Exosomes: the next-generation therapeutic platform for ischemic stroke.

Current therapeutic strategies for ischemic stroke fall short of the desired objective of neurological functional recovery. Therefore, there is an urgent need to develop new methods for the treatment of this condition. Exosomes are natural cell-derived vesicles that mediate signal transduction between cells under physiological and pathological conditions. They have low immunogenicity, good stability, high delivery efficiency, and the ability to cross the blood-brain barrier. These physiological properties of exosomes have the potential to lead to new breakthroughs in the treatment of ischemic stroke. The rapid development of nanotechnology has advanced the application of engineered exosomes, which can effectively improve targeting ability, enhance therapeutic efficacy, and minimize the dosages needed. Advances in technology have also driven clinical translational research on exosomes. In this review, we describe the therapeutic effects of exosomes and their positive roles in current treatment strategies for ischemic stroke, including their anti-inflammation, anti-apoptosis, autophagy-regulation, angiogenesis, neurogenesis, and glial scar formation reduction effects. However, it is worth noting that, despite their significant therapeutic potential, there remains a dearth of standardized characterization methods and efficient isolation techniques capable of producing highly purified exosomes. Future optimization strategies should prioritize the exploration of suitable isolation techniques and the establishment of unified workflows to effectively harness exosomes for diagnostic or therapeutic applications in ischemic stroke. Ultimately, our review aims to summarize our understanding of exosome-based treatment prospects in ischemic stroke and foster innovative ideas for the development of exosome-based therapies.

Beat-to-Beat Blood Pressure Variability Within 24 Hours of Ischemic Stroke Onset: A Potential Predictor of Functional Prognosis.

BACKGROUND: Beat-to-beat blood pressure variability (BPV) is based on each heartbeat and represents a dynamic equilibrium process modulated by artery and cardiac involvement of pressure-receptive reflexes. To date, there remains a lack of prospective studies illustrating the clinical value of beat-to-beat BPV within 24 hours of acute ischemic stroke onset. METHODS AND RESULTS: This study prospectively monitored beat-to-beat blood pressure and heart rate in patients with acute ischemic stroke within 24 hours of onset using a noninvasive plethysmograph and calculated beat-to-beat BPV, heart rate variability, and the cross-correlation baroreflex sensitivity. A modified Rankin Scale score of ≥2 at 90 days was defined as an unfavorable prognosis. Multivariate logistic regression was performed, and the nomogram model was developed by adding the beat-to-beat BPV to the traditional model for predicting prognosis. Beat-to-beat BPV increased significantly in the unfavorable outcome group (P<0.05) compared with that in the favorable outcome group, whereas no difference was observed in beat-to-beat heart rate variability and cross-correlation baroreflex sensitivity between both groups (P>0.05). Furthermore, beat-to-beat BPV within 24 hours of acute ischemic stroke onset was independently associated with unfavorable outcome at 90 days (P<0.005). The addition of beat-to-beat BPV to the traditional model for predicting prognosis enhanced the area under the receiver operating characteristic curve from 0.816 to 0.830. CONCLUSIONS: Increased beat-to-beat BPV within 24 hours of acute ischemic stroke onset was independently associated with a poor prognosis at 90 days and may be a potential predictor for discriminating unfavorable prognosis.

Targeted exosome-based nanoplatform for new-generation therapeutic strategies.

Exosomes, typically 30-150 nm in size, are lipid-bilayered small-membrane vesicles originating in endosomes. Exosome biogenesis is regulated by the coordination of various mechanisms whereby different cargoes (e.g. proteins, nucleic acids, and lipids) are sorted into exosomes. These components endow exosomes with bioregulatory functions related to signal transmission and intercellular communication. Exosomes exhibit substantial potential as drug-delivery nanoplatforms owing to their excellent biocompatibility and low immunogenicity. Proteins, miRNA, siRNA, mRNA, and drugs have been successfully loaded into exosomes, and these exosome-based delivery systems show satisfactory therapeutic effects in different disease models. To enable targeted drug delivery, genetic engineering and chemical modification of the lipid bilayer of exosomes are performed. Stimuli-responsive delivery nanoplatforms designed with appropriate modifications based on various stimuli allow precise control of on-demand drug delivery and can be utilized in clinical treatment. In this review, we summarize the general properties, isolation methods, characterization, biological functions, and the potential role of exosomes in therapeutic delivery systems. Moreover, the effective combination of the intrinsic advantages of exosomes and advanced bioengineering, materials science, and clinical translational technologies are required to accelerate the development of exosome-based delivery nanoplatforms.

Heart Rate Variability in Patients with Spontaneous Intracerebral Hemorrhage and its Relationship with Clinical Outcomes.

BACKGROUND: Although abnormal heart rate variability (HRV) is frequently observed in patients with spontaneous intracerebral hemorrhage (ICH), its time course and presentation of different indices remain unclear, and few studies have focused on its association with clinical outcomes. METHODS: We prospectively recruited consecutive patients with spontaneous ICH between June 2014 and June 2021. HRV was evaluated twice during hospitalization (within 7 days and 10-14 days after stroke). Time and frequency domain indices were calculated. A modified Rankin Scale score ≥ 3 at 3 months was defined as a poor outcome. RESULTS: Finally, 122 patients with ICH and 122 age- and sex-matched volunteers were included. Compared with controls, time domain and absolute frequency domain HRV parameters (total power, low frequency [LF], and high frequency [HF]) in the ICH group were significantly decreased within 7 days and 10-14 days. For relative values, normalized LF (LF%) and LF/HF were significantly higher, whereas normalized HF (HF%) was significantly lower, in the patient group than in the control group. Furthermore, LF% and HF% measured at 10-14 days were independently associated with 3-month outcomes. CONCLUSIONS: HRV values were impaired significantly within 14 days after ICH. Furthermore, HRV indices measured 10-14 days after ICH were independently associated with 3-month outcomes.

Changes in cerebral autoregulation, stroke-related blood biomarkers, and autonomic regulation after patent foramen ovale closure in severe migraine patients.

AIMS: This study aimed to investigate changes in dynamic cerebral autoregulation (dCA), 20 stroke-related blood biomarkers, and autonomic regulation after patent foramen ovale (PFO) closure in severe migraine patients. METHODS: Patent foramen ovale severe migraine patients, matched non-PFO severe migraine patients, and healthy controls were included. dCA and autonomic regulation were evaluated in each participant at baseline, and within 48-h and 30 days after closure in PFO migraineurs. A panel of stroke-related blood biomarkers was detected pre-surgically in arterial-and venous blood, and post-surgically in the arterial blood in PFO migraineurs. RESULTS: Forty-five PFO severe migraine patients, 50 non-PFO severe migraine patients, and 50 controls were enrolled. The baseline dCA function of PFO migraineurs was significantly lower than that of non-PFO migraineurs and controls but was rapidly improved with PFO closure, remaining stable at 1-month follow-up. Arterial blood platelet-derived growth factor-BB (PDGF-BB) levels were higher in PFO migraineurs than in controls, which was immediately and significantly reduced after closure. No differences in autonomic regulation were observed among the three groups. CONCLUSION: Patent foramen ovale closure can improve dCA and alter elevated arterial PDGF-BB levels in migraine patients with PFO, both of which may be related to the preventive effect of PFO closure on stroke occurrence/recurrence.

Time course of beat-to-beat blood pressure variability and outcome in patients with spontaneous intracerebral haemorrhage.

OBJECTIVES: Increased blood pressure variability (BPV) over 24 h or longer was associated with poor clinical outcomes in patients with intracerebral haemorrhage (ICH). However, the characteristics of beat-to-beat BPV, a rapid assessment of BPV and its association with outcome in ICH patients remain unknown. METHODS: We consecutively and prospectively recruited patients with ICH between June 2014 and December 2020. Five-minute noninvasive beat-to-beat recordings were measured serially at three time points, 1-2, 4-6 and 10-12 days after ICH onset. BPV was calculated using standard deviation (SD) and variation independent of mean (VIM). Favourable outcome was defined as modified Rankin Scale score of less than 2 at 90 days. RESULTS: The analysis included 66 participants (54.12 ±â€Š10.79 years; 71.2% men) and 66 age and sex-matched healthy controls. Compared with that in healthy adults, beat-to-beat BPV was significantly increased 1-2 days after ICH and was completely recovered 10-12 days later. BPV recorded 1-2 days after ICH onset was higher among patients with unfavourable outcomes than among those with favourable outcomes (all P < 0.05) and higher BPV on days 1-2 was independently associated with a 3-month unfavourable outcome after adjustment for major covariates. CONCLUSION: Beat-to-beat BPV was significantly increased among patients with ICH and could be completely recovered 10-12 days later. In addition, beat-to-beat BPV 1-2 days after ICH was independently associated with prognosis and could be regarded as a potential prognostic predictor and effective therapeutic target in the future.

Impaired dynamic cerebral autoregulation is associated with the severity of neuroimaging features of cerebral small vessel disease.

AIMS: Cerebral small vessel disease (CSVD) is characterized by functional and structural changes in small vessels. We aimed to elucidate the relationship between dynamic cerebral autoregulation (dCA) and neuroimaging characteristics of CSVD. METHODS: A case-control study was performed. Cerebral blood flow velocity (CBFV) of bilateral middle cerebral arteries and spontaneous arterial blood pressure were simultaneously recorded. Transfer function analysis was used to calculate dCA parameters (phase, gain, and the rate of recovery of CBFV [RoRc]). Neuroimaging characteristics of CSVD patients were evaluated, including lacunes, white matter hyperintensities (WMH), cerebral microbleeds (CMBs), perivascular spaces (PVS), and the total CSVD burden. RESULTS: Overall, 113 patients and 83 controls were enrolled. Compared with the control group, the phase at low frequency and the RoRc in CSVD patients were lower, and the gain at very low and low frequencies were higher, indicating bilaterally impaired dCA. Total CSVD burden, WMH (total, periventricular and deep), severe PVS, and lobar CMBs were independently correlated with the phase at low frequency. CONCLUSIONS: Our findings suggested that dCA was compromised in CSVD patients, and some specific neuroimaging characteristics (the total CSVD burden, WMH, severe PVS and lobar CMBs) might indicate more severe dCA impairment in CSVD patients.

Targeted nano-delivery strategies for facilitating thrombolysis treatment in ischemic stroke.

Ischemic stroke is one of the major causes of severe disability and death worldwide. It is mainly caused by a sudden reduction in cerebral blood flow due to obstruction of the supplying vessel by thrombi and subsequent initiation of a complex cascade of pathophysiological changes, which ultimately lead to brain ischemia and even irreversible infarction. Thus, timely and effective thrombolysis therapy remains a mainstay for acute ischemic stroke treatment. Tissue plasminogen activator (tPA), the only thrombolytic agent approved globally, provides substantial benefits by exerting a fibrinolysis effect, recovering the blood supply in occluded vessels and, thereby, salvaging the ischemic tissue. However, the clinical application of tPA was limited because of a few unsolved issues, such as a narrow therapeutic window, hemorrhagic complications, and limited thrombolytic efficacy, especially, for large thrombi. With the prosperous development of nanotechnology, a series of targeted delivery strategies and nanocomposites have been extensively investigated for delivering thrombolytic agents to facilitate thrombolysis treatment. Excitingly, numerous novel attempts have been reported to be effective in extending the half-life, targeting the thrombus site, and improving the thrombolytic efficacy in preclinical models. This article begins with a brief introduction to ischemic stroke, then describes the current state of thrombolysis treatment and, finally, introduces the application of various nanotechnology-based strategies for targeted delivery of thrombolytic agents. Representative studies are reviewed according to diverse strategies and nano-formulations, with the aim of providing integrated and up-to-date information and to improve the development of thrombolysis treatment for stroke patients.

Dynamic Cerebral Autoregulation in Embolic Stroke of Undetermined Source.

BACKGROUND AND PURPOSE: Dynamic cerebral autoregulation (dCA) in acute ischemic stroke is probably compromised. Although the characteristics of dCA in different types of stroke have been largely investigated, dCA in embolic stroke of undetermined source (ESUS) remains poorly understood. In this group, we aimed to elucidate the characteristics of dCA and their relevance to clinical outcomes. METHODS: The study enrolled 77 ESUS patients and 50 controls. Bilateral cerebral blood flow velocities (CBFV) of middle cerebral arteries and arterial blood pressure were simultaneously recorded using a transcranial Doppler combined with a servo-controlled finger plethysmograph. Transfer function analysis was used to obtain dCA parameters including phase, gain, coherence at very low frequency (VLF) and low frequency (LF), and the rate of recovery (RoRc) of CBFV. A multivariable logistic regression model was established to explore the relationship between dCA and clinical outcomes. RESULTS: Gain at VLF and LF, phase at LF, and RoRc of CBFV in bilateral hemispheres of the ESUS group were consistently worse than those of the control group (all P < 0.001). Bilateral RoRc of CBFV was significantly higher in patients with favorable outcomes than in those with unfavorable outcomes (stroke hemisphere: P < 0.001; non-stroke hemisphere, P = 0.029). Rate of recovery of CBFV in stroke hemisphere >13.3%/s was an independent predictor of favorable clinical outcomes (adjusted odds ratio = 30.95, 95% CI: 5.33-179.81, P < 0.001). CONCLUSIONS: Dynamic cerebral autoregulation was relatively impaired in both stroke and non-stroke hemispheres in ESUS patients, and functioning dCA after ESUS may indicate favorable clinical outcomes.

Venous sinus stenting improves cerebral autoregulation in a patient with venous sinus stenosis: a case report.

BACKGROUND: Venous sinus stenosis (VSS) is a type of cerebral venous vascular disease. Cerebral autoregulation is an indicator of cerebral arterial function. The cerebral circulatory system is composed of the venous system and arterial system. Impaired venous function may affect arterial function. Thus, cerebral venous stenosis may influence cerebral autoregulation. CASE PRESENTATION: In this case, a 50-year-old woman with transient blindness and headache was admitted to the hospital. The patient was diagnosed with VSS. A stent was placed at the stenosis. The stent released the intravenous pressure and remitted the patient's symptoms. Measurements of dynamic cerebral autoregulation (dCA) were performed at 3 time points: before stenting, after stenting, and 3 months later. The dCA gradually improved after stenting. CONCLUSION: VSS may have an influence on cerebral autoregulation, and effective treatment improves cerebral autoregulation in patients with VSS.

Compromised Dynamic Cerebral Autoregulation in Patients With Depression.

Background: Patients with depression tend to have various comorbid neurological symptoms, but the mechanisms remain unclear. The purpose of this study was to analyze the characteristics of dynamic cerebral autoregulation in depressed patients. Methods: Patients (aged ≥ 18 years) who were diagnosed with depression [17-item Hamilton Depression Rating Scale (HAMD) > 17] or suspected of depression (HAMD > 7) were enrolled in this study. Medically healthy volunteers were recruited as controls. The subjects also received the 7-item HAMD. We simultaneously recorded noninvasive continuous arterial blood pressure and bilateral middle cerebral artery blood flow velocity from each subject. Cerebral autoregulation was assessed by analyzing the phase difference using transfer function analysis. Results: This study enrolled 54 patients with suspected depression, 45 patients with depression, and 48 healthy volunteers. The mean phase difference values were significantly lower in the patients with depression (F = 9.071, P < 0.001). In the multiple regression analysis, depression was negatively correlated with the phase difference values. Conclusions: Dynamic cerebral autoregulation was compromised in patients with depression and negatively correlated with the depression score. Improving dynamic cerebral autoregulation may be a potential therapeutic method for treating the neurological symptoms of depression.

Changes in cerebral autoregulation and blood biomarkers after remote ischemic preconditioning.

OBJECTIVE: To determine the effect of remote ischemic preconditioning (RIPC) on dynamic cerebral autoregulation (dCA) and various blood biomarkers in healthy adults. METHODS: A self-controlled interventional study was conducted. Serial measurements of dCA were performed at 7 time points (7, 9, and 11 am; 2, 5, and 8 pm, and 8 am on the next day) without or with RIPC, carried out at 7:20 to 8 am. Venous blood samples were collected at baseline (7 am) and 1 hour after RIPC, and blood biomarkers, including 5 neuroprotective factors and 25 inflammation-related biomarkers, were measured with a quantitative protein chip. RESULTS: Fifty participants were enrolled (age 34.54 ± 12.01 years, 22 men). Compared with the results on the day without RIPC, dCA was significantly increased at 6 hours after RIPC, and the increase was sustained for at least 24 hours. After RIPC, 2 neuroprotective factors (glial cell-derived neurotrophic factor and vascular endothelial growth factor-A) and 4 inflammation-related biomarkers (transforming growth factor-ß1, leukemia inhibitory factor, matrix metallopeptidase-9, and tissue inhibitor of metalloproteinase-1) were significantly elevated compared with their baseline levels. Conversely, monocyte chemoattractant protein-1 was significantly lower compared with its baseline level. CONCLUSIONS: RIPC induces a sustained increase of dCA from 6 to at least 24 hours after treatment in healthy adults. In addition, several neuroprotective and inflammation-related blood biomarkers were differentially regulated shortly after RIPC. The increased dCA and altered blood biomarkers may collectively contribute to the beneficial effects of RIPC on cerebrovascular function. CLINICALTRIALSGOV IDENTIFIER: NCT02965547.

Preliminary Study of Dynamic Cerebral Autoregulation in Acute Ischemic Stroke: Association With Clinical Factors.

Background and Purpose: Dynamic cerebral autoregulation (dCA) is probably impaired in the acute and even subacute phases after acute ischemic stroke (AIS); however, the relationship between relevant clinical factors and dCA after AIS has not been investigated. The identification of possible determinants may therefore provide potential therapeutic targets to improve dCA in AIS. Methods: This study enrolled 67 consecutive patients diagnosed with AIS within 3 days from symptom onset. Serial measurements were performed 1-3 days (measurement 1) and 7-10 days (measurement 2) after the onset. Middle cerebral artery blood flow velocities and simultaneous arterial blood pressure (ABP) were recorded continuously with transcranial Doppler combined with a servo-controlled finger plethysmograph. Transfer function analysis was used to derive dCA parameters, phase difference (PD), and coherence in low-frequency range (0.06-0.12 Hz). Univariate and multivariate linear regression analyses were conducted to determine the relationship between clinical factors and PD within the two time points of measurements. Multivariate logistic regression was performed to reveal the relationship between PD and clinical outcomes. Results: Bilateral PD was significantly lower (indicating impaired dCA) in AIS patients, both in measurement 1 and measurement 2 when compared with those of healthy controls (all P < 0.001). After controlling for relevant clinical factors, in measurement 1, age (ß = -0.29, P = 0.01), recombinant tissue plasminogen activator (rt-PA) intravenous thrombolysis (ß = 0.25, P = 0.034), subtype of large-artery atherosclerosis (LAA) (ß = -0.31, P = 0.007), and uric acid level (ß = -0.32, P = 0.009) were significant independent predictors of ipsilateral PD. In measurement 2, subtype of LAA (ß = -0.28, P = 0.049) and uric acid level (ß = -0.43, P = 0.005) were still significant predictive values for ipsilateral PD. After adjusting for age and National Institutes of Health Stroke Scale at admission, ipsilateral PD >35.37° in measurement 2 was independent predictor of good clinical outcomes (adjusted OR = 6.97, 95% CI: 1.27-38.14, P = 0.03). Conclusion: DCA was sustained to be bilaterally impaired in the acute and even subacute phase after AIS. Patients who receiving rt-PA thrombolysis tended to have a better dCA in the acute phase. Increasing age, subtype of LAA, and higher uric acid level had prognostic value for disturbed autoregulation. A relatively preserved dCA may predict good clinical outcomes.

Dynamic Cerebral Autoregulation Remains Stable During the Daytime (8 a.m. to 8 p.m.) in Healthy Adults.

Many functions of the human body possess a daily rhythm, disruptions of which often lead to disease. Dynamic cerebral autoregulation (dCA) stabilizes the cerebral blood flow to prompt normal neural function. However, whether dCA is stable across the day remains unknown. This study aimed to investigate the daily rhythm of dCA. Fifty-one healthy adults (38.294 ± 13.279 years, 40 females) were recruited and received six dCA measurements per individual that were conducted at predefined time points: 8:00, 9:00, 11:00, 14:00, 17:00, and 20:00. Although the blood pressure fluctuated significantly, there was no statistical difference in phase difference and gain (autoregulatory parameters) across the six time points. This study demonstrates that dCA remains stable during the interval from 8 a.m. to 8 p.m. and underscores the importance of stable dCA in maintaining cerebral blood flow and neural function.

Antioxidant Melatonin: Potential Functions in Improving Cerebral Autoregulation After Subarachnoid Hemorrhage.

Subarachnoid hemorrhage (SAH) is a subtype of stroke with high mortality and morbidity. Impaired cerebral autoregulation following SAH has been reported owing to effects on sympathetic control, endothelial function, myogenic response, and cerebral metabolism. Impaired cerebral autoregulation is associated with early brain injury, cerebral vasospasm/delayed cerebral ischemia, and SAH prognosis. However, few drugs have been reported to improve cerebral autoregulation after SAH. Melatonin is a powerful antioxidant that is effective (easily crosses the blood brain barrier) and safe (tolerated in large doses without toxicity). Theoretically, melatonin may impact the control mechanisms of cerebral autoregulation via antioxidative effects, protection of endothelial cell integrity, suppression of sympathetic nerve activity, increase in nitric oxide bioavailability, mediation of the myogenic response, and amelioration of hypoxemia. Furthermore, melatonin may have a comprehensive effect on cerebral autoregulation. This review discusses the potential effects of melatonin on cerebral autoregulation following SAH, in terms of the association between pharmacological activities and the mechanisms of cerebral autoregulation.

The Impact of Variational Primary Collaterals on Cerebral Autoregulation.

The influence of the anterior and posterior communicating artery (ACoA and PCoA) on dynamic cerebral autoregulation (dCA) is largely unknown. In this study, we aimed to test whether substantial differences in collateral anatomy were associated with differences in dCA in two common types of stenosis according to digital subtraction angiography (DSA): either isolated basal artery and/or bilateral vertebral arteries severe stenosis/occlusion (group 1; group 1A: with bilateral PCoAs; and group 1B: without bilateral PCoAs), or isolated unilateral internal carotid artery severe stenosis/occlusion (group 2; group 2A: without ACoA and with PCoA; group 2B: with ACoA and without PCoAs; and group 2C: without both ACoA and PCoA). The dCA was calculated by transfer function analysis (a mathematical model), and was evaluated in middle cerebral artery (MCA) and/or posterior cerebral artery (PCA). Of a total of 231 non-acute phase ischemic stroke patients who received both dCA assessment and DSA in our lab between 2014 and 2017, 51 patients met inclusion criteria based on the presence or absence of ACoA or PCoA, including 21 patients in the group 1, and 30 patients in the group 2. There were no significant differences in gender, age, and mean blood pressure between group 1A and group 1B, and among group 2A, group 2B, and group 2C. In group 1, the PCA phase difference values (autoregulatory parameter) were significantly higher in the subgroup with patent PCoAs, compared to those without. In group 2, the MCA phase difference values were higher in the subgroup with patent ACoA, compared to those without. This pilot study found that the cross-flow of the ACoA/PCoA to the affected area compensates for compromised dCA in the affected area, which suggests an important role of the ACoA/PCoA in stabilizing cerebral blood flow.

Compromised Dynamic Cerebral Autoregulation in Patients with Epilepsy.

OBJECTIVE: The aim of this study is to analyze dynamic cerebral autoregulation (dCA) in patients with epilepsy. METHODS: One hundred patients with epilepsy and 100 age- and sex-matched healthy controls were recruited. Noninvasive continuous cerebral blood flow velocity of the bilateral middle artery and arterial blood pressure were recorded. Transfer function analyses were used to analyze the autoregulatory parameters (phase difference and gain). RESULTS: The overall phase difference of patients with epilepsy was significantly lower than that of the healthy control group (p = 0.046). Furthermore, patients with interictal slow wave had significant lower phase difference than the slow-wave-free patients (p = 0.012). There was no difference in overall phase between focal discharges and multifocal discharges in patients with epilepsy. Simultaneously, there was no difference in mean phase between the affected and unaffected hemispheres in patients with unilateral discharges. In particular, interictal slow wave was an independent factor that influenced phase difference in patients with epilepsy (p = 0.016). CONCLUSIONS: Our study documented that dCA is impaired in patients with epilepsy, especially in those with interictal slow wave. The impairment of dCA occurs irrespective of the discharge location and type. Interictal slow wave is an independent factor to predict impaired dCA in patients with epilepsy. CLINICAL TRIAL IDENTIFIER: This trial is registered with NCT02775682.

Hematoma volume is a predictive factor of disturbed autoregulation after spontaneous intracerebral hemorrhage.

BACKGROUND: Dynamic cerebral autoregulation (dCA) is probably disturbed after spontaneous intracerebral hemorrhage (ICH) and could be an independent predictor of clinical outcome. Clinical determinants of dCA status after ICH need to be further elucidated. METHODS: We finally enrolled 53 patients diagnosed with supratentorial ICH within 6days from onset. DCA was assessed 4-6days after ICH onset by monitoring middle cerebral artery blood flow velocities and simultaneous arterial blood pressure continuously, utilizing transcranial Doppler combined with a servo-controlled finger plethysmograph. Cerebral autoregulation was evaluated by phase difference (PD) in low frequency (0.06-0.12Hz) range derived from transfer function analysis. The previous clinical history was collected including hypertension, diabetes mellitus, prior stroke, smoking, heavy drinking history. Laboratory results during hospitalization were utilized for further risk factors screening, including fasting blood glucose, glycosylated hemoglobin A (1C), total cholesterol, low density lipoprotein cholesterol and homocysteine, etc. Computed tomography scans were performed to collect neuroimaging data, including hematoma location, volume and presence of intraventricular hemorrhage. Univariate and multivariate linear analyses were adopted to explore the relationship between clinical and laboratory variables and bilateral PD respectively. RESULTS: In ICH patients, PD was lower (indicating disturbed autoregulation) both on the ipsilateral (37.53±17.78 degree, P<0.001) and contralateral (34.45±14.92 degree, P<0.001) side of hematoma compared with healthy controls (56.13±16.11 degree). Hematoma volume was independently associated with ipsilateral PD according to multivariate analysis (ß=-0.383, P=0.024) after adjustment for clinical and laboratory factors. CONCLUSIONS: DCA is bilaterally disturbed after supratentorial ICH. Larger hematoma volume is likely to independently predict poorer cerebral autoregulation status ipsilateral to hematoma.

Temporal Course of Dynamic Cerebral Autoregulation in Patients With Intracerebral Hemorrhage.

BACKGROUND AND PURPOSE: Cerebral autoregulation is crucial in patients with intracerebral hemorrhage. Dynamic cerebral autoregulation is probably altered in acute intracerebral hemorrhage; however, the temporal course of dynamic cerebral autoregulation and its correlation with clinical factors and outcomes are poorly understood. METHODS: Forty-three acute supratentorial intracerebral hemorrhage patients (53.7±10.0 years old, 30 men) were enrolled for serial measurements performed on days 1 to 2, 4 to 6, 10 to 12, and 30 days after ictus. Noninvasive continuous cerebral blood flow velocity and arterial blood pressure were recorded simultaneously using transcranial Doppler and a servo-controlled plethysmograph, respectively. Transfer function analysis was used to derive the autoregulatory parameters, including phase difference (PD), gain, and the rate of recovery of cerebral blood flow velocity. Results were compared with healthy controls and correlated with clinical factors and the 90-day outcome. RESULTS: PD did not differ between affected and unaffected hemispheres over time. A significant lower PD (indicating dynamic cerebral autoregulation impaired) was found in bilateral hemispheres on days 1 to 2, 4 to 6, and 10 to 12, followed by later recovery on day 30. Lower bilateral PD on days 1 to 2 was associated with poorer Glasgow Coma Scale score at that time. Lower affected-side PD on days 4 to 6 was an independent predictive value for a poorer modified Rankin Scale at 90 days. CONCLUSIONS: In patients with supratentorial intracerebral hemorrhage, dynamic cerebral autoregulation is bilaterally impaired lasting at least 10 to 12 days and recovers within a month. Individual PD value is associated with clinical status at acute stage and affected-side PD on days 4 to 6 can be an independent predictor for clinical outcome.

Dynamic Cerebral Autoregulation in Asymptomatic Patients With Unilateral Middle Cerebral Artery Stenosis.

The aim of the study was to assess the capacity of dynamic cerebral autoregulation (dCA) in asymptomatic patients with unilateral middle cerebral artery (MCA) stenosis.Fifty-seven patients with asymptomatic mild, moderate, and severe unilateral MCA stenosis and 8 patients with symptomatic severe unilateral MCA stenosis diagnosed by transcranial Doppler were enrolled. Twenty-four healthy volunteers served as controls. The noninvasive continuous cerebral blood flow velocity and arterial blood pressure were recorded simultaneously from each subject in the supine position. Transfer function analysis was applied to determine the autoregulatory parameters (phase difference [PD] and gain).The PD values in the severe stenosis groups were significantly lower than those of the control group (60.71 ±â€Š18.63°), the asymptomatic severe stenosis group was impaired ipsilaterally (28.94 ±â€Š27.43°, P < 0.001), and the symptomatic severe stenosis group was impaired bilaterally (13.74 ±â€Š19.21°, P < 0.001; 19.68 ±â€Š14.50°, P = 0.006, respectively). The PD values in the mild and moderate stenosis groups were not significantly different than the controls (44.49 ±â€Š27.93°; 48.65 ±â€Š25.49°, respectively). The gain values in the mild and moderate groups were higher than in the controls (1.00 ±â€Š0.58 cm/s/mm Hg vs 0.86 ±â€Š0.34 cm/s/mm Hg, and 1.20 ±â€Š0.59 cm/s/mm Hg vs 0.86 ±â€Š0.34 cm/s/mm Hg, respectively). The gain values in the severe stenosis groups were significantly lower than that in the control group: the asymptomatic severe stenosis group was lower bilaterally (0.56 ±â€Š0.32 cm/s/mm Hg, P = 0.003; 0.60 ±â€Š0.32 cm/s/mm Hg, P < 0.05, respectively), whereas the symptomatic severe group was lower unilaterally (on the contralateral side) (0.53 ±â€Š0.43 cm/s/mm Hg, P < 0.05).In asymptomatic patients with unilateral MCA stenosis, only the dCA of the severe stenosis was ipsilaterally impaired. Acute stroke may aggravate the impaired dCA and even spread contralaterally.