of phylogenetic and functional alpha diversity to levels of phylogenetic and functional beta diversity to infer the mechanism or mechanisms responsible for the assembly of tree communities in six forests located in tropical and temperate latitudes. The results show that abiotic filtering plays a role in structuring local assemblages and governing spatial turnover in community composition and that phylogenetic measures of alpha and beta diversity are not strong predictors of functional alpha and beta diversity in the forests studied.
Chronic systemic sterile inflammation is implicated in the pathogenesis of cerebrovascular disease and white matter injury. Non-invasive blood markers for risk stratification and dissection of ...inflammatory molecular substrates in vivo are lacking. We sought to identify whether an interconnected network of inflammatory biomarkers centered on IL-18 and all previously associated with white matter lesions could detect overt and antecedent white matter changes in two populations at risk for cerebral small vessel disease. In a cohort of 167 older adults (mean age: 76, SD 7.1, 83 females) that completed a cognitive battery, physical examination, and blood draw in parallel with MR imaging including DTI, we measured cerebral white matter hyperintensities (WMH) and free water (FW). Concurrently, serum levels of a biologic network of inflammation molecules including MPO, GDF-15, RAGE, ST2, IL-18, and MCP-1 were measured. The ability of a log-transformed population mean-adjusted inflammatory composite score (ICS) to associate with MR variables was demonstrated in an age and total intracranial volume adjusted model. In this cohort, ICS was significantly associated with WMH (β = 0.222, p = 0.013), FW (β = 0.3, p = 0.01), and with the number of vascular risk factor diagnoses (r = 0.36, p<0.001). In a second cohort of 131 subjects presenting for the evaluation of acute neurologic deficits concerning for stroke, we used serum levels of 11 inflammatory biomarkers in an unbiased principal component analysis which identified a single factor significantly associated with WMH. This single factor was strongly correlated with the six component ICS identified in the first cohort and was associated with WMH in a generalized linear regression model adjusted for age and gender (p = 0.027) but not acute stroke. A network of inflammatory molecules driven by IL-18 is associated with overt and antecedent white matter injury resulting from cerebrovascular disease and may be a promising peripheral biomarker for vascular white matter injury.
There is increasing awareness that self-reported sleep abnormalities are negatively associated with brain structure and function in older adults. Less is known, however, about how objectively ...measured sleep associates with brain structure. We objectively measured at-home sleep to investigate how sleep architecture and sleep quality related to white matter microstructure in older adults. 43 cognitively normal, older adults underwent diffusion tensor imaging (DTI) and a sleep assessment within a six-month period. Participants completed the PSQI, a subjective measure of sleep quality, and used an at-home sleep recorder (Zeo, Inc.) to measure total sleep time (TST), sleep efficiency (SE), and percent time in light sleep (LS), deep sleep (DS), and REM sleep (RS). Multiple regressions predicted fractional anisotropy (FA) and mean diffusivity (MD) of the corpus callosum as a function of total PSQI score, TST, SE, and percent of time spent in each sleep stage, controlling for age and sex. Greater percent time spent in RS was significantly associated with higher FA (β = 0.41, p = 0.007) and lower MD (β = -0.30, p = 0.03). Total PSQI score, TST, SE, and time spent in LS or DS were not significantly associated with FA or MD (p>0.13). Percent time spent in REM sleep, but not quantity of light and deep sleep or subjective/objective measures of sleep quality, positively predicted white matter microstructure integrity. Our results highlight an important link between REM sleep and brain health that has the potential to improve sleep interventions in the elderly.
Recent theory predicts that stochastic dilution effects may result in species-rich communities with statistically independent species spatial distributions, even if the underlying ecological ...processes structuring the community are driven by deterministic niche differences. Stochastic dilution is a consequence of the stochastic geometry of biodiversity where the identities of the nearest neighbors of individuals of a given species are largely unpredictable. Under such circumstances, the outcome of deterministic species interactions may vary greatly among individuals of a given species. Consequently, nonrandom patterns in the biotic neighborhoods of species, which might be expected from coexistence or community assembly theory (e.g., individuals of a given species are neighbored by phylogenetically similar species), are weakened or do not emerge, resulting in statistical independence of species spatial distributions. We used data on phylogenetic and functional similarity of tree species in five large forest dynamics plots located across a gradient of species richness to test predictions of the stochastic dilution hypothesis. To quantify the biotic neighborhood of a focal species we used the mean phylogenetic (or functional) dissimilarity of the individuals of the focal species to all species within a local neighborhood. We then compared the biotic neighborhood of species to predictions from stochastic null models to test if a focal species was surrounded by more or less similar species than expected by chance. The proportions of focal species that showed spatial independence with respect to their biotic neighborhoods increased with total species richness. Locally dominant, high-abundance species were more likely to be surrounded by species that were statistically more similar or more dissimilar than expected by chance. Our results suggest that stochasticity may play a stronger role in shaping the spatial structure of species rich tropical forest communities than it does in species poorer forests. These findings represent an important step towards understanding the factors that govern the spatial configuration of local biotic communities. The stochastic dilution effect is a simple geometric mechanism that can explain why species' spatial distributions in species-rich communities approximate independence from their biotic neighborhood, even if deterministic niche processes are in effect.
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