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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.

[...]the lack of efficacy for amyloid-based targets may suggest amyloid is a by-product rather than causative agent of the disease process. [...]the potential efficacy in a sub-group of early AD (Tolar et al., 2020) suggests that amyloid is a late occurrence in the disease process, at which stage irrevocable damage and cognitive decline has ensued. [...]amyloid deposition damages the cerebrovasculature, both structurally and functionally, therefore worsening hypoperfusion in a cyclical fashion (Nelson et al., 2016). [...]deficiencies occurring in one or more components of the NVU threaten this tightly coordinated system.

Aims: Patients with Parkinson’s disease commonly have comorbid mental health conditions. There is a direct interplay between Parkinsonian and antipsychotic medication which can lead to difficult management decisions. Most mental health and Parkinsonian services are separate, with little coordination or communication between services. A multidisciplinary (MDT) clinic in Leicester was started two years ago to allow an MDT approach to the care of complex Parkinson’s patients. This is held by a geriatrician, an old age psychiatrist, and a Parkinson’s specialist nurse. The aim of this service evaluation was to formally evaluate the utility of the clinic. Methods: We gathered quantitative information from the medical notes of patients seen between November 2023–May 2024, and qualitative information via interviews with carers and Community mental health team (CMHT) psychiatrists. Demographic data was gathered, as well as whether the patient was under a CMHT, whether there was a psychiatric component to appointment, and have we avoided hospital admission. Carers and CMHT consultants were asked about their experience of the clinic and whether the joint service was helpful for them. Results: Notes of 23 patients were reviewed. Most had a primary diagnosis of Parkinson’s disease and were on two or more psychiatric medications (69.6%) and Parkinsonian medications (69.6%). 43.5% were already known to CMHT. Most had a clear psychiatric input to each consultation, such as medication change, cognitive assessment, or cancellation of CMHT appointment. The medical notes suggested 30.4% avoided CMHT referral and 17.4% may have avoided hospital admission. Six of the 23 patients had a reduction in carer strain. CMHT consultants felt it was a useful addition which could lead to more timely care of patients. Both felt they were not confident in managing complex Parkinson’s patients or adjusting Parkinsonian medication and would have to refer to either geriatrics, neurology or Parkinson’s specialist nurses. We interviewed three carers of patients. All were very happy with the care received, felt it was superior to the separate care they received before and felt they received more holistic and timely care. All felt it had reduced carer strain and prevented admission to hospital. Conclusion: Carers and patients have benefited from the joint geriatrics, old age psychiatry Complex Parkinson’s clinic, compared with the separate care they were receiving before. Clinicians and carers feel it has allowed for efficient and holistic treatment of patients, avoided further appointments, avoided hospital admission in some cases and reduced carer strain.

Stroke simulations are needed to run in-silico trials, develop hypotheses for clinical studies and to interpret ultrasound monitoring and radiological imaging. We describe proof-of-concept three-dimensional stroke simulations, carrying out in silico trials to relate lesion volume to embolus diameter and calculate probabilistic lesion overlap maps, building on our previous Monte Carlo method. Simulated emboli were released into an in silico vasculature to simulate 1000 s of strokes. Infarct volume distributions and probabilistic lesion overlap maps were determined. Computer-generated lesions were assessed by clinicians and compared with radiological images. The key result of this study is development of a three-dimensional simulation for embolic stroke and its application to an in silico clinical trial. Probabilistic lesion overlap maps showed that the lesions from small emboli are homogeneously distributed throughout the cerebral vasculature. Mid-sized emboli were preferentially found in posterior cerebral artery (PCA) and posterior region of the middle cerebral artery (MCA) territories. For large emboli, MCA, PCA and anterior cerebral artery (ACA) lesions were comparable to clinical observations, with MCA, PCA then ACA territories identified as the most to least probable regions for lesions to occur. A power law relationship between lesion volume and embolus diameter was found. In conclusion, this article showed proof-of-concept for large in silico trials of embolic stroke including 3D information, identifying that embolus diameter could be determined from infarct volume and that embolus size is critically important to the resting place of emboli. We anticipate this work will form the basis of clinical applications including intraoperative monitoring, determining stroke origins, and in silico trials for complex situations such as multiple embolisation.

Human sensory, cognitive, and motor processes often result in asymmetric cerebral hemisphere activation, observable through neurovascular coupling (NVC). Brain lateralization enables simultaneous performance of distinct functions, enhancing cognitive capacity. This study examined cognitive lateralization through NVC responses to the Addenbrooke's Cognitive Examination‐III (ACE‐III) assessment, using entropy‐based methods and statistical complexity measures (SCM). We tested whether applying dispersion entropy (DE) to cerebral blood velocity (CBv), critical closing pressure (CrCP), and resistance area‐product (RAP) signals could identify significant hemispheric differences during cognitive tasks. Statistical analysis revealed SCM effectively detected lateralization (best p‐value = 0.001), whereas entropy alone did not differentiate hemisphere activity. Furthermore, cognitive stimulation (attention, fluency, language, memory, and visuospatial tasks) generally produced lower SCM values compared to baseline, predominantly in the dominant hemisphere. These findings indicate that NVC exhibits distinct complexity patterns based on hemisphere dominance and cognitive domain stimulated. Additionally, comparison with prior ACE‐III analyses, using population‐normalized mean peak change, reinforces that advanced biomedical‐oriented information theory methods, such as DE and SCM, offer valuable insights into cerebral lateralization mechanisms and NVC responses during cognitive stimulation.

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.

Previous studies report contradicting age‐related neurovascular coupling (NVC). Few studies assess postural effects, but less investigate relationships between age and NVC within different postures. Therefore, this study investigated the effect of age on NVC in different postures with varying cognitive stimuli. Beat‐to‐beat blood pressure, heart rate and end‐tidal carbon dioxide were assessed alongside middle and posterior cerebral artery velocities (MCAv and PCAv, respectively) using transcranial Doppler ultrasonography in 78 participants (31 young‐, 23 middle‐ and 24 older‐aged) with visuospatial (VST) and attention tasks (AT) in various postures at two timepoints (T2 and T3). Between‐group significance testing utilized one‐way analysis‐of‐variance (ANOVA) (Tukey post‐hoc). Mixed three‐way/one‐way ANOVAs explored task, posture, and age interactions. Significant effects of posture on NVC were driven by a 3.8% increase from seated to supine. For AT, mean supine %MCAv increase was greatest in younger (5.44%) versus middle (0.12%) and older‐age (0.09%) at T3 (p = 0.005). For VST, mean supine %PCAv increase was greatest at T2 and T3 in middle (10.99%/10.12%) and older‐age (17.36%/17.26%) versus younger (9.44%/8.89%) (p = 0.004/p = 0.002). We identified significant age‐related NVC effects with VST‐induced hyperactivation. This may reflect age‐related compensatory processes in supine. Further work is required, using complex stimuli while standing/walking, examining NVC, aging and falls.

Squat‐stand maneuvers (SSMs) are a popular method of inducing blood pressure (BP) oscillations to reliably assess dynamic cerebral autoregulation (dCA), but their effects on the cerebral circulation remain controversial. We designed a protocol whereby participants would perform SSMs under hypercapnic conditions. Alarmingly high values of cerebral blood flow velocity (CBFV) were recorded, leading to early study termination after the recruitment of a single participant. One healthy subject underwent recordings at rest (5 min sitting, 5 min standing) and during two SSMs (fixed and random frequency). Two sets of recordings were collected; one while breathing room air, one while breathing 5% CO2. Continuous recordings of bilateral CBFV (transcranial Doppler), heart rate (ECG), BP (Finometer), and end‐tidal CO2 (capnography) were collected. Peak values of systolic CBFV were significantly higher during hypercapnia (p < 0.01), and maximal values exceeded 200 cm.s−1. Estimates of dCA (ARI) during hypercapnia were impaired relative to poikilocapnia (p = 0.03). The phase was significantly reduced under hypercapnic conditions (p = 0.03). Here we report extremely high values of CBFV in response to repeated SSMs during induced hypercapnia, in an otherwise healthy subject. Our findings suggest that protocols performing hypercapnic SSMs are potentially dangerous. We, therefore, urge caution if other research groups plan to undertake similar protocols. Squat‐stand maneuvers are a popular method of inducing blood pressure oscillations to reliably assess dynamic cerebral autoregulation, but their effects on the cerebral circulation remain controversial. In order to better understand the cerebrovascular response to SSMs, and test the hypothesis that the changes in CBFV seen during repeated SSMs are indeed due to autoregulation, we designed a protocol whereby participants would perform repeated SSMs while breathing 5% CO2. We recorded alarmingly high values of CBFV, and therefore report our findings to inform other research groups who may be planning similar work.

IntroductionNitrate-induced headache is common and may signify responsive cerebral vasculature. We assessed the relationship between nitrate headache and outcome in patients with acute stroke.Materials and methodsPatients were those randomised to glyceryl trinitrate (GTN) versus no GTN in the efficacy of nitric oxide in stroke trial. Development of headache by end of treatment (day 7), and functional outcome (modified Rankin Scale, primary outcome) at day 90, were assessed. Analyses are adjusted for baseline prognostic factors and give OR and mean difference (MD) with 95% CI.ResultsIn 4011 patients, headache was more common in GTN than control (360, 18.0% vs 170, 8.5%; p<0.001). Nitrate-related headache was associated with: younger age, female sex, higher diastolic blood pressure, non-total anterior circulation syndrome, milder stroke and absence of dysphasia (p<0.05). Nitrate headache was not associated with improved functional outcome (OR 0.90, 95% CI 0.73 to 1.10, p=0.30) or death (day 90) (HR 0.64, 95% CI 0.40 to 1.02, p=0.062), but reduced death or deterioration (day 7) (OR 0.45, 95% CI 0.25 to 0.82), death in hospital (OR 0.44, 95% CI 0.22 to 0.88) and improved activities of daily living (Barthel index, MD 3.7, 95% CI 0.3 to 7.1) and cognition (telephone interview cognitive screen, MD 2.0, 95% CI 0.7 to 3.3) (day 90). Non-nitrate headache was not associated with death, disability or cognition.Discussion and conclusionDevelopment of a nitrate headache by day 7 after stroke may be associated with improved activities of daily living and cognitive impairment at day 90, which was not seen with non-nitrate headache.

Aims and ObjectivesIncreased mortality has been observed among older people whose systolic pressure was at least 7mmHg below their baseline primary care value when they attended the emergency department (ED). This study aimed to (1) assess feasibility of identifying this ‘relative hypotension’ using readily available ED data, (2) externally validate the 7mmHg threshold, and (3) refine a threshold for clinically important relative hypotension.Method and DesignThis single-centre retrospective cohort study of people aged over 64 linked year 2019 ED attendance data to vital signs at hospital discharges within the previous eighteen months. Hospital frailty risk (HFRS) and Charlson 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 exceeding 7mmHg 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 pressure.Results and Conclusion5136 (16%) of 32548 ED attendances were linkable with recent discharge vital signs. Relative hypotension exceeding 7mmHg 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 1mmHg 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 alone (AUC: 0.73; sensitivity: 0.59; specificity: 0.78) and NEWS2 + relative systolic (AUC: 0.74; sensitivity: 0.62; specificity: 0.75).Comparing ED vital signs with recent discharge observations was feasible for 16% individuals. The association of relative hypotension exceeding 7mmHg 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.