Dynamics of Critical Closing Pressure Explain Cerebral Autoregulation Impairment in Acute Cerebrovascular Disease.

INTRODUCTION: Cerebral autoregulation (CA) is impaired in acute ischemic stroke (AIS) and is associated with worse patient outcomes, but the underlying physiological cause is unclear. This study tests whether depressed CA in AIS can be linked to the dynamic responses of critical closing pressure (CrCP) and resistance area product (RAP). METHODS: Continuous recordings of middle cerebral blood velocity (MCAv, transcranial Doppler), arterial blood pressure (BP), end-tidal CO2 and electrocardiography allowed dynamic analysis of the instantaneous MCAv-BP relationship to obtain estimates of CrCP and RAP. The dynamic response of CrCP and RAP to a sudden change in mean BP was obtained by transfer function analysis. Comparisons were made between younger controls (≤50 years), older controls (>50 years), and AIS patients. RESULTS: Data from 24 younger controls (36.4 ± 10.9 years, 9 male), 38 older controls (64.7 ± 8.2 years, 20 male), and 20 AIS patients (63.4 ± 13.8 years, 9 male) were included. Dynamic CA was impaired in AIS, with lower autoregulation index (affected hemisphere: 4.0 ± 2.3, unaffected: 4.5 ± 1.8) compared to younger (right: 5.8 ± 1.4, left: 5.8 ± 1.4) and older (right: 4.9 ± 1.6, left: 5.1 ± 1.5) controls. AIS patients also demonstrated an early (0-3 s) peak in CrCP dynamic response that was not influenced by age. CONCLUSION: These early transient differences in the CrCP dynamic response are a novel finding in stroke and occur too early to reflect underlying regulatory mechanisms. Instead, these may be caused by structural changes to cerebral vasculature.

Streamlined Clinical Management Pathways May Reduce Major Amputations in Patients with Chronic Limb Threatening Ischaemia: A Prospective Cohort Study with Historical Controls.

OBJECTIVE: Patient characteristics and patterns of disease in chronic limb threatening ischaemia (CLTI) have changed markedly in recent years. Urgent specialist referral and timely revascularisation are recommended in international guidelines. UK guidelines now recommend revascularisation within 5 days of referral for inpatients and 2 weeks in outpatients. This study compared the contemporary one year major amputation incidence in patients with CLTI with a historical cohort at a single UK centre. METHODS: This was a single centre, observational cohort study with historical controls. A prospective cohort was recruited between May 2019 and March 2022. A historical cohort presenting between 2013 and 2015 inclusive was identified retrospectively. Significant changes in management pathways, including establishing a rapid access limb salvage clinic, occurred between these periods aiming to expedite time from referral to revascularisation. The one year primary outcome was major amputation, and the secondary outcome was death. Major amputation was analysed by Fine-Gray competing risks models (death as the competing risk), presented as subdistribution hazard ratios (SHRs). One year mortality was analysed by Cox regression, presented as hazard ratios. Analyses were adjusted for propensity score. RESULTS: A total of 928 patients were included (432 prospective and 496 historical). Proportions of patients presenting with tissue loss (72.2% vs. 71.6%; p = .090) were similar in both cohorts. At one year, 48 patients (11.1%) in the prospective cohort and 124 patients (25.0%) in the historical cohort had undergone a major amputation (p < .001). Risk of major amputation was 57.0% lower in the prospective cohort compared with the historical cohort after adjustment for propensity score (SHR 0.43, 95% confidence interval 0.29 - 0.63; p < .001). CONCLUSION: An encouraging reduction in major amputation incidence was observed after improvements to CLTI management pathways, but residual confounding is likely. The generalisability of these results is uncertain.

New Horizons in Peripheral Artery Disease.

Peripheral artery disease (PAD) is the lower limb manifestation of systemic atherosclerotic disease. PAD may initially present with symptoms of intermittent claudication, whilst chronic limb-threatening ischaemia (CLTI), the end stage of PAD, presents with rest pain and/or tissue loss. PAD is an age-related condition present in over 10% of those aged ≥65 in high-income countries. Guidelines regarding definition, diagnosis and staging of PAD and CLTI have been updated to reflect the changing patterns and presentations of disease given the increasing prevalence of diabetes. Recent research has changed guidelines on optimal medical therapy, with low-dose anticoagulant plus aspirin recommended in some patients. Recently published randomised trials highlight where bypass-first or endovascular-first approaches may be optimal in infra-inguinal disease. New techniques in endovascular surgery have increased minimally invasive options for ever more complex disease. Increasing recognition has been given to the complexity of patients with CLTI where a high prevalence of both frailty and cognitive impairment are present and a significant burden of multi-morbidity and polypharmacy. Despite advances in minimally invasive revascularisation techniques and reduction in amputation incidence, survival remains poor for many with CLTI. Shared decision-making is essential, and conservative management is often appropriate for older patients. There is emerging evidence of the benefit of specialist geriatric team input in the perioperative management of older patients undergoing surgery for CLTI. Recent UK guidelines now recommend screening for frailty, cognitive impairment and delirium in older vascular surgery patients as well as recommending all vascular surgery services have support and input from specialist geriatrics teams.

Detection of Blood CO2 Influences on Cerebral Hemodynamics Using Transfer Entropy.

Cerebral hemodynamics describes an important physiological system affected by components such as blood pressure, CO2 levels, and endothelial factors. Recently, novel techniques have emerged to analyse cerebral hemodynamics based on the calculation of entropies, which quantifies or describes changes in the complexity of this system when it is affected by a pathological or physiological influence. One recently described measure is transfer entropy, which allows for the determination of causality between the various components of a system in terms of their flow of information, and has shown positive results in the multivariate analysis of physiological signals. This study aims to determine whether conditional transfer entropy reflects the causality in terms of entropy generated by hypocapnia on cerebral hemodynamics. To achieve this, non-invasive signals from 28 healthy individuals who undertook a hyperventilation maneuver were analyzed using conditional transfer entropy to assess the variation in the relevance of CO2 levels on cerebral blood velocity. By employing a specific method to discretize the signals, it was possible to differentiate the influence of CO2 levels during the hyperventilation phase (22.0% and 20.3% increase for the left and right hemispheres, respectively) compared to normal breathing, which remained higher during the recovery phase (15.3% and 15.2% increase, respectively).

Vascular and haemodynamic issues of brain ageing.

The population is ageing worldwide, thus increasing the burden of common age-related disorders to the individual, society and economy. Cerebrovascular diseases (stroke, dementia) contribute a significant proportion of this burden and are associated with high morbidity and mortality. Thus, understanding and promoting healthy vascular brain ageing are becoming an increasing priority for healthcare systems. In this review, we consider the effects of normal ageing on two major physiological processes responsible for vascular brain function: Cerebral autoregulation (CA) and neurovascular coupling (NVC). CA is the process by which the brain regulates cerebral blood flow (CBF) and protects against falls and surges in cerebral perfusion pressure, which risk hypoxic brain injury and pressure damage, respectively. In contrast, NVC is the process by which CBF is matched to cerebral metabolic activity, ensuring adequate local oxygenation and nutrient delivery for increased neuronal activity. Healthy ageing is associated with a number of key physiological adaptations in these processes to mitigate age-related functional and structural declines. Through multiple different paradigms assessing CA in healthy younger and older humans, generating conflicting findings, carbon dioxide studies in CA have provided the greatest understanding of intrinsic vascular anatomical factors that may mediate healthy ageing responses. In NVC, studies have found mixed results, with reduced, equivalent and increased activation of vascular responses to cognitive stimulation. In summary, vascular and haemodynamic changes occur in response to ageing and are important in distinguishing "normal" ageing from disease states and may help to develop effective therapeutic strategies to promote healthy brain ageing.

Determinants of cerebral blood flow velocity change during squat-stand maneuvers.

The large changes in mean arterial blood pressure (MABP) and cerebral blood flow velocity (CBFV) induced by squat-stand maneuvers (SSM) make this approach particularly suited for studying dynamic cerebral autoregulation (CA). However, the role of other systemic determinants of CBFV has not been described and could provide alternative physiological interpretations of SSM results. In 32 healthy subjects (16 female), continuous recordings of MABP (Finometer), bilateral CBFV (transcranial Doppler, MCA), end-tidal CO2 (EtCO2; capnography), and heart rate (HR; electrocardiogram) were performed for 5 min standing at rest, and during 15 SSM at the frequency of 0.05 Hz. A time-domain, multivariate dynamic model estimated the CBFV variance explained by different inputs, corresponding to significant contributions from MABP (P < 0.00001), EtCO2 (P < 0.0001), and HR (P = 0.041). The autoregulation index (ARI; range 0-9) was estimated from the CBFV response to a step change in MABP. At rest, ARI values (typically 5.7) were independent of the number of model inputs, but during SSM, ARI was reduced compared with baseline (P < 0.0001), and the three input model yielded lower values for the right and left MCA (3.4 ± 1.2, 3.1 ± 1.3) when compared with the single-input MABP-CBFV model (4.1 ± 1.1, 3.9 ± 1.0; P < 0.0001). The high coherence of the MABP-CBFV transfer function at 0.05 Hz (typically 0.98) was considerably reduced (around 0.71-0.73; P < 0.0001) when the contribution of CBFV covariates was taken into account. Not taking into consideration other determinants of CBFV, in addition to MABP, could be misleading and introduce biases in physiological and clinical studies.

Prevalence of Cognitive Impairment in Individuals with Vascular Surgical Pathology: a Systematic Review and Meta-Analysis.

OBJECTIVE: A significant proportion of vascular surgery patients may have undiagnosed cognitive impairment; however, its true prevalence and impact on outcomes are unknown. The aim of this review was to estimate the prevalence of cognitive impairment among individuals with clinically significant vascular surgical pathology and investigate its associations with post-operative outcomes in those undergoing vascular surgery. METHODS: MEDLINE, EMBASE, EMCare, CINAHL, PsycINFO, and Scopus were searched for relevant studies. Included studies assessed cognitive function among individuals with either symptomatic vascular surgical pathology, or disease above threshold for intervention, using a validated cognitive assessment tool. The primary outcome measure was prevalence of cognitive impairment. Secondary outcomes included incidence of post-operative delirium (POD). Two reviewers independently extracted relevant study data and assessed risk of bias (ROBINS-E or RoB 2 tool). Prevalence (%) of cognitive impairment was calculated for individual studies and presented with 95% confidence intervals (CI). Prevalence data from comparable studies were pooled using the Mantel-Haenszel method (random effects model) for separate vascular disease types. Certainty of effect estimates was assessed using the GRADE criteria. RESULTS: Twenty-four studies (2 564 participants) were included in the systematic review, and nine studies (1 310 participants) were included in the meta-analyses. The prevalence of cognitive impairment was 61% (95% CI 48 - 74; 391 participants; low certainty) in studies including multiple vascular surgical pathologies, 38% (95% CI 32 - 44; 278 participants; very low certainty) in carotid artery disease, and 19% (95% CI 10 - 33; 641 participants; low certainty) in those with intermittent claudication. Lower cognitive assessment scores were associated with POD (five studies; 841 participants), but data were not suitable for pooling. CONCLUSION: Screening elective vascular surgery patients for cognitive impairment may be appropriate given its high prevalence, and the association of worse cognition with POD, among individuals with clinically significant vascular surgical pathology.

Associations of Clinical Frailty with Severity of Limb Threat and Outcomes in Chronic Limb-threatening Ischaemia.

OBJECTIVE: Investigate the relationship of frailty and severity of chronic limb-threatening ischaemia (CLTI), and their comparative associations with one-year outcomes, in patients presenting to a vascular limb salvage (VaLS) clinic. METHODS: This retrospective cohort study utilised data collected from a prospectively maintained VaLS clinic database. Patients aged ≥50 presenting to the VaLS clinic with CLTI between February 2018 and April 2019 were included. Frailty was measured using the Clinical Frailty Scale (CFS) and limb threat severity by the Wound, Ischaemia, and foot Infection (WIfI) score. Excessive polypharmacy was defined as ≥10 medications. Anticholinergic burden (ACB) score and Charlson comorbidity index (CCI) were calculated for all patients. The primary outcome measure was a composite endpoint of death or amputation at one-year. Associations with outcome were assessed using Cox regression and reported as hazards ratios (HR) with 95% confidence intervals (CI). RESULTS: A total of 198 patients were included, with CFS scores available for 190 patients. 98 patients (52%) were frail (CFS ≥5). 127 patients (67%) initially underwent endovascular revascularisation. Excessive polypharmacy was common (55 patients; 28%). Frailty was associated with increased WIfI stage (P = 0.025) as well as age, female sex, CCI score, number of medications, excessive polypharmacy but not ACB score. Frail patients were more frequently managed non-operatively (P = 0.017). Frailty (HR 1.91; 95% CI 1.09, 3.34; P = 0.024) and WIfI stage 4 (HR 3.29; 95%CI 1.23, 8.80; P = 0.018) were associated with death or amputation on univariable analysis. WIfI stage 4 (HR 2.80; 95%CI 1.04, 7.57; P = 0.042) and CCI score (HR 1.21; 95%CI 1.03, 1.41; P = 0.015), but not frailty (HR 1.25; 95%CI 0.67, 2.33; P = 0.474), were independently associated with death or amputation on multivariable analysis. CONCLUSIONS: Frailty is highly prevalent among CLTI patients and related to severity of limb threat. The CFS may be a useful adjunct to patient risk assessment in CLTI.

Increasing Blood Pressure Variability Predicts Poor Functional Outcome Following Acute Stroke.

INTRODUCTION: Increasing blood pressure variability has been reported following acute stroke, but there is uncertainty about how best to measure it and about the impact on prognosis following acute ischaemic stroke and transient ischaemic attack. METHODS: Enhanced casual blood pressure and ambulatory blood pressure monitoring were completed at baseline (≤48 h post symptom onset). Blood pressure variability was defined by standard deviation and coefficient of variation of systolic, diastolic, mean arterial pressure, and pulse pressure. Modified Rankin scale score ≥3 described poor functional outcome assessed at 1- and 12-months post-stroke. Multivariable logistic regression models incorporating blood pressure variability measurement and other factors were performed, and odds ratio and 95% confidence intervals reported. RESULTS: 232 patients were recruited; 45 were dependent at 1-month, and 37 at 12-months. Dependent patients were more likely to be older, with a higher burden of pre-morbid conditions, and with increased blood pressure variability. Enhanced casual standard deviations of diastolic blood pressure [1.19 (1.02 to 1.39)] and mean arterial pressure [1.20 (1.00 to 1.43)] predicted dependency at 1-month. Predictors of 12-month dependency included: enhanced casual standard deviation of mean arterial pressure [1.21 (1.0-1.46)]; 24 h ambulatory monitor standard deviations of diastolic blood pressure [2.30 (1.08-4.90)] and mean arterial pressure [1.72 (1.09-2.72)], and the coefficient of variation of mean arterial pressure [1.76 (1.05-2.94)]; day-time ambulatory monitor coefficient of variation of systolic blood pressure [1.44 (1.02-2.03)] and mean arterial pressure [1.46 (1.02-2.08)]; and night-time ambulatory standard deviation of diastolic blood pressure [1.65 (1.03 -2.63)], and the coefficient of variation of mean arterial pressure and [1.38 (1.00- 1.90)] and pulse pressure [1.29 (1.00-1.65)]. CONCLUSION: Increasing blood pressure variability is independently and modestly associated with poor functional outcome at 1- and 12-months following acute stroke.

Frailty Factors and Outcomes in Vascular Surgery Patients: A Systematic Review and Meta-analysis.

OBJECTIVE: To describe and critique tools used to assess frailty in vascular surgery patients, and investigate its associations with patient factors and outcomes. BACKGROUND: Increasing evidence shows negative impacts of frailty on outcomes in surgical patients, but little investigation of its associations with patient factors has been undertaken. METHODS: Systematic review and meta-analysis of studies reporting frailty in vascular surgery patients (PROSPERO registration: CRD42018116253) searching Medline, Embase, CINAHL, PsycINFO, and Scopus. Quality of studies was assessed using Newcastle-Ottawa scores (NOS) and quality of evidence using Grading of Recommendations Assessment, Development, and Evaluation criteria. Associations of frailty with patient factors were investigated by difference in means (MD) or expressed as risk ratios (RRs), and associations with outcomes expressed as odds ratios (ORs) or hazard ratios (HRs). Data were pooled using random-effects models. RESULTS: Fifty-three studies were included in the review and only 8 (15%) were both good quality (NOS ≥ 7) and used a well-validated frailty measure. Eighteen studies (62,976 patients) provided data for the meta-analysis. Frailty was associated with increased age [MD 4.05 years; 95% confidence interval (CI) 3.35, 4.75], female sex (RR 1.32; 95% CI 1.14, 1.54), and lower body mass index (MD -1.81; 95% CI -2.94, -0.68). Frailty was associated with 30-day mortality [adjusted OR (AOR) 2.77; 95% CI 2.01-3.81), postoperative complications (AOR 2.16; 95% CI 1.55, 3.02), and long-term mortality (HR 1.85; 95% CI 1.31, 2.62). Sarcopenia was not associated with any outcomes. CONCLUSION: Frailty, but not sarcopenia, is associated with worse outcomes in vascular surgery patients. Well-validated frailty assessment tools should be preferred clinically, and in future research.

COVID-19 in older people: a rapid clinical review.

INTRODUCTION: the COVID-19 pandemic poses a high risk to older people. The aim of this article is to provide a rapid overview of the COVID-19 literature, with a specific focus on older adults. We frame our findings within an overview of the disease and have also evaluated the inclusion of older people within forthcoming clinical trials. METHODS: we searched PubMed and bioRxiv/medRxiv to identify English language papers describing the testing, treatment and prognosis of COVID-19. PubMed and bioRxiv/medRxiv searches took place on 20 and 24 March 2020, respectively. RESULTS: screening of over 1,100 peer-reviewed and pre-print papers yielded n = 22 on COVID-19 testing, n = 15 on treatment and n = 13 on prognosis. Viral polymerase chain reaction (PCR) and serology are the mainstays of testing, but a positive diagnosis may be increasingly supported by radiological findings. The current evidence for the effectiveness of antiviral, corticosteroid and immunotherapies is inconclusive, although trial data are largely based on younger people. In addition to age, male gender and comorbidities, specific laboratory and radiology findings are important prognostic factors. Evidence suggests that social distancing policies could have important negative consequences, particularly if in place for an extended period. CONCLUSION: given the established association between increasing age and poor prognosis in COVID-19, we anticipate that this rapid review of the current and emergent evidence might form a basis on which future work can be established. Exclusion of older people, particularly those with comorbidities, from clinical trials is well recognised and is potentially being perpetuated in the field of current COVID-19 research.

Determining differences between critical closing pressure and resistance-area product: responses of the healthy young and old to hypocapnia.

Healthy ageing has been associated with lower cerebral blood flow velocities (CBFVs); however, the behaviour of hemodynamic parameters associated with cerebrovascular tone (critical closing pressure, CrCP) and cerebrovascular resistance (resistance-area product, RAP) remains unclear. Specifically, evidence supports ageing being associated with greater cerebrovascular tone and resistance during exercise with elevated CrCP and RAP in older individuals at rest and during exercise. Comprehensive hemodynamic assessment of CrCP and RAP during hyperventilation-induced hypocapnia in two distinct age groups (young ≤ 49 and old > 50) has not been described. CBFV in the middle cerebral artery (CBFV, transcranial Doppler), blood pressure (BP, Finometer) and end-tidal CO2 (EtCO2, capnography) were recorded in 104 healthy individuals (43 young [age 33.8 (9.3) years], 61 old [age 64.1 (8.5) years]) during a minimum of 60 s of metronome-driven hyperventilation-induced hypocapnia. Autoregulation index was calculated as a function of time, using a moving window autoregressive-moving average model. CBFV was reduced in response to age (p < 0.0001) and hypocapnia (p = 0.023) (young 57.3 (14.4) vs. 44.9 cm s-1 (11.1), old 51.7 (12.9) vs. 37.8 cm s-1 (9.6)). Critical closing pressure (CrCP) increased significantly in response to hypocapnia (young 37.6 (18.5) vs. 39.7 mmHg (16.0), old 33.9 (13.5) vs. 39.3 mmHg (11.4); p < 0.0001). Resistance-area product was increased in response to age (p = 0.001) and hypocapnia (p = 0.004) (young 1.02 (0.40) vs. 1.09 mmHg cm s-1 (11.07), old 1.16 (0.34) vs. 1.34 mmHg cm s-1 (0.39)). RAP and not CrCP mediates differences in cerebrovascular resistance responses to hypocapnia between the healthy young and old individuals.

Alternative representation of neural activation in multivariate models of neurovascular coupling in humans.

Neural stimulation leads to increases in cerebral blood flow (CBF), but simultaneous changes in covariates, such as arterial blood pressure (BP) and PaCO2, rule out the use of CBF changes as a reliable marker of neurovascular coupling (NVC) integrity. Healthy subjects performed repetitive (1 Hz) passive elbow flexion with their dominant arm for 60 s. CBF velocity (CBFV) was recorded bilaterally in the middle cerebral artery with transcranial Doppler, BP with the Finometer device, and end-tidal CO2 (EtCO2) with capnography. The simultaneous effects of neural stimulation, BP, and PaCO2 on CBFV were expressed with a dynamic multivariate model, using BP, EtCO2, and stimulation [s(t)] as inputs. Two versions of s(t) were considered: a gate function [sG(t)] or an orthogonal decomposition [sO(t)] function. A separate CBFV step response was extracted from the model for each of the three inputs, providing estimates of dynamic cerebral autoregulation [CA; autoregulation index (ARI)], CO2 reactivity [vasomotor reactivity step response (VMRSR)], and NVC [stimulus step response (STIMSR)]. In 56 subjects, 224 model implementations produced excellent predictive CBFV correlation (median r = 0.995). Model-generated sO(t), for both dominant (DH) and nondominant (NDH) hemispheres, was highly significant during stimulation (<10-5) and was correlated with the CBFV change (r = 0.73, P = 0.0001). The sO(t) explained a greater fraction of CBFV variance (~50%) than sG(t) (44%, P = 0.002). Most CBFV step responses to the three inputs were physiologically plausible, with better agreement for the CBFV-BP step response yielding ARI values of 7.3 for both DH and NDH for sG(t), and 6.9 and 7.4 for sO(t), respectively. No differences between DH and NDH were observed for VMRSR or STIMSR. A new procedure is proposed to represent the contribution from other aspects of CBF regulation than BP and CO2 in response to sensorimotor stimulation, as a tool for integrated, noninvasive, assessment of the multiple influences of dynamic CA, CO2 reactivity, and NVC in humans.NEW & NOTEWORTHY A new approach was proposed to identify the separate contributions of stimulation, arterial blood pressure (BP), and arterial CO2 (PaCO2) to the cerebral blood flow (CBF) response observed in neurovascular coupling (NVC) studies in humans. Instead of adopting an empirical gate function to represent the stimulation input, a model-generated function is derived as part of the modeling process, providing a representation of the NVC response, independent of the contributions of BP or PaCO2. This new marker of NVC, together with the model-predicted outputs for the contributions of BP, PaCO2 and stimulation, has considerable potential to both quantify and simultaneously integrate the separate mechanisms involved in CBF regulation, namely, cerebral autoregulation, CO2 reactivity and other contributions.

Dynamic cerebral autoregulation measurement using rapid changes in head positioning: experiences in acute ischemic stroke and healthy control populations.

The ideal technique for dynamic cerebral autoregulation (dCA) assessment in critically ill patients should provide considerable variability in blood pressure (BP) but without the need for patient cooperation. We proposed using rapid head positioning (RHP) over spontaneous BP fluctuations for dCA assessment in patients with acute ischemic stroke (AIS). Cerebral blood velocity (transcranial Doppler), beat-to-beat BP (Finometer), and end-tidal CO2 (capnography) were recorded during 5-min baseline and RHP in 16 controls (8 women and 8 men, mean age: 57 ± 16 yr) and 15 patients with AIS (7 women and 8 men, mean age: 69 ± 8 yr) at two (12 ± 8 days) and three visits (13.3 ± 6.9 h, 4.8 ± 3.2 days, and 93.9 ± 11.5 days from the symptom onset), respectively. All participants were able to complete the RHP protocol without difficulty. Compared with controls, patients with AIS were hypocapnic (all visits, P < 0.0024) and hypertensive ( visit 1, P = 0.011), although BP gradually reduced after the acute phase. RHP demonstrated greater beat-to-beat BP variability (BPV) in controls ( visits 1 and 2, P < 0.001) but not in patients with AIS at any visit. Compared with controls, a reduced autoregulation index (ARI) was demonstrated in patients with AIS, at visit 2 for the baseline recording but not at other visits or during RHP. The area under the receiver-operating curve was 0.53 and 0.54 for baseline and RHP, respectively. The RHP paradigm required minimal patient cooperation and could be considered a feasible alternative for assessing dCA, mainly in conditions leading to increased BPV. The lack of BPV increase in AIS with RHP deserves further investigation. NEW & NOTEWORTHY This study used rapid head positioning (RHP) to enhance blood pressure (BP) variability (BPV) to improve BP signal-to-noise ratio and reliability of dynamic cerebral autoregulation (dCA). RHP was well accepted by controls and acute ischemic stroke (AIS); the increased BPV induced in controls was not observed in AIS, suggesting BPV at rest was already elevated. RHP did not improve detection of impaired CA in AIS; further work is needed to understand the different responses observed.

Movement disorders: a themed collection.

Movement disorders are a diverse and challenging group of neurological conditions. Geriatricians and allied health professionals play a key role in the care of patients living with these disorders. Age and Ageing is making freely available online a collection of 15 papers that highlight the breadth and depth of this field. Perhaps unsurprisingly papers on Parkinson's disease predominate, but rarer movement disorders, including those seen following stroke and Huntington's disease, are also represented. Difficulties in diagnosis are explored, together with innovative approaches to management of both motor and non-motor symptoms. The collection includes qualitative work, longitudinal studies and clinical trials, and both the individual patient perspective and the international perspective are considered. There are papers for generalists, papers for specialists, papers for clinical commissioners and papers for researchers. Comprehensive review articles provide clarity, guidance and pragmatism. Finally, a New Horizons article encourages us to look to the future of movement disorders, which lies not only in developing novel therapies and trials but also in recognising the enormous value of palliative care and the multidisciplinary approach.

Addenbrooke's Cognitive Examination III (ACE-III) and mini-ACE for the detection of dementia and mild cognitive impairment.

BACKGROUND: The number of new cases of dementia is projected to rise significantly over the next decade. Thus, there is a pressing need for accurate tools to detect cognitive impairment in routine clinical practice. The Addenbrooke's Cognitive Examination III (ACE-III), and the mini-ACE are brief, bedside cognitive screens that have previously reported good sensitivity and specificity. The quality and quantity of this evidence has not, however, been robustly investigated. OBJECTIVES: To assess the diagnostic test accuracy of the ACE-III and mini-ACE for the detection of dementia, dementia sub-types, and mild cognitive impairment (MCI) at published thresholds in primary, secondary, and community care settings in patients presenting with, or at high risk of, cognitive decline. SEARCH METHODS: We performed the search for this review on 13 February 2019. We searched MEDLINE (OvidSP), Embase (OvidSP), BIOSIS Previews (ISI Web of Knowledge), Web of Science Core Collection (ISI Web of Knowledge), PsycINFO (OvidSP), and LILACS (BIREME). We applied no language or date restrictions to the electronic searches; and to maximise sensitivity we did not use methodological filters. The search yielded 5655 records, of which 2937 remained after we removed duplicates. We identified a further four articles through PubMed 'related articles'. We found no additional records through reference list citation searching, or grey literature. SELECTION CRITERIA: Cross-sectional studies investigating the accuracy of the ACE-III or mini-ACE in patients presenting with, or at high risk of, cognitive decline were suitable for inclusion. We excluded case-control, delayed verification and longitudinal studies, and studies which investigated a secondary cause of dementia. We did not restrict studies by language; and we included those with pre-specified thresholds (88 and 82 for the ACE-III, and 21 or 25 for the mini-ACE). DATA COLLECTION AND ANALYSIS: We extracted information on study and participant characteristics and used information on dementia and MCI prevalence, sensitivity, specificity, and sample size to generate 2×2 tables in Review Manager 5. We assessed methodological quality of included studies using the QUADAS-2 tool; and we assessed the quality of study reporting with the STARDdem tool. Due to significant heterogeneity in the included studies and an insufficient number of studies, we did not perform meta-analyses. MAIN RESULTS: This review identified seven studies (1711 participants in total) of cross-sectional design, four examining the accuracy of the ACE-III, and three of the mini-ACE. Overall, the majority of studies were at low or unclear risk of bias and applicability on quality assessment. Studies were at high risk of bias for the index test (n = 4) and reference standard (n = 2). Study reporting was variable across the included studies. No studies investigated dementia sub-types. The ACE-III had variable sensitivity across thresholds and patient populations (range for dementia at 82 and 88: 82% to 97%, n = 2; range for MCI at 88: 75% to 77%, n = 2), but with more variability in specificity (range for dementia: 4% to 77%, n = 2; range for MCI: 89% to 92%, n = 2). Similarly, sensitivity of the mini-ACE was variable (range for dementia at 21 and 25: 70% to 99%, n = 3; range for MCI at 21 and 25: 64% to 95%, n = 3) but with more variability specificity (range for dementia: 32% to 100%, n = 3; range for MCI: 46% to 79%, n = 3). We identified no studies in primary care populations: four studies were conducted in outpatient clinics, one study in an in-patient setting, and in two studies the settings were unclear. AUTHORS' CONCLUSIONS: There is insufficient information in terms of both quality and quantity to recommend the use of either the ACE-III or mini-ACE for the screening of dementia or MCI in patients presenting with, or at high risk of, cognitive decline. No studies were conducted in a primary care setting so the accuracy of the ACE-III and mini-ACE in this setting are not known. Lower thresholds (82 for the ACE-III, and 21 for the mini-ACE) provide better specificity with acceptable sensitivity and may provide better clinical utility. The ACE-III and mini-ACE should only be used to support the diagnosis as an adjunct to a full clinical assessment. Further research is needed to determine the utility of the ACE-III and mini-ACE for the detection of dementia, dementia sub-types, and MCI. Specifically, the optimal thresholds for detection need to be determined in a variety of settings (primary care, secondary care (inpatient and outpatient), and community services), prevalences, and languages.

The assessment of neurovascular coupling with the Addenbrooke's Cognitive Examination: a functional transcranial Doppler ultrasonographic study.

Cerebrovascular dysfunction occurs early in dementia and can be identified by transcranial Doppler ultrasonography (TCD). Few studies have examined cerebral blood flow velocity (CBFv) responses to a detailed cognitive battery. This study aimed to characterize all CBFv responses, and the effect of hemispheric dominance, to the Addenbrooke's Cognitive Examination (ACE-III) in healthy volunteers. Forty volunteers 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, all tasks from the ACE-III were performed in 3 sections (A: attention, fluency, memory; B: language; C: visuospatial, memory). Data are population mean normalized percentage (PM%) change from a 20-s baseline period before task initiation. Forty bilateral data sets were obtained (27 women, 37 right-hand dominant). All paradigms produced a sharp increase in CBFv in both dominant (PM% range: 3.29 to 9.70%) and nondominant (PM% range: 4.34 to 11.63%) hemispheres at task initiation, with associated increases in MAP (PM% range: 3.06 to 16.04%). ETCO2 did not differ significantly at task initiation (PM% range: -1.1 to 2.4%, P > 0.05). HR differed significantly across A and C tasks at initiation (PM% range: -1.1 to 2.4%, P < 0.05), but not B tasks. In conclusion, all tasks resulted in increases in CBFv, differing significantly between paradigms. These results require further investigation in a cognitively impaired population. NEW & NOTEWORTHY This study is the first to provide a normative data set of cerebral blood flow velocity (CBFv) responses to a complete cognitive assessment (Addenbrooke's Cognitive Examination, ACE-III) in a large sample ( n = 40) of healthy volunteers. All tasks produced peak and sustained increases in CBFv to different extents. The ACE-III is a feasible tool to assess neurovascular coupling with transcranial Doppler ultrasonography. These data can be used to inform the most appropriate cognitive task to elicit CBFv responses for future studies.

Directional sensitivity of dynamic cerebral autoregulation in squat-stand maneuvers.

Dynamic cerebral autoregulation (CA), the transient response of cerebral blood flow (CBF) to rapid changes in arterial blood pressure (BP), is usually modeled as a linear mechanism. We tested the hypothesis that dynamic CA can display nonlinear behavior resulting from differential efficiency dependent on the direction of BP changes. Cerebral blood velocity (CBV) (transcranial Doppler), heart rate (HR) (three-lead ECG), continuous BP (Finometer), and end-tidal CO2 (capnograph) were measured in 10 healthy young subjects during 15 squat-stand maneuvers (SSM) with a frequency of 0.05 Hz. The protocol was repeated with a median (interquartile range) of 44 (35-64) days apart. Dynamic CA was assessed with the autoregulation index (ARI) obtained from CBV step responses estimated with an autoregressive moving-average model. Mean BP, HR, and CBV were different (all P < 0.001) between squat and stand, regardless of visits. ARI showed a strong interaction ( P < 0.001) of SSM with the progression of transients; in general, the mean ARI was higher for the squat phase compared with standing. The changes in ARI were partially explained by concomitant changes in CBV ( P = 0.023) and pulse pressure ( P < 0.001), but there was no evidence that ARI differed between visits ( P = 0.277). These results demonstrate that dynamic CA is dependent on the direction of BP change, but further work is needed to confirm if this finding can be generalized to other physiological conditions and also to assess its dependency on age, sex and pathology.

Is cerebral vasomotor reactivity impaired in Parkinson disease?

PURPOSE: The ability of a blood vessel to change diameter in response to a change in carbon dioxide concentration is often referred to as vasomotor reactivity. This study aimed to determine whether vasomotor reactivity is impaired in patients with idiopathic Parkinson's Disease in comparison to healthy controls. METHODS: Transcranial Doppler was used to measure cerebral blood flow velocity in the middle cerebral arteries at baseline and under hypocapnic conditions in 40 patients with idiopathic Parkinson's disease and 50 healthy controls. RESULTS/CONCLUSIONS: Vasomotor reactivity, assessed under hypocapnic conditions, is not impaired in patients with idiopathic Parkinson's Disease in comparison to healthy controls.