Plasma and cerebrospinal fluid ABeta42 for the differential diagnosis of Alzheimer's disease dementia in participants diagnosed with any dementia subtype in a specialist care setting

BackgroundDementia is a syndrome that comprises many differing pathologies, including Alzheimer's disease dementia (ADD), vascular dementia (VaD) and frontotemporal dementia (FTD). People may benefit from knowing the type of dementia they live with, as this could inform prognosis and may allow for tailored treatment. Beta-amyloid (1-42) (ABeta42) is a protein which decreases in both the plasma and cerebrospinal fluid (CSF) of people living with ADD, when compared to people with no dementia. However, it is not clear if changes in ABeta42 are specific to ADD or if they are also seen in other types of dementia. It is possible that ABeta42 could help differentiate ADD from other dementia subtypes.ObjectivesTo determine the accuracy of plasma and CSF ABeta42 for distinguishing ADD from other dementia subtypes in people who meet the criteria for a dementia syndrome.Search methodsWe searched MEDLINE, and nine other databases up to 18 February 2020. We checked reference lists of any relevant systematic reviews to identify additional studies.Selection criteriaWe considered cross-sectional studies that differentiated people with ADD from other dementia subtypes. Eligible studies required measurement of participant plasma or CSF ABeta42 levels and clinical assessment for dementia subtype.Data collection and analysisSeven review authors working independently screened the titles and abstracts generated by the searches. We collected data on study characteristics and test accuracy. We used the second version of the 'Quality Assessment of Diagnostic Accuracy Studies' (QUADAS-2) tool to assess internal and external validity of results. We extracted data into 2 x 2 tables, cross-tabulating index test results (ABeta42) with the reference standard (diagnostic criteria for each dementia subtype). We performed meta-analyses using bivariate, random-effects models. We calculated pooled estimates of sensitivity, specificity, positive predictive values, positive and negative likelihood ratios, and corresponding 95% confidence intervals (CIs). In the primary analysis, we assessed accuracy of plasma or CSF ABeta42 for distinguishing ADD from other mixed dementia types (non-ADD). We then assessed accuracy of ABeta42 for differentiating ADD from specific dementia types: VaD, FTD, dementia with Lewy bodies (DLB), alcohol-related cognitive disorder (ARCD), Creutzfeldt-Jakob disease (CJD) and normal pressure hydrocephalus (NPH). To determine test-positive cases, we used the ABeta42 thresholds employed in the respective primary studies. We then performed sensitivity analyses restricted to those studies that used common thresholds for ABeta42.Main resultsWe identified 39 studies (5000 participants) that used CSF ABeta42 levels to differentiate ADD from other subtypes of dementia. No studies of plasma ABeta42 met the inclusion criteria. No studies were rated as low risk of bias across all QUADAS-2 domains. High risk of bias was found predominantly in the domains of patient selection (28 studies) and index test (25 studies). The pooled estimates for differentiating ADD from other dementia subtypes were as follows: ADD from non-ADD: sensitivity 79% (95% CI 0.73 to 0.85), specificity 60% (95% CI 0.52 to 0.67), 13 studies, 1704 participants, 880 participants with ADD; ADD from VaD: sensitivity 79% (95% CI 0.75 to 0.83), specificity 69% (95% CI 0.55 to 0.81), 11 studies, 1151 participants, 941 participants with ADD; ADD from FTD: sensitivity 85% (95% CI 0.79 to 0.89), specificity 72% (95% CI 0.55 to 0.84), 17 studies, 1948 participants, 1371 participants with ADD; ADD from DLB: sensitivity 76% (95% CI 0.69 to 0.82), specificity 67% (95% CI 0.52 to 0.79), nine studies, 1929 participants, 1521 participants with ADD. Across all dementia subtypes, sensitivity was greater than specificity, and the balance of sensitivity and specificity was dependent on the threshold used to define test positivity.Authors' conclusionsOur review indicates that measuring ABeta42 levels in CSF may help differentiate ADD from other dementia subtypes, but the test is imperfect and tends to misdiagnose those with non-ADD as having ADD. We would caution against the use of CSF ABeta42 alone for dementia classification. However, ABeta42 may have value as an adjunct to a full clinical assessment, to aid dementia diagnosis

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication

Cerebral Autoregulation in Ischemic Stroke: From Pathophysiology to Clinical Concepts

Ischemic stroke (IS) is one of the most impacting diseases in the world. In the last decades, new therapies have been introduced to improve outcomes after IS, most of them aiming for recanalization of the occluded vessel. However, despite this advance, there are still a large number of patients that remain disabled. One interesting possible therapeutic approach would be interventions guided by cerebral hemodynamic parameters such as dynamic cerebral autoregulation (dCA). Supportive hemodynamic therapies aiming to optimize perfusion in the ischemic area could protect the brain and may even extend the therapeutic window for reperfusion therapies. However, the knowledge of how to implement these therapies in the complex pathophysiology of brain ischemia is challenging and still not fully understood. This comprehensive review will focus on the state of the art in this promising area with emphasis on the following aspects: (1) pathophysiology of CA in the ischemic process; (2) methodology used to evaluate CA in IS; (3) CA studies in IS patients; (4) potential non-reperfusion therapies for IS patients based on the CA concept; and (5) the impact of common IS-associated comorbidities and phenotype on CA status. The review also points to the gaps existing in the current research to be further explored in future trials

Cerebral Autoregulation Monitoring: A Guide While Navigating in Troubled Waters.

Letter to the editor</p

The Effect of Translation and Cultural Adaptations on Diagnostic Accuracy and Test Performance in Dementia Cognitive Screening Tools: A Systematic Review

Background: The current cognitive tests have been developed based on and standardized against Western constructs and normative data. With older people of minority ethnic background increasing across Western countries, there is a need for cognitive screening tests to address factors which influence performance bias and timely diagnostic dementia accuracy. The diagnostic accuracy in translated and culturally adapted cognitive screening tests and their impact on test performance in diverse populations have not been well addressed to date. Objective: This review aims to highlight considerations relating to the adaptation processes, language, cultural influences, impact of immigration, and level of education to assess for dementia in non-Western and/or non-English speaking populations. Methods: We conducted a systematic search for studies addressing the effects of translation and cultural adaptations of cognitive screening tests (developed in a Western context) upon their diagnostic accuracy and test performance across diverse populations. Four electronic databases and manual searches were conducted, using a predefined search strategy. A narrative synthesis of findings was conducted. Results: Search strategy yielded 2,890 articles, and seventeen studies (4,463 participants) met the inclusion criteria. There was variability in the sensitivity and specificity of cognitive tests, irrespective of whether they were translated only, culturally adapted only, or both. Cognitive test performance was affected by education, linguistic ability, and aspects of acculturation. Conclusions: We highlight the importance of translating and culturally adapting tests that have been developed in the Western context. However, these findings should be interpreted with caution as results varied due to the broad selection of included cognitive tests

Diagnostic test accuracy of remote, multidomain cognitive assessment (telephone and video call) for dementia

Background: Remote cognitive assessments are increasingly needed to assist in the detection of cognitive disorders, but the diagnostic accuracy of telephone‐ and video‐based cognitive screening remains unclear. Objectives:\ud To assess the test accuracy of any multidomain cognitive test delivered remotely for the diagnosis of any form of dementia. To assess for potential differences in cognitive test scoring when using a remote platform, and where a remote screener was compared to the equivalent face‐to‐face test. Search methods: We searched ALOIS, the Cochrane Dementia and Cognitive Improvement Group Specialized Register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, Web of Science, LILACS, and ClinicalTrials.gov (www.clinicaltrials.gov/) databases on 2 June 2021. We performed forward and backward searching of included citations. Selection criteria: We included cross‐sectional studies, where a remote, multidomain assessment was administered alongside a clinical diagnosis of dementia or equivalent face‐to‐face test. Data collection and analysis: Two review authors independently assessed risk of bias and extracted data; a third review author moderated disagreements. Our primary analysis was the accuracy of remote assessments against a clinical diagnosis of dementia. Where data were available, we reported test accuracy as sensitivity and specificity. We did not perform quantitative meta‐analysis as there were too few studies at individual test level. For those studies comparing remote versus in‐person use of an equivalent screening test, if data allowed, we described correlations, reliability, differences in scores and the proportion classified as having cognitive impairment for each test. Main results: The review contains 31 studies (19 differing tests, 3075 participants), of which seven studies (six telephone, one video call, 756 participants) were relevant to our primary objective of describing test accuracy against a clinical diagnosis of dementia. All studies were at unclear or high risk of bias in at least one domain, but were low risk in applicability to the review question. Overall, sensitivity of remote tools varied with values between 26% and 100%, and specificity between 65% and 100%, with no clearly superior test. Across the 24 papers comparing equivalent remote and in‐person tests (14 telephone, 10 video call), agreement between tests was good, but rarely perfect (correlation coefficient range: 0.48 to 0.98). Authors' conclusions: Despite the common and increasing use of remote cognitive assessment, supporting evidence on test accuracy is limited. Available data do not allow us to suggest a preferred test. Remote testing is complex, and this is reflected in the heterogeneity seen in tests used, their application, and their analysis. More research is needed to describe accuracy of contemporary approaches to remote cognitive assessment. While data comparing remote and in‐person use of a test were reassuring, thresholds and scoring rules derived from in‐person testing may not be applicable when the equivalent test is adapted for remote use

The Interaction of Dynamic Cerebral Autoregulation and Neurovascular Coupling in Cognitive Impairment

Background: Dynamic cerebral autoregulation (dCA) remains intact in both ageing and dementia, but studies of neurovascular coupling (NVC) have produced mixed findings.Objective: We investigated the effects of task-activation on dCA in healthy older adults (HOA), and patients with mild cognitive impairment (MCI) and Alzheimer’s Disease (AD).Methods: Resting and task-activated data from thirty HOA, twenty-two MCI, and thirty-four AD were extracted from a database. The autoregulation index (ARI) was determined at rest and during five cognitive tasks from transfer function analysis. NVC responses were present where group-specific thresholds of cross-correlation peak function and variance ratio were exceeded. Cumulative response rate (CRR) was the total number of positive responses across five tasks and two hemispheres.Results: ARI differed between groups in dominant (p=0.012) and non-dominant (p=0.042) hemispheres at rest but not during task-activation (p=0.33). ARI decreased during language and memory tasks in HOA (p=0.002) but not in MCI or AD (p=0.40). There was a significant positive correlation between baseline ARI and CRR in all groups (r=0.26, p=0.018), but not within sub-groups.Conclusion: dCA efficiency was reduced in task-activation in healthy but not cognitively impaired participants. These results indicate differences in neurovascular processing in healthy older adults relative to cognitively impaired individuals.</div