Regulation of cerebral blood flow in humans: physiology and clinical implications of autoregulation.

Brain function critically depends on a close matching between metabolic demands, appropriate delivery of oxygen and nutrients, and removal of cellular waste. This matching requires continuous regulation of cerebral blood flow (CBF), which can be categorized into four broad topics: 1) autoregulation, which describes the response of the cerebrovasculature to changes in perfusion pressure; 2) vascular reactivity to vasoactive stimuli [including carbon dioxide (CO2)]; 3) neurovascular coupling (NVC), i.e., the CBF response to local changes in neural activity (often standardized cognitive stimuli in humans); and 4) endothelium-dependent responses. This review focuses primarily on autoregulation and its clinical implications. To place autoregulation in a more precise context, and to better understand integrated approaches in the cerebral circulation, we also briefly address reactivity to CO2 and NVC. In addition to our focus on effects of perfusion pressure (or blood pressure), we describe the impact of select stimuli on regulation of CBF (i.e., arterial blood gases, cerebral metabolism, neural mechanisms, and specific vascular cells), the interrelationships between these stimuli, and implications for regulation of CBF at the level of large arteries and the microcirculation. We review clinical implications of autoregulation in aging, hypertension, stroke, mild cognitive impairment, anesthesia, and dementias. Finally, we discuss autoregulation in the context of common daily physiological challenges, including changes in posture (e.g., orthostatic hypotension, syncope) and physical activity.

Cerebrovascular Endothelial Dysfunction: Role of BACE1.

Dysfunctional endothelium is increasingly recognized as a mechanistic link between cardiovascular risk factors and dementia, including Alzheimer disease. BACE1 (ß-site amyloid-ß precursor protein-cleaving enzyme 1) is responsible for ß-processing of APP (amyloid-ß precursor protein), the first step in the production of Aß (amyloid-ß) peptides, major culprits in the pathogenesis of Alzheimer disease. Under pathological conditions, excessive activation of BACE1 exerts detrimental effects on endothelial function by Aß-dependent and Aß-independent mechanisms. High local concentration of Aß in the brain blood vessels is responsible for the loss of key vascular protective functions of endothelial cells. More recent studies recognized significant contribution of Aß-independent proteolytic activity of endothelial BACE1 to the pathogenesis of endothelial dysfunction. This review critically evaluates existing evidence supporting the concept that excessive activation of BACE1 expressed in the cerebrovascular endothelium impairs key homeostatic functions of the brain blood vessels. This concept has important therapeutic implications. Indeed, improved understanding of the mechanisms of endothelial dysfunction may help in efforts to develop new approaches to the protection and preservation of healthy cerebrovascular function.

From Software to Hardware: A Case Series of Functional Neurological Symptoms and Cerebrovascular Disease.

OBJECTIVE: Neuroimaging studies have identified alterations in both brain structure and functional connectivity in patients with functional neurological disorder (FND). For many patients, FND emerges from physical precipitating events. Nevertheless, there are a limited number of case series in the literature that describe the clinical presentation and neuroimaging correlates of FND following cerebrovascular disease. METHODS: The authors collected data from two clinics in the United Kingdom on 14 cases of acute, improving, or delayed functional neurological symptoms following cerebrovascular events. RESULTS: Most patients had functional neurological symptoms that were localized to cerebrovascular lesions, and the lesions mapped onto regions known to be part of functional networks disrupted in FND, including the thalamus, anterior cingulate gyrus, insula, and temporoparietal junction. CONCLUSIONS: The findings demonstrate that structural lesions can lead to FND symptoms, possibly explained through changes in relevant mechanistic functional networks.

Two surgical strategies (early carotid reperfusion vs. Central aortic repair-first) of acute type a aortic dissection complicated with cerebral malperfusion syndrome: a meta-analysis and systematic review.

OBJECTIVE: Cerebral malperfusion (CM) is a common comorbidity in acute type A aortic dissection (ATAAD), which is associated with high mortality and poor neurological prognosis. This meta-analysis investigated the surgical strategy of ATAAD patients with CM, aiming to compare the difference in therapeutic effectiveness between the central repair-first and the early reperfusion-first according to clinical outcomes. METHODS: The meta-analysis and systematic review was conducted based on studies sourced from the PubMed, Embase, and Cochrane literature database, in which cases of ATAAD with CM underwent surgical repair were included. Data for baseline characteristics, mortality, survival were extracted, and risk ratio (RR) values and the pooled mortality were calculated. RESULTS: A total of 17 retrospective studies were analyzed, including 1010 cases of ATAAD with CM underwent surgical repair. The pooled early mortality in early reperfusion group was lower (8.1%; CI, 0.02 to 0.168) than that in the central repair group (16.2%; CI, 0.115 to 0.216). The pooled long-term mortality was 7.9% in the early reperfusion cohort and 17.4% the central repair-first cohort, without a statistically significant heterogeneity (I [2] = 51.271%; p = 0.056). The mean time of symptom-onset-to-the-operation-room in all the reports was 8.87 ± 12.3 h. CONCLUSION: This meta-analysis suggested that early reperfusion-first may achieved better outcomes compared to central repair-first in ATAAD patients complicated with CM to some extent. Early operation and early restoration of cerebral perfusion may reduce the occurrence of some neurological complications. TRIAL REGISTRATION: The meta-analysis was registered in the International Prospective Register of Systematic Reviews database (No. CRD CRD42023475629) on Nov. 8th, 2023.

mTOR Attenuation with Rapamycin Reverses Neurovascular Uncoupling and Memory Deficits in Mice Modeling Alzheimer's Disease.

Vascular dysfunction is a universal feature of aging and decreased cerebral blood flow has been identified as an early event in the pathogenesis of Alzheimer's disease (AD). Cerebrovascular dysfunction in AD includes deficits in neurovascular coupling (NVC), a mechanism that ensures rapid delivery of energy substrates to active neurons through the blood supply. The mechanisms underlying NVC impairment in AD, however, are not well understood. We have previously shown that mechanistic/mammalian target of rapamycin (mTOR) drives cerebrovascular dysfunction in models of AD by reducing the activity of endothelial nitric oxide synthase (eNOS), and that attenuation of mTOR activity with rapamycin is sufficient to restore eNOS-dependent cerebrovascular function. Here we show mTOR drives NVC impairments in an AD model through the inhibition of neuronal NOS (nNOS)- and non-NOS-dependent components of NVC, and that mTOR attenuation with rapamycin is sufficient to restore NVC and even enhance it above WT responses. Restoration of NVC and concomitant reduction of cortical amyloid-ß levels effectively treated memory deficits in 12-month-old hAPP(J20) mice. These data indicate that mTOR is a critical driver of NVC dysfunction and underlies cognitive impairment in an AD model. Together with our previous findings, the present studies suggest that mTOR promotes cerebrovascular dysfunction in AD, which is associated with early disruption of nNOS activation, through its broad negative impact on nNOS as well as on non-NOS components of NVC. Our studies highlight the potential of mTOR attenuation as an efficacious treatment for AD and potentially other neurologic diseases of aging.SIGNIFICANCE STATEMENT Failure of the blood flow response to neuronal activation [neurovascular coupling (NVC)] in a model of AD precedes the onset of AD-like cognitive symptoms and is driven, to a large extent, by mammalian/mechanistic target of rapamycin (mTOR)-dependent inhibition of nitric oxide synthase activity. Our studies show that mTOR also drives AD-like failure of non-nitric oxide (NO)-mediated components of NVC. Thus, mTOR attenuation may serve to treat AD, where we find that neuronal NO synthase is profoundly reduced early in disease progression, and potentially other neurologic diseases of aging with cerebrovascular dysfunction as part of their etiology.

Spreading Depression, Spreading Depolarizations, and the Cerebral Vasculature.

Spreading depression (SD) is a transient wave of near-complete neuronal and glial depolarization associated with massive transmembrane ionic and water shifts. It is evolutionarily conserved in the central nervous systems of a wide variety of species from locust to human. The depolarization spreads slowly at a rate of only millimeters per minute by way of grey matter contiguity, irrespective of functional or vascular divisions, and lasts up to a minute in otherwise normal tissue. As such, SD is a radically different breed of electrophysiological activity compared with everyday neural activity, such as action potentials and synaptic transmission. Seventy years after its discovery by Leão, the mechanisms of SD and its profound metabolic and hemodynamic effects are still debated. What we did learn of consequence, however, is that SD plays a central role in the pathophysiology of a number of diseases including migraine, ischemic stroke, intracranial hemorrhage, and traumatic brain injury. An intriguing overlap among them is that they are all neurovascular disorders. Therefore, the interplay between neurons and vascular elements is critical for our understanding of the impact of this homeostatic breakdown in patients. The challenges of translating experimental data into human pathophysiology notwithstanding, this review provides a detailed account of bidirectional interactions between brain parenchyma and the cerebral vasculature during SD and puts this in the context of neurovascular diseases.

Risk Factors, Lifestyle Behaviors, and Vascular Brain Health.

Although a relationship between traditional cardiovascular risk factors and stroke has long been recognized, these risk factors likely play a role in other aspects of brain health. Clinical stroke is only the tip of the iceberg of vascular brain injury that includes covert infarcts, white matter hyperintensities, and microbleeds. Furthermore, an individual's risk for not only stroke but poor brain health includes not only these traditional vascular risk factors but also lifestyle and genetic factors. The purpose of this narrative review is to summarize the state of the evidence on traditional and nontraditional vascular risk factors and their contributions to brain health. Additionally, we will review important modifiers that interact with these risk factors to increase, or, in some cases, reduce risk of adverse brain health outcomes, with an emphasis on genes and biomarkers associated with Alzheimer disease. Finally, we will consider the importance of social determinants of health in brain health outcomes.

Vascular Contributions to Brain Health: Cross-Cutting Themes.

As life expectancy grows, brain health is increasingly seen as central to what we mean by successful aging-and vascular brain health as central to overall brain health. Cerebrovascular pathologies are highly prevalent independent contributors to age-related cognitive impairment and at least partly modifiable with available treatments. The current Focused Update addresses vascular brain health from multiple angles, ranging from pathophysiologic mechanisms and neuroimaging features to epidemiologic risk factors, social determinants, and candidate treatments. Here we highlight some of the shared themes that cut across these distinct perspectives: (1) the lifetime course of vascular brain injury pathogenesis and progression; (2) the scientific and ethical imperative to extend vascular brain health research in non-White and non-affluent populations; (3) the need for improved tools to study the cerebral small vessels themselves; (4) the potential role for brain recovery mechanisms in determining vascular brain health and resilience; and (5) the cross-pathway mechanisms by which vascular and neurodegenerative processes may interact. The diverse perspectives featured in this Focused Update offer a sense of the multidisciplinary approaches and collaborations that will be required to launch our populations towards improved brain health and successful aging.

Inflammation and the Link to Vascular Brain Health: Timing Is Brain.

Inflammation and its myriad pathways are now recognized to play both causal and consequential roles in vascular brain health. From acting as a trigger for vascular brain injury, as evidenced by the COVID-19 pandemic, to steadily increasing the risk for chronic cerebrovascular disease, distinct inflammatory cascades play differential roles in varying states of cerebrovascular injury. New evidence is regularly emerging that characterizes the role of specific inflammatory pathways in these varying states including those at risk for stroke and chronic cerebrovascular injury as well as during the acute, subacute, and repair phases of stroke. Here, we aim to highlight recent basic science and clinical evidence for many distinct inflammatory cascades active in these varying states of cerebrovascular injury. The role of cerebrovascular infections, spotlighted by the severe acute respiratory syndrome coronavirus 2 pandemic, and its association with increased stroke risk is also reviewed. Rather than converging on a shared mechanism, these emerging studies implicate varied and distinct inflammatory processes in vascular brain injury and repair. Recognition of the phasic nature of inflammatory cascades on varying states of cerebrovascular disease is likely essential to the development and implementation of an anti-inflammatory strategy in the prevention, treatment, and repair of vascular brain injury. Although advances in revascularization have taught us that time is brain, targeting inflammation for the treatment of cerebrovascular disease will undoubtedly show us that timing is brain.

Noninvasive Characterization of Human Glymphatics and Meningeal Lymphatics in an in vivo Model of Blood-Brain Barrier Leakage.

OBJECTIVE: To evaluate human glymphatics and meningeal lymphatics noninvasively. METHODS: This prospective study implemented 3-dimensional (3D) isotropic contrast-enhanced T2 fluid-attenuated inversion recovery (CE-T2-FLAIR) imaging with a 3T magnetic resonance machine to study cerebral glymphatics and meningeal lymphatics in patients with reversible cerebral vasoconstriction syndrome (RCVS) with (n = 92) or without (n = 90) blood-brain barrier (BBB) disruption and a diseased control group with cluster headache (n = 35). The contrast agent gadobutrol (0.2mmol/kg [0.2ml/kg]) was administered intravenously in all study subjects. RESULTS: In total, 217 patients (182 RCVS, 35 cluster headache) were analyzed and separated into 2 groups based on the presence or absence of visible gadolinium (Gd) leakage. Para-arterial tracer enrichment was clearly depicted in those with overt BBB disruption, while paravenous and parasinus meningeal contrast enrichment was evident in both groups. Paravenous and parasinus contrast enrichment remained in RCVS patients in the remission stage and in cluster headache patients, suggesting that these meningeal lymphatic channels were universal anatomical structures rather than being phase- or condition-specific. Additionally, we demonstrated nodular leptomeningeal enhancement in 32.3% of participants, which might represent potential lymphatic reservoirs. Four selected RCVS patients who received consecutive contrasted 3D isotropic FLAIR imaging after gadobutrol administration showed that the Gd persisted for at least 54 minutes and was completely cleared within 18 hours. INTERPRETATION: This large-scale in vivo study successfully demonstrated the putative human para-arterial glymphatic transports and meningeal lymphatics by clear depiction of para-arterial, parasinus, and paravenous meningeal contrast enrichment using high-resolution 3D isotropic CE-T2-FLAIR imaging noninvasively; this technique may serve as a basis for further studies to delineate clinical relevance of glymphatic clearance. ANN NEUROL 2021;89:111-124.

Circulating microRNAs Associated With Reversible Cerebral Vasoconstriction Syndrome.

OBJECTIVE: The purpose of this study was to investigate the significance of circulating micro RNAs (miRNAs) in the pathogenesis of reversible cerebral vasoconstriction syndrome (RCVS). METHODS: We prospectively recruited 3 independent cohorts of patients with RCVS and age-matched and sex-matched controls in a single medical center. Next-generation small RNA sequencing followed by quantitative polymerase chain reaction (PCR) was used to identify and validate differentially expressed miRNAs, which was cross-validated in migraine patients in ictal stage or interictal stage. Computational analysis was used to predict the target genes of miRNAs, followed by in vitro functional analysis. RESULTS: We identified a panel of miRNAs including miR-130a-3p, miR-130b-3p, let-7a-5p, let-7b-5p, and let-7f-5p that well differentiated patients with RCVS from controls (area under the receiver operating characteristics curve [AUC] was 0.906, 0.890, and 0.867 in the 3 cohorts, respectively). The abundance of let-7a-5p, let-7b-5p, and let-7f-5p, but not miR-130a-3p nor miR-130b-3p, was significantly higher in patients with ictal migraine compared with that of controls and patients with interictal migraine. Target prediction and pathway enrichment analysis suggested that the transforming growth factor-ß signaling pathway and endothelin-1 responsible for vasomotor control might link these miRNAs to RCVS pathogenesis, which was confirmed in vitro by transfecting miRNAs mimics or incubating the patients' cerebrospinal fluid (CSF) in 3 different vascular endothelial cells. Moreover, miR-130a-3p was associated with imaging-proven disruption of the blood-brain barrier (BBB) in patients with RCVS and its overexpression led to reduced transendothelial electrical resistance (ie, increased permeability) in in vitro human BBB model. INTERPRETATION: We identified the circulating miRNA signatures associated with RCVS, which may be functionally linked to its headache, BBB integrity, and vasomotor function. ANN NEUROL 2021;89:459-473.

Cerebral blood flow regulation and neurovascular dysfunction in Alzheimer disease.

Cerebral blood flow (CBF) regulation is essential for normal brain function. The mammalian brain has evolved a unique mechanism for CBF control known as neurovascular coupling. This mechanism ensures a rapid increase in the rate of CBF and oxygen delivery to activated brain structures. The neurovascular unit is composed of astrocytes, mural vascular smooth muscle cells and pericytes, and endothelia, and regulates neurovascular coupling. This Review article examines the cellular and molecular mechanisms within the neurovascular unit that contribute to CBF control, and neurovascular dysfunction in neurodegenerative disorders such as Alzheimer disease.

Cerebrovascular alterations in NAFLD: Is it increasing our risk of Alzheimer's disease?

Non-alcoholic fatty liver disease (NAFLD) is a multisystem disease, which has been classified as an emerging epidemic not only confined to liver-related morbidity and mortality. It is also becoming apparent that NAFLD is associated with moderate cerebral dysfunction and cognitive decline. A possible link between NAFLD and Alzheimer's disease (AD) has only recently been proposed due to the multiple shared genes and pathological mechanisms contributing to the development of these conditions. Although AD is a progressive neurodegenerative disease, the exact pathophysiological mechanism remains ambiguous and similarly to NAFLD, currently available pharmacological therapies have mostly failed in clinical trials. In addition to the usual suspects (inflammation, oxidative stress, blood-brain barrier alterations and ageing) that could contribute to the NAFLD-induced development and progression of AD, changes in the vasculature, cerebral perfusion and waste clearance could be the missing link between these two diseases. Here, we review the most recent literature linking NAFLD and AD, focusing on cerebrovascular alterations and the brain's clearance system as risk factors involved in the development and progression of AD, with the aim of promoting further research using neuroimaging techniques and new mechanism-based therapeutic interventions.

Relationship Between Central Artery Stiffness, Brain Arterial Dilation, and White Matter Hyperintensities in Older Adults: The ARIC Study-Brief Report.

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Modifications in Near Infrared Spectroscopy for Cerebral Monitoring During Carotid Endarterectomy in Asymptomatic and Symptomatic Patients.

BACKGROUND: To evaluate trends and differences in Near Infrared Spectroscopy (NIRS) monitoring during carotid endarterectomy (CEA) in patients affected by asymptomatic and symptomatic carotid artery stenosis, to predict postoperative neurological complications (PNCs). METHODS: NIRS data of CEAs performed in a University Hospital were retrospectively reviewed. All the interventions were performed under general anesthesia and patients with intraoperative complications were excluded. Mean regional Oxygen Saturation Index (rSO2), pre-clamp values (mean baseline value, MBv and Single Mark Baseline value, SMBv) were collected and compared to the lowest rSO2 values during carotid cross-clamp (LSO2v) calculated within 3 min (percentage drop, PD). ROC curve analysis with Youden's Test was performed to determine the best threshold value of PD, in order to identify PNCs in both asymptomatic and symptomatic groups. RESULTS: Between 2007 and 2015, a total of 399 CEAs were consecutively performed with NIRS monitoring. Three-hundred-seventy-two CEAs in 355 patients were reviewed. Asymptomatic stenoses were 291 (81.9%), eleven (2.9%) PNC were registered (5 in asymptomatic and 6 in symptomatic group). Asymptomatic and symptomatic diseases had different MBv (69.5 ± 7.5 vs. 71.8 ± 6.9, respectively; P = 0.011) and similar rSO2 value during carotid clamping (63.7 ± 8.0 vs. 63.7 ± 6.7, respectively: P = 0.958). Asymptomatic patients experiencing PNCs had a greater PD than non-PNCs group (20.5 ± 10.2% vs. 12.5 ± 7.6%, respectively using MBv as baseline value; P = 0.002), in contrast, in symptomatic patients, in which a low PD was associated with PNCs, it does not reach statistical significance (using MBv, 12.6 ± 5.4% vs. 14.8 ± 6.7%, respectively; P= 0.476). In order to detect PNCs, ROC analysis revealed an optimal PD cut-off value of -17% in asymptomatic CEAs. (Sensibility (Se) 0.80, Specificity (Sp) 0.76, PPV 0.05, NPV 0.99, Youden's index 0.56; P = 0.020) In symptomatic a threshold value of -9% was found, without reaching statistical significance. CONCLUSIONS: NIRS as cerebral monitoring during CEA can predict PNCs in asymptomatic stenosis. Asymptomatic and symptomatic groups differ in baseline and intraprocedural cut-off values to detect an augmented PNCs risk.

Acute cerebral venous outflow obstruction during convexity meningioma resection.

BACKGROUND: Cerebral venous outflow obstruction involves idiopathic intracranial hypertension, and the most common related condition is dural venous sinus stenosis or, in other words, an obstruction of the dural venous sinuses. In these cases, the pathological process is often chronic, displays only mild symptoms, and rarely requires urgent surgical intervention. In this study, we present a unique case involving an acute cerebral venous outflow obstruction that occurred during meningioma resection that ultimately had catastrophic consequences. MATERIALS AND METHODS: The patient's preoperative imaging only revealed an unremarkable frontal convexity meningioma with an average diameter exceeding 8 cm. She was admitted for a scheduled right frontoparietal craniotomy for lesion resection. RESULTS: The patient's unique congenital dural venous sinus structure along with a non-surgical epidural hematoma both contributed to a catastrophic outcome, causing a progressive hemispheric encephalocele, significant blood loss, and wound closure difficulties. CONCLUSION: Neurosurgeons should place an additional focus on cerebral venous outflow patency during tumor resection, even if the tumor does not involve the transverse or sigmoid sinuses. It is well known that the tacking sutures play an essential role in preventing an epidural hematoma, but the procedure to mitigate hematomas occurring outside the surgical field of view is not fully recognized by neurosurgeons. If dural tacking sutures are placed after complete tumor resection, the prophylactic effect for preventing EDH in the non-surgical areas may not be guaranteed. Therefore, we strongly advocate for the tacking sutures to be accurately placed before dural incisions are made.

tPA Deficiency Underlies Neurovascular Coupling Dysfunction by Amyloid-ß.

The amyloid-ß (Aß) peptide, a key pathogenic factor in Alzheimer's disease, attenuates the increase in cerebral blood flow (CBF) evoked by neural activity (functional hyperemia), a vital homeostatic response in which NMDA receptors (NMDARs) play a role through nitric oxide, and the CBF increase produced by endothelial factors. Tissue plasminogen activator (tPA), which is reduced in Alzheimer's disease and in mouse models of Aß accumulation, is required for the full expression of the NMDAR-dependent component of functional hyperemia. Therefore, we investigated whether tPA is involved in the neurovascular dysfunction of Aß. tPA activity was reduced, and the tPA inhibitor plasminogen inhibitor-1 (PAI-1) was increased in male mice expressing the Swedish mutation of the amyloid precursor protein (tg2576). Counteracting the tPA reduction with exogenous tPA or with pharmacological inhibition or genetic deletion of PAI-1 completely reversed the attenuation of the CBF increase evoked by whisker stimulation but did not ameliorate the response to the endothelium-dependent vasodilator acetylcholine. The tPA deficit attenuated functional hyperemia by suppressing NMDAR-dependent nitric oxide production during neural activity. Pharmacological inhibition of PAI-1 increased tPA activity, prevented neurovascular uncoupling, and ameliorated cognition in 11- to 12-month-old tg2576 mice, effects associated with a reduction of cerebral amyloid angiopathy but not amyloid plaques. The data unveil a selective role of the tPA in the suppression of functional hyperemia induced by Aß and in the mechanisms of cerebral amyloid angiopathy, and support the possibility that modulation of the PAI-1-tPA pathway may be beneficial in diseases associated with amyloid accumulation.SIGNIFICANCE STATEMENT Amyloid-ß (Aß) peptides have profound neurovascular effects that may contribute to cognitive impairment in Alzheimer's disease. We found that Aß attenuates the increases in blood flow evoked by neural activation through a reduction in tissue plasminogen activator (tPA) caused by upregulation of its endogenous inhibitor plasminogen inhibitor-1 (PAI-1). tPA deficiency prevents NMDA receptors from triggering nitric oxide production, thereby attenuating the flow increase evoked by neural activity. PAI-1 inhibition restores tPA activity, rescues neurovascular coupling, reduces amyloid deposition around blood vessels, and improves cognition in a mouse model of Aß accumulation. The findings demonstrate a previously unappreciated role of tPA in Aß-related neurovascular dysfunction and in vascular amyloid deposition. Restoration of tPA activity could be of therapeutic value in diseases associated with amyloid accumulation.

Detection of Large Vessel Occlusion Stroke in the Prehospital Setting: Electroencephalography as a Potential Triage Instrument.

A reliable and fast instrument for prehospital detection of large vessel occlusion (LVO) stroke would be a game-changer in stroke care, because it would enable direct transportation of LVO stroke patients to the nearest comprehensive stroke center for endovascular treatment. This strategy would substantially improve treatment times and thus clinical outcomes of patients. Here, we outline our view on the requirements of an effective prehospital LVO detection method, namely: high diagnostic accuracy; fast application and interpretation; user-friendliness; compactness; and low costs. We argue that existing methods for prehospital LVO detection, including clinical scales, mobile stroke units and transcranial Doppler, do not fulfill all criteria, hindering broad implementation of these methods. Instead, electroencephalography may be suitable for prehospital LVO detection since in-hospital studies have shown that quantification of hypoxia-induced changes in the electroencephalography signal have good diagnostic accuracy for LVO stroke. Although performing electroencephalography measurements in the prehospital setting comes with challenges, solutions for fast and simple application of this method are available. Currently, the feasibility and diagnostic accuracy of electroencephalography in the prehospital setting are being investigated in clinical trials.

The association of epigenetic clocks in brain tissue with brain pathologies and common aging phenotypes.

Epigenetic clocks are calculated by combining DNA methylation states across select CpG sites to estimate biologic age, and have been noted as the most successful markers of biologic aging to date. Yet, limited research has considered epigenetic clocks calculated in brain tissue. We used DNA methylation states in dorsolateral prefrontal cortex specimens from 721 older participants of the Religious Orders Study and Rush Memory and Aging Project, to calculate DNA methylation age using four established epigenetic clocks: Hannum, Horvath, PhenoAge, GrimAge, and a new Cortical clock. The four established clocks were trained in blood samples (Hannum, PhenoAge, GrimAge) or using 51 human tissue and cell types (Horvath); the recent Cortical clock is the first trained in postmortem cortical tissue. Participants were recruited beginning in 1994 (Religious Orders Study) and 1997 (Memory and Aging Project), and followed annually with questionnaires and clinical evaluations; brain specimens were obtained for 80-90% of participants. Mean age at death was 88.0 (SD 6.7) years. We used linear regression, logistic regression, and linear mixed models, to examine relations of epigenetic clock ages to neuropathologic and clinical aging phenotypes, controlling for chronologic age, sex, education, and depressive symptomatology. Hannum, Horvath, PhenoAge and Cortical clock ages were related to pathologic diagnosis of Alzheimer's disease (AD), as well as to Aß load (a hallmark pathology of Alzheimer's disease). However, associations were substantially stronger for the Cortical than other clocks; for example, each standard deviation (SD) increase in Hannum, Horvath, and PhenoAge clock age was related to approximately 30% greater likelihood of pathologic AD (all p < 0.05), while each SD increase in Cortical age was related to 90% greater likelihood of pathologic AD (odds ratio = 1.91, 95% confidence interval 1.38, 2.62). Moreover, Cortical age was significantly related to other AD pathology (eg, mean tau tangle density, p = 0.003), and to odds of neocortical Lewy body pathology (for each SD increase in Cortical age, odds ratio = 2.00, 95% confidence 1.27, 3.17), although no clocks were related to cerebrovascular neuropathology. Cortical age was the only epigenetic clock significantly associated with the clinical phenotypes examined, from dementia to cognitive decline (5 specific cognitive systems, and a global cognitive measure averaging 17 tasks) to Parkinsonian signs. Overall, our findings provide evidence of the critical necessity for bespoke clocks of brain aging for advancing research to understand, and eventually prevent, neurodegenerative diseases of aging.

Hydroxycarbamide treatment reduces transcranial Doppler velocity in the absence of transfusion support in children with sickle cell anaemia, elevated transcranial Doppler velocity, and cerebral vasculopathy: the EXTEND trial.

EXpanding Treatment for Existing Neurological Disease (EXTEND) investigated whether hydroxycarbamide lowers transcranial Doppler (TCD) velocities in Jamaican children with sickle cell anaemia (SCA) and elevated TCD velocity with or without previous stroke. Forty-three children (age 2-17 years) with baseline maximum time-averaged mean velocity (TAMV) ≥ 170 cm/s were stratified into three risk categories based on treatment status and stroke history: Group 1 (no history of stroke, on hydroxycarbamide, n = 12); and Groups 2 (no stroke, no hydroxycarbamide, n = 21) and 3 (previous stroke, no hydroxycarbamide, n = 10). Open-label hydroxycarbamide at 20 mg/kg/day was commenced, with escalation to maximum tolerated dose (MTD) based on mild marrow suppression (average dose 25·4 ± 4·5 mg/kg/day). TCD was performed every six months with brain magnetic resonance imaging (MRI)/magnetic resonance angiography (MRA) at baseline and after 18-months of hydroxycarbamide. The maximum TAMV decreased significantly compared to baseline (24 ± 30 cm/s, P < 0·0001), with similar declines in all groups. Clinical stroke occurred in five children, one in Group 1, none in Group 2, and four in Group 3, P = 0·0032, comparing group incidence rates. Brain MRI/MRA was stable in children without clinical stroke. EXTEND documents the feasibility and benefits of hydroxycarbamide at MTD to lower TCD velocities and reduce stroke risk in children with SCA and no history of primary stroke in low-resource settings without transfusion management.