An Umbrella Review of Aphasia Intervention descriPtion In Research: the AsPIRE project

Background: Recent reviews conclude that aphasia intervention is effective. However, replication and implementation require detailed reporting of intervention is and a specification of participant profiles. To date, reviews concentrate more on efficacy than on intervention reporting quality. Aims : The aim of this project is to review the descriptions of aphasia interventions and participants appearing in recent systematic reviews of aphasia intervention effectiveness. The relationship between the quality of these descriptions and the robustness of research design is explored, and the replicability of aphasia interventions is evaluated. Methods and Procedures : The scope of our search was an analysis of the aphasia intervention studies included in the and EBRSR 2018 systematic reviews, and in the RCSLT 2014 literature synthesis. Intervention descriptions published separately from the intervention study (i.e. published online, in clinical tools, or a separate trial protocols) were not included. The criteria for inclusion were that participants had aphasia, the intervention involved language and/or communication, and included the following research designs: Randomised Controlled Trial (RCT), comparison or control, crossover design, case series. Exclusion criteria included non-SLT interventions, studies involving fewer than four participants, conference abstracts, studies not available in English. Studies were evaluated for completeness of intervention description using the TIDieR Checklist. Additionally, we rated the quality of patient and intervention description, with particular reference to replicability. Outcomes and Results: Ninety-three studies were included. Only 14 studies (15%) had >50 participants. Fifty-six studies (60%) did not select participants with a specific aphasia profile, and a further 10 studies only described participants as non-fluent. Across the studies, an average of eight (of 12) TIDieR checklist items were given but information on where, tailoring, modification and fidelity items was rarely available. Studies that evaluated general aphasia intervention approaches tended to use RCT designs, whereas more specific intervention studies were more likely to use case series designs. Conclusions: Group studies were generally under-powered and there was a paucity of research looking at specific aphasia interventions for specific aphasia profiles. There was a trade-off between the robustness of the design and the level of specificity of the intervention described. While the TIDieR framework is a useful guide to information which should be included in an intervention study, it is insufficiently sensitive for assessing replicability. We consider possible solutions to the challenges of making large-scale trials more useful for determining effective aphasia intervention

Comparison of plasma and CSF biomarkers in predicting cognitive decline

OBJECTIVES: Concentrations of amyloid-β peptides (Aβ42/Aβ40) and neurofilament light (NfL) can be measured in plasma or cerebrospinal fluid (CSF) and are associated with Alzheimer\u27s disease brain pathology and cognitive impairment. This study directly compared plasma and CSF measures of Aβ42/Aβ40 and NfL as predictors of cognitive decline. METHODS: Participants were 65 years or older and cognitively normal at baseline with at least one follow-up cognitive assessment. Analytes were measured with the following types of assays: plasma Aβ42/Aβ40, immunoprecipitation-mass spectrometry; plasma NfL, Simoa; CSF Aβ42/Aβ40, automated immunoassay; CSF NfL plate-based immunoassay. Mixed effects models evaluated the global cognitive composite score over a maximum of 6 years as predicted by the fluid biomarkers. RESULTS: Analyses included 371 cognitively normal participants, aged 72.7 ± 5.2 years (mean ± standard deviation) with an average length of follow-up of 3.9 ± 1.6 years. Standardized concentrations of biomarkers were associated with annualized cognitive change: plasma Aβ42/Aβ40, 0.014 standard deviations (95% confidence intervals 0.002 to 0.026); CSF Aβ42/Aβ40, 0.020 (0.008 to 0.032); plasma Nfl, -0.018 (-0.030 to -0.005); and CSF NfL, -0.024 (-0.036 to -0.012). Power analyses estimated that 266 individuals in each treatment arm would be needed to detect a 50% slowing of decline if identified by abnormal plasma measures versus 229 for CSF measures. INTERPRETATION: Both plasma and CSF measures of Aβ42/Aβ40 and NfL predicted cognitive decline. A clinical trial that enrolled individuals based on abnormal plasma Aβ42/Aβ40 and NfL levels would require only a marginally larger cohort than if CSF measures were used

Predicting continuous amyloid PET values with CSF and plasma Aβ42/Aβ40

INTRODUCTION: Continuous measures of amyloid burden as measured by positron emission tomography (PET) are being used increasingly to stage Alzheimer\u27s disease (AD). This study examined whether cerebrospinal fluid (CSF) and plasma amyloid beta (Aβ)42/Aβ40 could predict continuous values for amyloid PET. METHODS: CSF Aβ42 and Aβ40 were measured with automated immunoassays. Plasma Aβ42 and Aβ40 were measured with an immunoprecipitation-mass spectrometry assay. Amyloid PET was performed with Pittsburgh compound B (PiB). The continuous relationships of CSF and plasma Aβ42/Aβ40 with amyloid PET burden were modeled. RESULTS: Most participants were cognitively normal (427 of 491 [87%]) and the mean age was 69.0 ± 8.8 years. CSF Aβ42/Aβ40 predicted amyloid PET burden until a relatively high level of amyloid accumulation (69.8 Centiloids), whereas plasma Aβ42/Aβ40 predicted amyloid PET burden until a lower level (33.4 Centiloids). DISCUSSION: CSF Aβ42/Aβ40 predicts the continuous level of amyloid plaque burden over a wider range than plasma Aβ42/Aβ40 and may be useful in AD staging. HIGHLIGHTS: Cerebrospinal fluid (CSF) amyloid beta (Aβ)42/Aβ40 predicts continuous amyloid positron emission tomography (PET) values up to a relatively high burden.Plasma Aβ42/Aβ40 is a comparatively dichotomous measure of brain amyloidosis.Models can predict regional amyloid PET burden based on CSF Aβ42/Aβ40.CSF Aβ42/Aβ40 may be useful in staging AD

A blood-based diagnostic test incorporating plasma Aβ42/40 ratio, ApoE proteotype, and age accurately identifies brain amyloid status: Findings from a multi cohort validity analysis

BACKGROUND: The development of blood-based biomarker tests that are accurate and robust for Alzheimer\u27s disease (AD) pathology have the potential to aid clinical diagnosis and facilitate enrollment in AD drug trials. We developed a high-resolution mass spectrometry (MS)-based test that quantifies plasma Aβ42 and Aβ40 concentrations and identifies the ApoE proteotype. We evaluated robustness, clinical performance, and commercial viability of this MS biomarker assay for distinguishing brain amyloid status. METHODS: We used the novel MS assay to analyze 414 plasma samples that were collected, processed, and stored using site-specific protocols, from six independent US cohorts. We used receiver operating characteristic curve (ROC) analyses to assess assay performance and accuracy for predicting amyloid status (positive, negative, and standard uptake value ratio; SUVR). After plasma analysis, sites shared brain amyloid status, defined using diverse, site-specific methods and cutoff values; amyloid PET imaging using various tracers or CSF Aβ42/40 ratio. RESULTS: Plasma Aβ42/40 ratio was significantly (p \u3c 0.001) lower in the amyloid positive vs. negative participants in each cohort. The area under the ROC curve (AUC-ROC) was 0.81 (95% CI = 0.77-0.85) and the percent agreement between plasma Aβ42/40 and amyloid positivity was 75% at the optimal (Youden index) cutoff value. The AUC-ROC (0.86; 95% CI = 0.82-0.90) and accuracy (81%) for the plasma Aβ42/40 ratio improved after controlling for cohort heterogeneity. The AUC-ROC (0.90; 95% CI = 0.87-0.93) and accuracy (86%) improved further when Aβ42/40, ApoE4 copy number and participant age were included in the model. CONCLUSIONS: This mass spectrometry-based plasma biomarker test: has strong diagnostic performance; can accurately distinguish brain amyloid positive from amyloid negative individuals; may aid in the diagnostic evaluation process for Alzheimer\u27s disease; and may enhance the efficiency of enrolling participants into Alzheimer\u27s disease drug trials

Development of an evidence-based aphasia therapy implementation tool: an international survey of speech pathologists' access to and use of aphasia therapy resources

Background Speech and language therapy can reduce the level of impairment and disability caused by aphasia (Brady et al., 2016). Selecting a therapy can be challenging for clinicians who may struggle to stay abreast of the best evidence to support therapy selection (Rose et al., 2014). Once a therapy is selected, accessing relevant resources is a significant barrier to implementation (Shrubsole et al., 2019). The Aphasia Therapy Finder (ATF) is proposed to be an online repository of therapy resources designed to aid selection of evidence-based aphasia therapies and to bridge the evidence-practice gap in aphasia rehabilitation. Aims In this study, we aimed to explore speech pathologists’ selection and use of aphasia therapy approaches, and access to aphasia therapy resources in clinical practice. We further aimed to explore speech pathologists’ perspectives on the proposed ATF. Methods & Procedures A cross-sectional, mixed-methods, survey design was employed. A 22-item web-based survey was developed and disseminated to speech pathologists via professional networks internationally. Data analyses included descriptive statistics and conventional content analysis. Outcomes & Results Eligible responses from 176 speech pathologists across 19 countries were included in the analyses (86.3% completion rate). Speech pathologists reported using a range of therapy approaches (n = 43) in aphasia rehabilitation, consistent with previous findings (Rose et al., 2014). Information regarding new therapy approaches was predominantly obtained from academic sources including conferences, research literature, and professional development workshops. Speech pathologists placed high importance on research evidence when selecting therapy approaches. Resource limitations, including time and budget constraints, were identified as key barriers to implementing evidence-based aphasia therapy approaches in clinical practice. There was strong support for development of the ATF; 91.7% of respondents indicated they would use it in clinical practice. Recency of research, equity of access with the inclusion of linguistically and culturally diverse resources, and usability of resources were identified as priorities when developing the ATF. Conclusions While speech pathologists report using a range of aphasia therapy approaches in clinical practice and consider research evidence when selecting therapy approaches, resource limitations continue to present a barrier to the implementation of evidence-based practice. The development of the ATF may support the translation of research evidence into clinical practice

Effect of Race on Prediction of Brain Amyloidosis by Plasma Aβ42/Aβ40, Phosphorylated Tau, and Neurofilament Light

OBJECTIVE: To evaluate whether plasma biomarkers of amyloid (Aβ42/Aβ40), tau (p-tau181 and p-tau231) and neuroaxonal injury (neurofilament light chain [NfL]) detect brain amyloidosis consistently across racial groups. METHODS: Individuals enrolled in studies of memory and aging who self-identified as African American (AA) were matched 1:1 to self-identified non-Hispanic White (NHW) individuals by age, APOE ε4 carrier status and cognitive status. Each participant underwent blood and cerebrospinal fluid (CSF) collection, and amyloid PET was performed in 103 participants (68%). Plasma Aβ42/Aβ40 was measured by a high-performance immunoprecipitation-mass spectrometry assay. Plasma p-tau181, p-tau231, and NfL were measured by Simoa immunoassays. CSF Aβ42/Aβ40 and amyloid PET status were used as primary and secondary reference standards of brain amyloidosis, respectively. RESULTS: There were 76 matched pairs of AA and NHW participants (n=152 total). For both AA and NHW groups, the median age was 68.4 years, 42% were APOE ε4 carriers and 91% were cognitively normal. AA were less likely than NHW to have brain amyloidosis by CSF Aβ42/Aβ40 (22% versus 43% positive, p = 0.003). The Receiver Operating Characteristic Area Under the Curve (ROC AUC) of CSF Aβ42/Aβ40 status with the plasma biomarkers was as follows: Aβ42/Aβ40, 0.86 (95% confidence intervals [CI] 0.79-0.92); p-tau181, 0.76 (0.68-0.84); p-tau231, 0.69 (0.60-0.78); and NfL, 0.64 (0.55-0.73). In models predicting CSF Aβ42/Aβ40 status with plasma Aβ42/Aβ40 that included covariates (age, sex, APOE ε4 carrier status, race, and cognitive status), race did not affect the probability of CSF Aβ42/Aβ40 positivity. In similar models based on plasma p-tau181, p-tau231 or Nfl, AA had a lower probability of CSF Aβ42/Aβ40 positivity (Odds Ratio [OR] 0.31 [95% CI 0.13-0.73], OR 0.30 [0.13-0.71]) and OR 0.27 [0.12-0.64], respectively. Models of amyloid PET status yielded similar findings. CONCLUSIONS: Models predicting brain amyloidosis using a high performance plasma Aβ42/Aβ40 assay may provide an accurate and consistent measure of brain amyloidosis across AA and NHW groups, but models based on plasma p-tau181, p-tau231, and NfL may perform inconsistently and could result in disproportionate misdiagnosis of AA

An Umbrella Review of Aphasia Intervention descriPtion In Research: the AsPIRE project

Background: Recent reviews conclude that aphasia intervention is effective. However, replication and implementation require detailed reporting of intervention is and a specification of participant profiles. To date, reviews concentrate more on efficacy than on intervention reporting quality. Aims: The aim of this project is to review the descriptions of aphasia interventions and participants appearing in recent systematic reviews of aphasia intervention effectiveness. The relationship between the quality of these descriptions and the robustness of research design is explored, and the replicability of aphasia interventions is evaluated. Methods and Procedures: The scope of our search was an analysis of the aphasia intervention studies included in the Brady et al. 2016 and EBRSR 2018 systematic reviews, and in the RCSLT 2014 literature synthesis. Intervention descriptions published separately from the intervention study (i.e. published online, in clinical tools, or a separate trial protocols) were not included. The criteria for inclusion were that participants had aphasia, the intervention involved language and/or communication, and included the following research designs: Randomised Controlled Trial (RCT), comparison or control, crossover design, case series. Exclusion criteria included non-SLT interventions, studies involving fewer than four participants, conference abstracts, studies not available in English. Studies were evaluated for completeness of intervention description using the TIDieR Checklist. Additionally, we rated the quality of patient and intervention description, with particular reference to replicability. Outcomes and Results: Ninety-three studies were included. Only 14 studies (15%) had >50 participants. Fifty-six studies (60%) did not select participants with a specific aphasia profile, and a further 10 studies only described participants as non-fluent. Across the studies, an average of eight (of 12) TIDieR checklist items were given but information on where, tailoring, modification and fidelity items was rarely available. Studies that evaluated general aphasia intervention approaches tended to use RCT designs, whereas more specific intervention studies were more likely to use case series designs. Conclusions: Group studies were generally under-powered and there was a paucity of research looking at specific aphasia interventions for specific aphasia profiles. There was a trade-off between the robustness of the design and the level of specificity of the intervention described. While the TIDieR framework is a useful guide to information which should be included in an intervention study, it is insufficiently sensitive for assessing replicability. We consider possible solutions to the challenges of making large-scale trials more useful for determining effective aphasia intervention

Strange reading: Keith Windschuttle on race, Asia and White Australia

In his recently published book, The White Australia Policy, Keith Windschuttle accuses academic historians of errors of fact and judgement in their accounts of white Australia. This article examines these claims of exaggeration and distortion with particular reference to the nature and meaning of race, racism and representations of Asia in Australian history. The article rejects Winschuttle\u27s sweeping claim that academic historians have sought to make Australia appear a much more racist society than the historical record would suggest.<br /

Extracellular pH Modulates Neuroendocrine Prostate Cancer Cell Metabolism and Susceptibility to the Mitochondrial Inhibitor Niclosamide.

Neuroendocrine prostate cancer is a lethal variant of prostate cancer that is associated with castrate-resistant growth, metastasis, and mortality. The tumor environment of neuroendocrine prostate cancer is heterogeneous and characterized by hypoxia, necrosis, and numerous mitoses. Although acidic extracellular pH has been implicated in aggressive cancer features including metastasis and therapeutic resistance, its role in neuroendocrine prostate cancer physiology and metabolism has not yet been explored. We used the well-characterized PNEC cell line as a model to establish the effects of extracellular pH (pH 6.5, 7.4, and 8.5) on neuroendocrine prostate cancer cell metabolism. We discovered that alkalinization of extracellular pH converted cellular metabolism to a nutrient consumption-dependent state that was susceptible to glucose deprivation, glutamine deprivation, and 2-deoxyglucose (2-DG) mediated inhibition of glycolysis. Conversely, acidic pH shifted cellular metabolism toward an oxidative phosphorylation (OXPHOS)-dependent state that was susceptible to OXPHOS inhibition. Based upon this mechanistic knowledge of pH-dependent metabolism, we identified that the FDA-approved anti-helminthic niclosamide depolarized mitochondrial potential and depleted ATP levels in PNEC cells whose effects were enhanced in acidic pH. To further establish relevance of these findings, we tested the effects of extracellular pH on susceptibility to nutrient deprivation and OXPHOS inhibition in a cohort of castrate-resistant prostate cancer cell lines C4-2B, PC-3, and PC-3M. We discovered similar pH-dependent toxicity profiles among all cell lines with these treatments. These findings underscore a potential importance to acidic extracellular pH in the modulation of cell metabolism in tumors and development of an emerging paradigm that exploits the synergy of environment and therapeutic efficacy in cancer