Cognitive testing following transient ischaemic attack: A systematic review of clinical assessment tools

Cognitive deficits are prevalent after transient ischaemic attack (TIA) and result in loss of function, poorer quality of life and increased risks of dependency and mortality. This systematic review aimed to synthesise the available evidence on cognitive assessment in TIA patients to determine the prevalence of cognitive deficits, and the optimal tests for cognitive assessment. Medline, Embase, PsychINFO and CINAHL databases were searched for relevant articles. Articles were screened by title and abstract. Full-text analysis and quality assessment was performed using the National Institute of Health Tool. Data were extracted on study characteristics, prevalence of TIA deficits, and key study findings. Due to significant heterogeneity, meta-analysis was not possible. Twenty-five full-text articles met the review inclusion criteria. There was significant heterogeneity in terms of cognitive tests used, definitions of cognitive impairment and TIA, time points post-event, and analysis methods. The majority of studies used the Mini-Mental State Examination (MMSE) or Montreal Cognitive Assessment (MoCA) (n = 23). Prevalence of cognitive impairment ranged from 2% to 100%, depending on the time-point and cognitive domain studied. The MoCA was more sensitive than the MMSE for identifying cognitive deficits. Deficits were common in executive function, attention, and language. No studies assessed diagnostic test accuracy against a reference standard diagnosis of cognitive impairment. Recommendations on cognitive testing after TIA are hampered by significant heterogeneity between studies, as well as a lack of diagnostic test accuracy studies. Future research should focus on harmonising tools, definitions, and time-points, and validating tools specifically for the TIA population

Principal component analysis to identify the major contributors to task-activated neurovascular responses

Background: Consensus on the optimal metrics for neurovascular coupling (NVC) is lacking. The aim of this study was to use principal component analysis (PCA) to determine the most significant contributors to NVC responses in healthy adults (HC), Alzheimer's disease (AD), and mild cognitive impairment (MCI). New method: PCA was applied to three datasets: 1) 69 HC, 2) 30 older HC, 34 AD, and 22 MCI, 3) 1&2 combined. Data were extracted on peak percentage change in cerebral blood flow velocity (CBFv), variance ratio (VR), cross-correlation function peak (CCF), and blood pressure, for five cognitive tasks. An equamax rotation was applied and factors were significant where the eignevalue was ≥1. Rotated factor loadings ≥0.4 determined significant NVC variables. Results: PCA identified 12 significant factors accounting for 78% of variance (all datasets). Contributing variables loaded differently on the factors across the datasets. In datasets 1&2, peak percentage change in CBFv contributed to factors explaining the most variance (45–58%), whereas cognitive test scores, fluency and memory domains contributed the least (15–37%). In the combined dataset, CBFv, CCF and fluency domain contributed the majority (33–43%), whereas VR and attention the least (6–24%). Conclusions: Peak percentage change in CBFv and the visuospatial task consistently accounted for a large proportion of the variance, suggesting these are robust NVC markers for future studies

Neurovascular coupling response to cognitive examination in healthy controls: a multivariate analysis.

Cognitive testing with transcranial Doppler ultrasonography (TCD) has been used to assess neurovascular coupling (NVC), but few studies address its multiple contributions. Subcomponent analysis considers the relative myogenic (resistance area product, RAP) and metabolic (critical closing pressure (CrCP)) contributors. The aim of this study was to investigate the changes in subcomponents that occur with cognitive stimulation with the Addenbrooke's Cognitive Examination (ACE-III) in healthy controls. Healthy volunteers underwent continuous recording of bilateral TCD, heart rate (HR, three-lead ECG), end-tidal CO2 (ETCO2 , capnography), and mean arterial pressure (MAP, Finometer). The study comprised a 5-min baseline recording, followed by all 20 paradigms from the ACE-III. The cerebral blood flow velocity (CBFv) response was decomposed into the relative contributions (subcomponents); VBP (MAP), VCrCP (CrCP), and VRAP (RAP). Data are presented as peak population normalized mean changes from baseline, and median area under the curve (AUC). Forty bilateral datasets were obtained (27 female, 37 right hand dominant). VBP increased at task initiation in all paradigms but differed between tasks (range (SD): 4.06 (8.92)-16.04 (12.23) %, P < 0.05). HR, but not ETCO2 , also differed significantly (P < 0.05). Changes in VRAP reflected changes in MAP, but in some paradigms atypical responses were seen. VCrCP AUC varied significantly within paradigm sections (range [SD]: 18.4 [24.17] to 244.21 [243.21] %*s, P < 0.05). All paradigms demonstrated changes in subcomponents with cognitive stimulation, and can be ranked based on their relative presumed metabolic demand. The integrity of NVC requires further investigation in patient populations

Reproducibility of task activation using the Addenbrooke's cognitive examination in healthy controls: A functional Transcranial Doppler ultrasonography study

Introduction Cerebral blood flow velocity (CBFv) changes occurring with cognitive stimulation can be measured by Transcranial Doppler ultrasonography (TCD). The aim of this study was to assess the reproducibility of CBFv changes to the Addenbrooke's cognitive examination (ACE-III). New method 13 volunteers underwent bilateral TCD (middle cerebral artery), continuous heart rate (HR, 3-lead ECG, Finometer), beat-to-beat mean arterial pressure (MAP, Finometer), and end-tidal CO2 (ETCO2, capnography). After 5 min baseline, all ACE-III tasks were performed in 3 domains (A/B/C). Data presented are population CBFv peak normalised changes and area under the curve (AUC). Statistical analysis was by 2-way repeated measures (ANOVA), intra-class correlation coefficient (ICC), standard error of measurement (SEM) and coefficient of variation (CV). Results 12 bilateral data sets were obtained (10 right hand dominant, 6 female). Baseline parameters (MAP, HR, ETCO2) did not differ between visits. All tasks increased CBFv. Only domain A on AUC analysis differed significantly on ANOVA, and one task on post hoc testing (p < 0.05). ICC values were poor (<0.4) for most tasks, but 3 tasks produced more consistent results on AUC and peak CBFv analysis (range ICC: 0.15–0.73, peak CV: 16.2–56.1(%), AUC CV: 23.2–60.2(%), peak SEM: 2.5–6.0 (%), AUC SEM: 21.8–135.8 (%*s). Comparison with existing methods This is the first study to examine reproducibility of CBFv changes to a complete cognitive assessment tool. Conclusions Reproducibility of CBFv measurements to the ACE-III was variable. AUC may provide more reliable estimates than peak CBFv responses. These data need validating in patient populations

The effect of relative hypotension on 30-day mortality in older people receiving emergency care

Research has observed increased mortality among older people attending the emergency department (ED) who had systolic pressure > 7 mmHg lower than baseline primary care values. This study aimed to (1) assess feasibility of identifying this ‘relative hypotension’ using readily available ED data, (2) externally validate the 7 mmHg threshold, and (3) refine a threshold for clinically important relative hypotension. A single-centre retrospective cohort study linked year 2019 data for ED attendances by people aged over 64 to hospital discharge vital signs within the previous 18 months. Frailty and comorbidity scores were calculated. Previous discharge (‘baseline’) vital signs were subtracted from initial ED values to give individuals’ relative change. Cox regression analysis compared relative hypotension > 7 mmHg with mean time to mortality censored at 30 days. The relative hypotension threshold was refined using a fully adjusted risk tool formed of logistic regression models. Receiver operating characteristics were compared to NEWS2 models with and without incorporation of relative systolic. 5136 (16%) of 32,548 ED attendances were linkable with recent discharge vital signs. Relative hypotension > 7 mmHg was associated with increased 30-day mortality (HR 1.98; 95% CI 1.66–2.35). The adjusted risk tool (AUC: 0.69; sensitivity: 0.61; specificity: 0.68) estimated each 1 mmHg relative hypotension to increase 30-day mortality by 2% (OR 1.02; 95% CI 1.02–1.02). 30-day mortality prediction was marginally better with NEWS2 (AUC: 0.73; sensitivity: 0.59; specificity: 0.78) and NEWS2 + relative systolic (AUC: 0.74; sensitivity: 0.63; specificity: 0.75). Comparison of ED vital signs with recent discharge observations was feasible for 16% individuals. The association of relative hypotension > 7 mmHg with 30-day mortality was externally validated. Indeed, any relative hypotension appeared to increase risk, but model characteristics were poor. These findings are limited to the context of older people with recent hospital admissions.</p

Effects of brain training on brain blood flow (The Cognition and Flow Study-CogFlowS): protocol for a feasibility randomised controlled trial of cognitive training in dementia.

INTRODUCTION: Cognitive training is an emerging non-pharmacological treatment to improve cognitive and physical function in mild cognitive impairment (MCI) and early Alzheimer's disease (AD). Abnormal brain blood flow is a key process in the development of cognitive decline. However, no studies have explored the effects of cognitive training on brain blood flow in dementia. The primary aim of this study is to assess the feasibility for a large-scale, randomised controlled trial of cognitive training in healthy older adults (HC), MCI and early AD. METHODS AND ANALYSIS: This study will recruit 60 participants, in three subgroups of 20 (MCI, HC, AD), from primary, secondary and community services. Participants will be randomised to a 12-week computerised cognitive training programme (five × 30 min sessions per week), or waiting-list control. Participants will undergo baseline and follow-up assessments of: mood, cognition, quality of life and activities of daily living. Cerebral blood flow will be measured at rest and during task activation (pretraining and post-training) by bilateral transcranial Doppler ultrasonography, alongside heart rate (3-lead ECG), end-tidal CO2 (capnography) and beat-to-beat blood pressure (Finometer). Participants will be offered to join a focus group or semistructured interview to explore barriers and facilitators to cognitive training in patients with dementia. Qualitative data will be analysed using framework analysis, and data will be integrated using mixed methods matrices. ETHICS AND DISSEMINATION: Bradford Leeds Research Ethics committee awarded a favourable opinion (18/YH/0396). Results of the study will be published in peer-reviewed journals, and presented at national and international conferences on ageing and dementia. TRIALS REGISTRATION NUMBER: NCT03656107; Pre-results

The Effects of Healthy Ageing on Cerebral Blood Flow Responses to Cognitive Testing.

Background Transcranial Doppler Ultrasonography (TCD) can be utilised to measure the tight coupling of cerebral blood flow velocity (CBFv) in response to cognitive demand by task activation, termed neurovascular coupling. AIMS: To investigate the differences in neurovascular coupling between healthy older (>50 years) and younger (18-49 years) adults in response to cognitive testing. METHODS: Fifty-four older (n=25) and younger (n=29) adults underwent continuous bilateral TCD, beat-to-beat blood pressure (MAP; Finapres), heart rate (HR; electrocardiogram), and end-tidal CO2 (ETCO2; capnography) monitoring. After a 5-min baseline period, memory (M1-4: recalling three learnt words, learning a name and address, recalling US presidents and UK prime ministers, and recalling the previously learnt name and address) and visuospatial (V1-4: drawing a cube and infinity diagram, drawing a clock face, counting dots, and recognising obscured letters) tasks from the Addenbrooke's Cognitive Examination (ACE-III) were performed. Data are mean (standard deviation). RESULTS: In the memory paradigms, peak percentage change in CBFv differed significantly between younger and older groups only in the dominant hemisphere during the M1 task, (2.17 (9.16)% vs. 8.38 (9.27)%, respectively, p=0.017). In the visuospatial paradigm, there were also significant differences in peak percentage change in CBFv between younger and older groups in the V1 (5.87 (8.32)% vs. 11.89 (6.60)%, p=0.005) and V2 tasks (6.30 (8.72)% vs. 11.30 (7.77)%, p=0.032). Conclusions Healthy older adults demonstrate augmented cerebrovascular physiology in response to cognitive challenge compared to younger adults. The impact of abnormal ageing on cerebrovascular physiology, for example related to cognitively impaired states, requires further investigation

INFOMATAS multi-center systematic review and meta-analysis individual patient data of dynamic cerebral autoregulation in ischemic stroke

Rationale: Disturbances in dynamic cerebral autoregulation after ischemic stroke may have important implications for prognosis. Recent meta-analyses have been hampered by heterogeneity and small samples. Aim and/or hypothesis: The aim of study is to undertake an individual patient data meta-analysis (IPD-MA) of dynamic cerebral autoregulation changes post-ischemic stroke and to determine a predictive model for outcome in ischemic stroke using information combined from dynamic cerebral autoregulation, clinical history, and neuroimaging. Sample size estimates: To detect a change of 2% between categories in modified Rankin scale requires a sample size of ∼1500 patients with moderate to severe stroke, and a change of 1 in autoregulation index requires a sample size of 45 healthy individuals (powered at 80%, α = 0.05). Pooled estimates of mean and standard deviation derived from this study will be used to inform sample size calculations for adequately powered future dynamic cerebral autoregulation studies in ischemic stroke. Methods and design: This is an IPD-MA as part of an international, multi-center collaboration (INFOMATAS) with three phases. Firstly, univariate analyses will be constructed for primary (modified Rankin scale) and secondary outcomes, with key co-variates and dynamic cerebral autoregulation parameters. Participants clustering from within studies will be accounted for with random effects. Secondly, dynamic cerebral autoregulation variables will be validated for diagnostic and prognostic accuracy in ischemic stroke using summary receiver operating characteristic curve analysis. Finally, the prognostic accuracy will be determined for four different models combining clinical history, neuroimaging, and dynamic cerebral autoregulation parameters. Study outcome(s): The outcomes for this study are to determine the relationship between clinical outcome, dynamic cerebral autoregulation changes, and baseline patient demographics, to determine the diagnostic and prognostic accuracy of dynamic cerebral autoregulation parameters, and to develop a prognostic model using dynamic cerebral autoregulation in ischemic stroke. Discussion: This is the first international collaboration to use IPD-MA to determine prognostic models of dynamic cerebral autoregulation for patients with ischemic stroke

High non-adherence rates to secondary prevention by chemical adherence testing in patients with TIA

Introduction: Transient ischaemic attack (TIA) clinics are important for secondary prevention of fatal or disabling stroke. Non-adherence to prescribed medications is an important reason for treatment failure but difficult to diagnose. This study ascertained the utility of a novel biochemical tool in the objective biochemical diagnosis of non-adherence. Methods: One-hundred consecutive urine samples collected from patients attending the TIA clinic, at a tertiary centre, were analysed for presence or absence of prescribed cardiovascular medications using liquid chromatography-mass spectrometry (LC-MS/MS). Patients were classified as adherent or non-adherent, respectively. Demographic and clinical characteristics were compared between the two cohorts. Univariate regression analyses were performed for individual variables and model fitting was undertaken for significant variables. Results: The mean duration of follow-up from the index event was 31 days [standard deviation (SD): 18.9]. The overall rate of non-adherence for at least one medication was 24%. In univariate analysis, the number of comorbidities [3.4 (SD: 1.9) vs. 2.5 (1.9), P = 0.032] and total number of all prescribed medications [6.0 (3.3) vs 4.4 (2.1), P = 0.032] were higher in the non-adherent group. On multivariate analysis, the total number of medications prescribed correlated with increased non-adherence (odds ratio: 1.27, 95% Confidence Intervals: 1.1-1.5, P = 0.01). Conclusions: LC-MS/MS is a clinically useful tool for the diagnosis of non-adherence. Nearly a quarter of TIA patients were non-adherent to their cardiovascular medications Addressing non-adherence early may reduce the risk of future disabling cardiovascular events