Epigenetic and integrative cross-omics analyses of cerebral white matter hyperintensities on MRI.

Cerebral white matter hyperintensities on MRI are markers of cerebral small vessel disease, a major risk factor for dementia and stroke. Despite the successful identification of multiple genetic variants associated with this highly heritable condition, its genetic architecture remains incompletely understood. More specifically, the role of DNA methylation has received little attention. We investigated the association between white matter hyperintensity burden and DNA methylation in blood at ∼450 000 cytosine-phosphate-guanine (CpG) sites in 9732 middle-aged to older adults from 14 community-based studies. Single CpG and region-based association analyses were carried out. Functional annotation and integrative cross-omics analyses were performed to identify novel genes underlying the relationship between DNA methylation and white matter hyperintensities. We identified 12 single CpG and 46 region-based DNA methylation associations with white matter hyperintensity burden. Our top discovery single CpG, cg24202936 (P = 7.6 × 10-8), was associated with F2 expression in blood (P = 6.4 × 10-5) and co-localized with FOLH1 expression in brain (posterior probability = 0.75). Our top differentially methylated regions were in PRMT1 and in CCDC144NL-AS1, which were also represented in single CpG associations (cg17417856 and cg06809326, respectively). Through Mendelian randomization analyses cg06809326 was putatively associated with white matter hyperintensity burden (P = 0.03) and expression of CCDC144NL-AS1 possibly mediated this association. Differentially methylated region analysis, joint epigenetic association analysis and multi-omics co-localization analysis consistently identified a role of DNA methylation near SH3PXD2A, a locus previously identified in genome-wide association studies of white matter hyperintensities. Gene set enrichment analyses revealed functions of the identified DNA methylation loci in the blood-brain barrier and in the immune response. Integrative cross-omics analysis identified 19 key regulatory genes in two networks related to extracellular matrix organization, and lipid and lipoprotein metabolism. A drug-repositioning analysis indicated antihyperlipidaemic agents, more specifically peroxisome proliferator-activated receptor-alpha, as possible target drugs for white matter hyperintensities. Our epigenome-wide association study and integrative cross-omics analyses implicate novel genes influencing white matter hyperintensity burden, which converged on pathways related to the immune response and to a compromised blood-brain barrier possibly due to disrupted cell-cell and cell-extracellular matrix interactions. The results also suggest that antihyperlipidaemic therapy may contribute to lowering risk for white matter hyperintensities possibly through protection against blood-brain barrier disruption.

Blood pressure, executive function, and network connectivity in middle-aged adults at risk of dementia in late life.

Midlife blood pressure is associated with structural brain changes, cognitive decline, and dementia in late life. However, the relationship between early adulthood blood pressure exposure, brain structure and function, and cognitive performance in midlife is not known. A better understanding of these relationships in the preclinical stage may advance our mechanistic understanding of vascular contributions to late-life cognitive decline and dementia and may provide early therapeutic targets. To identify resting-state functional connectivity of executive control networks (ECNs), a group independent components analysis was performed of functional MRI scans of 600 individuals from the Coronary Artery Risk Development in Young Adults longitudinal cohort study, with cumulative systolic blood pressure (cSBP) measured at nine visits over the preceding 30 y. Dual regression analysis investigated performance-related connectivity of ECNs in 578 individuals (mean age 55.5 ± 3.6 y, 323 female, 243 Black) with data from the Stroop color-word task of executive function. Greater connectivity of a left ECN to the bilateral anterior gyrus rectus, right posterior orbitofrontal cortex, and nucleus accumbens was associated with better executive control performance on the Stroop. Mediation analyses showed that while the relationship between cSBP and Stroop performance was mediated by white matter hyperintensities (WMH), resting-state connectivity of the ECN mediated the relationship between WMH and executive function. Increased connectivity of the left ECN to regions involved in reward processing appears to compensate for the deleterious effects of WMH on executive function in individuals across the burden of cumulative systolic blood pressure exposure in midlife.

The Neurovasculome: Key Roles in Brain Health and Cognitive Impairment: A Scientific Statement From the American Heart Association/American Stroke Association.

BACKGROUND: Preservation of brain health has emerged as a leading public health priority for the aging world population. Advances in neurovascular biology have revealed an intricate relationship among brain cells, meninges, and the hematic and lymphatic vasculature (the neurovasculome) that is highly relevant to the maintenance of cognitive function. In this scientific statement, a multidisciplinary team of experts examines these advances, assesses their relevance to brain health and disease, identifies knowledge gaps, and provides future directions. METHODS: Authors with relevant expertise were selected in accordance with the American Heart Association conflict-of-interest management policy. They were assigned topics pertaining to their areas of expertise, reviewed the literature, and summarized the available data. RESULTS: The neurovasculome, composed of extracranial, intracranial, and meningeal vessels, as well as lymphatics and associated cells, subserves critical homeostatic functions vital for brain health. These include delivering O2 and nutrients through blood flow and regulating immune trafficking, as well as clearing pathogenic proteins through perivascular spaces and dural lymphatics. Single-cell omics technologies have unveiled an unprecedented molecular heterogeneity in the cellular components of the neurovasculome and have identified novel reciprocal interactions with brain cells. The evidence suggests a previously unappreciated diversity of the pathogenic mechanisms by which disruption of the neurovasculome contributes to cognitive dysfunction in neurovascular and neurodegenerative diseases, providing new opportunities for the prevention, recognition, and treatment of these conditions. CONCLUSIONS: These advances shed new light on the symbiotic relationship between the brain and its vessels and promise to provide new diagnostic and therapeutic approaches for brain disorders associated with cognitive dysfunction.

Perspectives on Cognitive Phenotypes and Models of Vascular Disease.

Clinical investigations have established that vascular-associated medical conditions are significant risk factors for various kinds of dementia. And yet, we are unable to associate certain types of vascular deficiencies with specific cognitive impairments. The reasons for this are many, not the least of which are that most vascular disorders are multi-factorial and the development of vascular dementia in humans is often a multi-year or multi-decade progression. To better study vascular disease and its underlying causes, the National Heart, Lung, and Blood Institute of the National Institutes of Health has invested considerable resources in the development of animal models that recapitulate various aspects of human vascular disease. Many of these models, mainly in the mouse, are based on genetic mutations, frequently using single-gene mutations to examine the role of specific proteins in vascular function. These models could serve as useful tools for understanding the association of specific vascular signaling pathways with specific neurological and cognitive impairments related to dementia. To advance the state of the vascular dementia field and improve the information sharing between the vascular biology and neurobehavioral research communities, National Heart, Lung, and Blood Institute convened a workshop to bring in scientists from these knowledge domains to discuss the potential utility of establishing a comprehensive phenotypic cognitive assessment of a selected set of existing mouse models, representative of the spectrum of vascular disorders, with particular attention focused on age, sex, and rigor and reproducibility. The workshop highlighted the potential of associating well-characterized vascular disease models, with validated cognitive outcomes, that can be used to link specific vascular signaling pathways with specific cognitive and neurobehavioral deficits.

Blood pressure variability, dementia, and role of antihypertensive medications in older adults.

INTRODUCTION: We assessed the association between visit-to-visit blood pressure variability (BPV) up to 12 years and subsequent dementia risk, and tested the modifying effect of antihypertensive medications. METHODS: We studied 2234 participants from two community-based cohorts of older adults with normal cognition or mild cognitive impairment. Participants were followed through annual assessments for up to 27 years. Visit-to-visit BPV was quantified over 3, 6, 9, and 12 years, respectively. RESULTS: Higher systolic BPV (SBPV) during 3, 6, 9, and 12 years was associated with a subsequent increased risk of dementia, with hazard ratios ranging from 1.02 (95% confidence interval [CI]: 1.01-1.04) to 1.10 (95% CI: 1.05-1.16). The association between SBPV and dementia risk was stronger among participants not taking calcium channel blockers (p-for interaction < 0.05). DISCUSSION: Among older adults, long-term exposure to higher visit-to-visit SBPV is associated with an increased risk of dementia later in life, and calcium channel blockers may modify this association. HIGHLIGHTS: Among adults aged >65, higher systolic blood pressure variability spanning 3-12 years is associated with an increased risk of dementia later in life. Single blood pressure measurement or mean blood pressure levels does not seem to associate with dementia risk among older adults. The association between systolic blood pressure variability and dementia risk is stronger among those not taking calcium channel blocker medications.

Association of change in cardiovascular risk factors with incident dementia.

INTRODUCTION: We evaluated whether better cardiovascular health at midlife and improvement of cardiovascular health within midlife were associated with dementia risk. METHODS: Two longitudinal population-based studies were used: Atherosclerosis Risk in Communities (ARIC) (n = 11,460/visits at ages 54 and 60), and Age, Gene/Environment Susceptibility (AGES)-Reykjavik (n = 3907/visit at age 51). A cardiovascular health score (range 0-12/0-14, depending on diet availability) including six/seven items was calculated at each visit, with weight assigned to each item as poor (0), intermediate (1), or ideal (2). Cardiovascular health was defined as low (score 0-4/0-5), intermediate (5-7/6-9), or high (8-12/10-14). Incident dementia was ascertained through linkage to health records and with neuropsychological examinations. RESULTS: Midlife high compared to low cardiovascular health (hazard ratios [HRs]: for ARIC: 0.60 [95% confidence interval: 0.52, 0.69]); for AGES-Reykjavik: 0.83 [0.66, 0.99] and improvement of cardiovascular health score within midlife (HR per one-point increase: ARIC: 0.94 [0.92, 0.96]) were associated with lower dementia risk. DISCUSSION: Better cardiovascular health at midlife and improvement of cardiovascular health within midlife are associated with lower dementia risk. HIGHLIGHTS: Cardiovascular health and dementia were studied in two large cohort studies. Better cardiovascular health at midlife relates to lower dementia risk. Improvement of cardiovascular health within midlife relates to lower dementia risk. Promotion of cardiovascular health at midlife can help to reduce dementia risk.

Intracranial Blood Flow Quantification by Accelerated Dual-venc 4D Flow MRI: Comparison With Transcranial Doppler Ultrasound.

BACKGROUND: Dual-venc 4D flow MRI, recently introduced for the assessment of intracranial hemodynamics, may provide a promising complementary approach to well-established tools such as transcranial Doppler ultrasound (TCD) and overcome some of their disadvantages. However, data comparing intracranial flow measures from dual-venc 4D flow MRI and TCD are lacking. PURPOSE: To compare cerebral blood flow velocity measures derived from dual-venc 4D flow MRI and TCD. STUDY TYPE: Prospective cohort. SUBJECTS: A total of 25 healthy participants (56 ± 4 years old, 44% female). FIELD STRENGTH/SEQUENCE: A 3 T/dual-venc 4D flow MRI using a time-resolved three-dimensional phase-contrast sequence with three-dimensional velocity encoding. ASSESSMENT: Peak velocity measurements in bilateral middle cerebral arteries (MCA) were quantified from dual-venc 4D flow MRI and TCD. The MRI data were quantified by two independent observers (S.M and Y.M.) and TCD was performed by a trained technician (A.L.M.). We assessed the agreement between 4D flow MRI and TCD measures, and the interobserver agreement of 4D flow MRI measurements. STATISTICAL TESTS: Peak velocity from MRI and TCD was compared using Bland-Altman analysis and coefficient of variance. Intraclass correlation coefficient (ICC) was used to assess MRI interobserver agreement. A P value < 0.05 was considered statistically significant. RESULTS: There was excellent interobserver agreement in dual-venc 4D flow MRI-based measurements of peak velocity in bilateral MCA (ICC = 0.97 and 0.96 for the left and right MCA, respectively). Dual-venc 4D flow MRI significantly underestimated peak velocity in the left and right MCA compared to TCD (bias = 0.13 [0.59, -0.33] m/sec and 0.15 [0.47, -0.17] m/sec, respectively). The coefficient of variance between dual-venc 4D flow MRI and TCD measurements was 26% for the left MCA and 22% for the right MCA. DATA CONCLUSION: There was excellent interobserver agreement for the assessment of MCA peak velocity using dual-venc 4D flow MRI, and ≤20% under-estimation compared with TCD. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 2.

Could salt intake directly affect the cerebral microvasculature in hypertension?

OBJECTIVES: Excess dietary salt and chronic kidney disease (CKD) are acknowledged stroke risk factors. The development of small vessel disease, similarly affecting the cerebral and renal microvasculatures, may be an important mechanistic link underlying this interaction. Therefore, we aimed to evaluate if the dietary salt intake and markers of CKD (estimated glomerular filtration rate, albuminuria) relate to transcranial Doppler (TCD) markers of cerebral small vessel disease (CSVD) in hypertensive patients. MATERIALS AND METHODS: Fifty-six hypertensive patients (57% with diabetes) underwent TCD monitoring in the middle (MCA) and posterior (PCA) cerebral arteries for evaluating neurovascular coupling (NVC), dynamic cerebral autoregulation (dCA), and vasoreactivity to carbon dioxide (VRCO2). We investigated the relation between renal parameters and TCD studies using Pearson's correlation coefficient and linear regression analyses. RESULTS: There were no associations between dCA, VRCO2, NVC, and renal function tests. However, there was a negative association between the daily salt intake and the natural frequency during visual stimulation (r2=0.101, ß=-0.340, p=0.035), indicative of increased rigidity of the cerebral resistance vessels that react to cognitive activation. CONCLUSIONS: In this cross-sectional study, we found an association between excess dietary salt consumption and CSVD in hypertensive patients. Future research is needed to evaluate whether the natural frequency could be an early, non-invasive, surrogate marker for microvascular dysfunction in hypertension.

Cumulative Blood Pressure Exposure During Young Adulthood and Mobility and Cognitive Function in Midlife.

BACKGROUND: High blood pressure (BP) is a known risk factor for mobility and cognitive impairment in older adults. This study tested the association of cumulative BP exposure from young adulthood to midlife with gait and cognitive function in midlife. Furthermore, we tested whether these associations were modified by cerebral white matter hyperintensity (WMH) burden. METHODS: We included 191 participants from the CARDIA study (Coronary Artery Risk Development in Young Adults), a community-based cohort of young individuals followed over 30 years. Cumulative BP was calculated as the area under the curve (mm Hg×years) from baseline up to year 30 examination. Gait and cognition were assessed at the year 30 examination. Cerebral WMH was available at year 30 in a subset of participants (n=144) who underwent magnetic resonance imaging. Multiple linear regression models were used to assess the association of cumulative BP exposure with gait and cognition. To test effect modification by WMH burden, participants were stratified at the median of WMH and tested for interaction. RESULTS: Higher cumulative systolic and diastolic BPs were associated with slower walking speed (both P=0.010), smaller step length (P=0.011 and 0.005, respectively), and higher gait variability (P=0.018 and 0.001, respectively). Higher cumulative systolic BP was associated with lower cognitive performance in the executive (P=0.021), memory (P=0.015), and global domains (P=0.010), and higher cumulative diastolic BP was associated with lower cognitive performance in the memory domain (P=0.012). All associations were independent of socio-demographics and vascular risk factors (body mass index, smoking, diabetes mellitus and total cholesterol). The association between cumulative BP and gait was moderated by WMH burden (interaction P<0.05). However, the relation between cumulative BP and cognitive function was not different based on the WMH burden (interaction P>0.05). CONCLUSIONS: Exposure to higher BP levels from young to midlife is associated with worse gait and cognitive performance in midlife. Furthermore, WMH moderates the association of cumulative BP exposure with gait, but not with cognitive function in midlife. The mechanisms underpinning the impact of BP exposure on brain structure and function must be investigated in longitudinal studies using a life course approach.

Rapid Assessment of Blood Pressure Variability and Outcome After Successful Thrombectomy.

BACKGROUND AND PURPOSE: High blood pressure (BP) variability after endovascular stroke therapy is associated with poor outcome. Conventional BP variability measures require long recordings, limiting their utility as a risk assessment tool to guide clinical decision-making. Here, we performed rapid assessment of BP variability by spectral analysis and evaluated its association with early clinical improvement and long-term functional outcomes. METHODS: We conducted a prospective study of 146 patients with anterior circulation ischemic stroke who underwent successful endovascular stroke therapy. Spectral analysis of 5-minute recordings of beat-to-beat BP was used to quantify BP variability. Outcomes included initial clinical response and modified Rankin Scale at 90 days. RESULTS: Increased BP variability at high frequencies was independently associated with poor functional outcome at 90 days (adjusted odds ratio [aOR], 1.85 [95% CI, 1.07-3.25], P=0.03; low-/high-frequency ratio aOR, 0.67 [95% CI, 0.46-0.92], P=0.02) and reduced likelihood of an early neurological recovery (aOR, 0.62 [95% CI, 0.44-0.91], P=0.01 and aOR, 1.37 [95% CI, 1.03-1.87], P=0.04, respectively). CONCLUSIONS: High-frequency BP oscillations after successful reperfusion may be harmful and associate with a decreased likelihood of neurological recovery and favorable functional outcomes. Rapid assessment of BP variability throughout the postreperfusion period is feasible and may allow for a more personalized BP management.

A Primary Care Agenda for Brain Health: A Scientific Statement From the American Heart Association.

A healthy brain is critical for living a longer and fuller life. The projected aging of the population, however, raises new challenges in maintaining quality of life. As we age, there is increasing compromise of neuronal activity that affects functions such as cognition, also making the brain vulnerable to disease. Once pathology-induced decline begins, few therapeutic options are available. Prevention is therefore paramount, and primary care can play a critical role. The purpose of this American Heart Association scientific statement is to provide an up-to-date summary for primary care providers in the assessment and modification of risk factors at the individual level that maintain brain health and prevent cognitive impairment. Building on the 2017 American Heart Association/American Stroke Association presidential advisory on defining brain health that included "Life's Simple 7," we describe here modifiable risk factors for cognitive decline, including depression, hypertension, physical inactivity, diabetes, obesity, hyperlipidemia, poor diet, smoking, social isolation, excessive alcohol use, sleep disorders, and hearing loss. These risk factors include behaviors, conditions, and lifestyles that can emerge before adulthood and can be routinely identified and managed by primary care clinicians.

Hypertension and cognitive dysfunction: a review of mechanisms, life-course observational studies and clinical trial results.

Hypertension is one of the most prevalent vascular risk factors and a leading cause of disability and mortality worldwide. The negative impact of hypertension on brain health is substantial. Already well-established as a risk factor for cerebrovascular disease, hypertension also has been shown to increase the risk for cognitive impairment and dementia. Mounting evidence from epidemiological studies suggests that hypertension, particularly in midlife, is associated with late-life cognitive impairment and the development of dementia. The link between late-life hypertension and cognitive function is, however, less clear. Experimental and neuroimaging studies have revealed complexities of mechanisms underlying the link between hypertension and cognitive function. Furthermore, the effect of blood pressure lowering on cognitive function, the optimal target and timing of the intervention, and the optimal antihypertensive agent in the context of cognitive function remain unclear. In this review, we discuss contemporary science on the link between hypertension and cognitive function by reviewing experimental, neuroimaging, and life-course observational studies. Furthermore, we provide a detailed review of randomized clinical trials addressing the effect of blood pressure lowering on cognitive function. Finally, unanswered questions, challenges, and other considerations for blood pressure lowering are highlighted.

Vascular health across young adulthood and midlife cerebral autoregulation, gait, and cognition.

INTRODUCTION: To test the association of vascular health (VH) across young adulthood with midlife dynamic cerebral autoregulation (dCA), gait, and cognition; and to test whether dCA is a modifying factor. METHODS: We studied 196 participants from the Coronary Artery Risk Development in Young Adults cohort who were followed over 30 years. VH was assessed at each visit according to American Heart Association recommendations. At year 30, dCA was measured using transcranial Doppler ultrasound and several gait and cognitive domains were assessed. RESULTS: Worse VH from baseline through year 7, but not at year 30, was associated with less efficient dCA (all P < .05). Worse VH at all visits was associated with slower gait speed, and at year 7 with worse executive and global cognition (all P < .05). The association of baseline VH and midlife gait, but not cognition, was moderated by dCA (interaction P < .05). CONCLUSIONS: VH as early as young adulthood may influence midlife brain health, and dCA may modify this relationship.

Transcranial Doppler Ultrasound Evidence of Active Cerebral Embolization in COVID-19.

OBJECTIVE: To report six consecutive patients with confirmed coronavirus disease-2019 (COVID-19) who underwent Transcranial Doppler (TCD) ultrasonography evaluation for cerebral microemboli in the setting of suspected or confirmed acute ischemic stroke. METHODS: Patient data were obtained from medical records from Northwestern Memorial Hospital, Chicago, IL between May and June 2020. All patients with confirmed COVID-19 who underwent clinical TCD ultrasonography for microemboli detection were included. RESULTS: A total of eight TCD studies were performed in six patients with COVID-19 (4 men and 2 women, median age 65±5), four with confirmed ischemic stroke and two with refractory encephalopathy. Microemboli were detected in three male patients, two patients had suffered a confirmed ischemic stroke and one who developed prolonged encephalopathy. Microemboli of varying intensity were identified in multiple vascular territories in two patients, and microemboli persisted despite therapeutic anticoagulation in a third patient. Of the three patients without evidence of microemboli on TCD ultrasonography, two patients had suffered a confirmed ischemic stroke, while one remained with refractory encephalopathy. CONCLUSIONS: TCD ultrasonography for microemboli detection identified three patients with confirmed COVID-19 with evidence of cerebral arterial microemboli, including one who was therapeutically anticoagulated. TCD ultrasonography provides a non-invasive method for evaluating cerebral microemboli in patients with COVID-19 and may be useful in assessing response to treatment in cases with suspected or confirmed disorders of hypercoagulability. Further studies investigating the prevalence of cerebral microemboli and associated risk factors are needed to characterize their pathogenic mechanism and guide therapeutic interventions in hospitalized COVID-19 patients.

COVID-19 Respiratory Illness and Subsequent Cerebrovascular Events, the Initial Iranian Experience.

OBJECTIVES: COVID-19 disproportionately affects older adults and individuals with cardiovascular co-morbidities. This report presents fifteen patients who had COVID-19 respiratory illness followed by cerebrovascular events. MATERIALS AND METHODS: A call by the Iranian Neurological Association gathered cases across the country who developed neurological symptoms attributed to hemorrhagic or ischemic stroke after a definite or probable Covid-19 respiratory illness. Definite cases were those with a typical respiratory illness, positive nasopharyngeal Covid-19 PCR test, and chest CT consistent with Covid-19 infection. Probable cases were defined by a typical respiratory illness, history of contacts with a Covid-19 case, and chest CT characteristic for Covid-19 infection. RESULTS: Fifteen patients (12 men and 3 women) with an age range of 38 to 93 years old (median: 65 years old) were included. Fourteen patients had a first-ever acute ischemic stroke and one patient had a subarachnoid hemorrhage. Eleven patients (73%) had previous cardiovascular comorbidities. The median time between respiratory symptoms and neurological symptoms was seven days (range 1-16 days). Stroke severity in two patients was mild (NIHSS ≤ 6), in six patients moderate (NIHSS: 7-12), and in seven patients severe (NIHSS ≥13). One patient received intravenous tissue plasminogen activator ( IV-tPA) with improved neurological symptoms. Six out of 15 patients (40%) died. All but one of those who survived had significant disability assessed by a modified ranking scale >2. The majority of patients in this case series had vascular risk factors and their stroke was associated with severe disability and death. CONCLUSION: This report highlights the need for further investigation of the links between Covid-19 and cerebrovascular events.

Microemboli After Successful Thrombectomy Do Not Affect Outcome but Predict New Embolic Events.

Background and Purpose- We aimed to determine if microemboli after endovascular thrombectomy correlate with unfavorable outcomes despite successful recanalization. Methods- This is a prospective multicenter study of consecutive patients with ischemic stroke and occlusion of anterior circulation vessels (terminal internal carotid or main trunk of the middle cerebral artery/first-order branch of the main trunk of the middle cerebral artery segments of middle cerebral artery) after successful thrombectomy (modified Treatment In Cerebral Ischemia grades 2b-3). Microembolic signals (MES) were assessed by 30 minutes of transcranial Doppler monitoring within 72 hours of the last-seen-well time. Major outcomes included modified Rankin Scale at 90 days and infarct volume on head computed tomography at 24 hours. We also assessed early outcomes based on National Institutes of Health Stroke Scale variation and recurrence of stroke, transient ischemic attack, or systemic embolism within 90 days. Results- Among 111 patients, MES were detected in 43 (39%), with a median rate of 4 counts/h (interquartile range 2-12). The occurrence of MES was not associated with a significant difference in modified Rankin Scale (ordinal shift analysis, adjusted odds ratio, 1.06 [95% CI, 0.48-2.34] P=0.85) nor in functional independence (modified Rankin Scale, 0-2: adjusted odds ratio, 0.52 [95% CI, 0.19-1.39] P=0.19). Patients with and without MES had similar infarct volumes (adjusted beta, 11.2 [95% CI, -46.6 to +22.9] P=0.51) on 24-hour computed tomography. MES did predict new embolic events (adjusted Cox hazard ratio, 6.78 [95% CI, 1.63-27.8] P=0.01). Conclusions- MES detected by transcranial Doppler following endovascular treatment of anterior circulation occlusions do not predict clinical or radiological outcome. However, such emboli are an independent marker of recurrent embolic events within 90 days.

Serum osmolality, cerebrospinal fluid specific gravity and overt hepatic encephalopathy severity in patients with liver failure.

BACKGROUND AND AIMS: Hepatic encephalopathy (HE) is a leading contributor to morbidity in liver disease. While hyperammonaemia plays a key role, the mechanisms of cerebral toxicity are unclear. We hypothesized that serum hyperosmolality contributes to HE during acute (ALF) and acute-on-chronic liver failure (ACLF) through mechanisms that affect the water and solute composition of the cerebral environment. METHODS: We performed a retrospective analysis of serum osmolality, cerebral spinal fluid (CSF) solute density (specific gravity, determined from computed tomography attenuation) and clinical HE severity (Glasgow Coma Score [GCS]) at the time of intensive care admission in a prospectively identified cohort of liver failure patients with overt HE. RESULTS: Seventy-three patients (39 ALF and 34 ACLF) were included, of whom 28 (38%) were comatose. Serum osmolality (303.9 ± 15.4 mOsm/kg) was elevated despite normal serum sodium (136.6 ± 6.3 mEq/L). Increased osmolality was independently associated with more severe encephalopathy (ordinal adjusted OR 0.26 [95% CI 0.22, 0.31] for higher GCS per standard deviation increase in osmolality) and lower CSF-specific gravity (linear adjusted ß = -0.039 [95% CI -0.069, -0.009] Hounsfield unit per 1 mOsm/kg). CONCLUSIONS: In the context of related research, these data suggest that hyperosmolality increases brain exposure to metabolic toxins by blood-brain barrier alteration and may be a unique therapeutic target.

Heart failure patients have enhanced cerebral autoregulation response in acute ischemic stroke.

The cerebrovascular effects of a failing heart-pump are largely unknown. Chronic heart failure (HF) might cause pre-conditioning effect on cerebral hemodynamics but not study so far in acute stroke. We aimed to investigate if HF induces effects in dynamic cerebral autoregulation (CA), within 6 h of symptom-onset through chronic stage of ischemic stroke. We enrolled 50 patients with acute ischemic stroke. Groups with (N = 8) and without HF and 20 heathy controls were compared. Arterial blood pressure (Finometer) and cerebral blood flow velocity (transcranial Doppler) were monitored within 6 and at 24 h from symptom-onset and at 3 months. We assessed dynamic CA by transfer function analysis and cardiac disease markers. HF associated with higher phase (better dynamic CA) at ischemic hemisphere within 6 (p = 0.042) and at 24 h (p = 0.006) but this effect was not evident at 3 months (p > 0.05). Gain and coherence trends were similar between groups. We found a positive correlation between phase and admission troponin I levels (Spearman's r = 0.348, p = 0.044). Our findings advances on the knowledge of how brain and heart interact in acute ischemic stroke by showing a sustained dynamic cerebral autoregulation response in HF patients mainly with severe aortic valve disease. Understanding the physiological mechanisms that govern this complex interplay can be useful to find novel therapeutic targets which can improve outcome in ischemic stroke.

Elevated Cerebrospinal Fluid Protein Is Associated with Unfavorable Functional Outcome in Spontaneous Subarachnoid Hemorrhage.

BACKGROUND/OBJECTIVE: Subarachnoid hemorrhage (SAH) is a devastating neurologic event for which markers to assess poor outcome are needed. Elevated cerebrospinal fluid (CSF) protein may result from inflammation and blood-brain barrier (BBB) disruption that occurs during SAH. We sought to determine if CSF protein level is associated with functional outcome after SAH. METHODS: We prospectively collected single-center demographic and clinical data for consecutive patients admitted with spontaneous SAH. Inclusion required an external ventricular drain and daily CSF protein and cellular counts starting within 48 hours of symptom onset and extending through 7 days after onset. Seven-day average CSF protein was determined from daily measured values after correcting for contemporaneous CSF red blood cell (RBC) count. Three-month functional outcome was assessed by telephone interview with good outcome defined as modified Rankin score 0-3. Variables univariately associated with outcome at P less than .25 and measures of hemorrhage volume were included for binary logistic regression model development. RESULTS: The study included 130 patients (88% aneurysmal SAH, 69% female, 54.8 ± 14.8 years, Glasgow Coma Scale [GCS] 14 [7-15]). Three-month outcome assessment was complete in 112 (86%) patients with good functional outcome in 74 (66%). CSF protein was lower in good outcome (35.3 [20.4-49.7] versus 80.5 [40.5-115.5] mg/dL; P < .001). CSF protein was not associated with cerebral vasospasm, but delayed radiographic infarction on 3 to 12-month neuroimaging was associated with higher CSF protein (46.3 [32.0-75.0] versus 30.2 [20.4-47.8] mg/dL; P = .023). Good 3-month outcome was independently associated with lower CSF protein (odds ratios [OR] .39 [.23-.70] for 75th versus 25th percentile of protein; P = .001) and higher admission GCS (OR 1.23 [1.10-1.37] for good outcome per GCS point increase; P < .001). Parenchymal hematoma predicted worse outcome (OR 6.31 [1.58-25.25]; P = .009). Results were similar after excluding nonaneurysmal SAH and after including CSF RBC count, CT score, and intraventricular hemorrhage volume in models. CONCLUSIONS: Elevated average CSF protein is associated with poor outcome after spontaneous SAH. Further research should investigate if elevated CSF protein identifies patients in whom mechanisms such as BBB disruption contribute to poor outcome.

Role of age-related alterations of the cerebral venous circulation in the pathogenesis of vascular cognitive impairment.

There has been an increasing appreciation of the role of vascular contributions to cognitive impairment and dementia (VCID) associated with old age. Strong preclinical and translational evidence links age-related dysfunction and structural alterations of the cerebral arteries, arterioles, and capillaries to the pathogenesis of many types of dementia in the elderly, including Alzheimer's disease. The low-pressure, low-velocity, and large-volume venous circulation of the brain also plays critical roles in the maintenance of homeostasis in the central nervous system. Despite its physiological importance, the role of age-related alterations of the brain venous circulation in the pathogenesis of vascular cognitive impairment and dementia is much less understood. This overview discusses the role of cerebral veins in the pathogenesis of VCID. Pathophysiological consequences of age-related dysregulation of the cerebral venous circulation are explored, including blood-brain barrier disruption, neuroinflammation, exacerbation of neurodegeneration, development of cerebral microhemorrhages of venous origin, altered production of cerebrospinal fluid, impaired function of the glymphatics system, dysregulation of cerebral blood flow, and ischemic neuronal dysfunction and damage. Understanding the age-related functional and phenotypic alterations of the cerebral venous circulation is critical for developing new preventive, diagnostic, and therapeutic approaches to preserve brain health in older individuals.