Blood-brain barrier integrity is linked to cognitive function, but not to cerebral arterial pulsatility, among elderly.

Blood-brain barrier (BBB) disruption may contribute to cognitive decline, but questions remain whether this association is more pronounced for certain brain regions, such as the hippocampus, or represents a whole-brain mechanism. Further, whether human BBB leakage is triggered by excessive vascular pulsatility, as suggested by animal studies, remains unknown. In a prospective cohort (N = 50; 68-84 years), we used contrast-enhanced MRI to estimate the permeability-surface area product (PS) and fractional plasma volume ( v p ), and 4D flow MRI to assess cerebral arterial pulsatility. Cognition was assessed by the Montreal Cognitive Assessment (MoCA) score. We hypothesized that high PS would be associated with high arterial pulsatility, and that links to cognition would be specific to hippocampal PS. For 15 brain regions, PS ranged from 0.38 to 0.85 (·10-3 min-1) and v p from 0.79 to 1.78%. Cognition was related to PS (·10-3 min-1) in hippocampus (ß = - 2.9; p = 0.006), basal ganglia (ß = - 2.3; p = 0.04), white matter (ß = - 2.6; p = 0.04), whole-brain (ß = - 2.7; p = 0.04) and borderline-related for cortex (ß = - 2.7; p = 0.076). Pulsatility was unrelated to PS for all regions (p > 0.19). Our findings suggest PS-cognition links mainly reflect a whole-brain phenomenon with only slightly more pronounced links for the hippocampus, and provide no evidence of excessive pulsatility as a trigger of BBB disruption.

CSF formation rate-a potential glymphatic flow parameter in hydrocephalus?

BACKGROUND: Studies indicate that brain clearance via the glymphatic system is impaired in idiopathic normal pressure hydrocephalus (INPH). This has been suggested to result from reduced cerebrospinal fluid (CSF) turnover, which could be caused by a reduced CSF formation rate. The aim of this study was to determine the formation rate of CSF in a cohort of patients investigated for INPH and compare this to a historical control cohort. METHODS: CSF formation rate was estimated in 135 (75 ± 6 years old, 64/71 men/women) patients undergoing investigation for INPH. A semiautomatic CSF infusion investigation (via lumbar puncture) was performed. CSF formation rate was assessed by downregulating and steadily maintaining CSF pressure at a zero level. During the last 10 min, the required outflow to maintain zero pressure, i.e., CSF formation rate, was continuously measured. The values were compared to those of a historical reference cohort from a study by Ekstedt in 1978. RESULTS: Mean CSF formation rate was 0.45 ± 0.15 ml/min (N = 135), equivalent to 27 ± 9 ml/hour. There was no difference in the mean (p = 0.362) or variance (p = 0.498) of CSF formation rate between the subjects that were diagnosed as INPH (N = 86) and those who were not (N = 43). The CSF formation rate in INPH was statistically higher than in the reference cohort (0.46 ± 0.15 vs. 0.40 ± 0.08 ml/min, p = 0.005), but the small difference was probably not physiologically relevant. There was no correlation between CSF formation rate and baseline CSF pressure (r = 0.136, p = 0.115, N = 135) or age (-0.02, p = 0.803, N = 135). CONCLUSIONS: The average CSF formation rate in INPH was not decreased compared to the healthy reference cohort, which does not support reduced CSF turnover. This emphasizes the need to further investigate the source and routes of the flow in the glymphatic system and the cause of the suggested impaired glymphatic clearance in INPH.

Establishing the distribution of cerebrovascular resistance using computational fluid dynamics and 4D flow MRI.

Cerebrovascular resistance (CVR) regulates blood flow in the brain, but little is known about the vascular resistances of the individual cerebral territories. We present a method to calculate these resistances and investigate how CVR varies in the hemodynamically disturbed brain. We included 48 patients with stroke/TIA (29 with symptomatic carotid stenosis). By combining flow rate (4D flow MRI) and structural computed tomography angiography (CTA) data with computational fluid dynamics (CFD) we computed the perfusion pressures out from the circle of Willis, with which CVR of the MCA, ACA, and PCA territories was estimated. 56 controls were included for comparison of total CVR (tCVR). CVR were 33.8 ± 10.5, 59.0 ± 30.6, and 77.8 ± 21.3 mmHg s/ml for the MCA, ACA, and PCA territories. We found no differences in tCVR between patients, 9.3 ± 1.9 mmHg s/ml, and controls, 9.3 ± 2.0 mmHg s/ml (p = 0.88), nor in territorial CVR in the carotid stenosis patients between ipsilateral and contralateral hemispheres. Territorial resistance associated inversely to territorial brain volume (p < 0.001). These resistances may work as reference values when modelling blood flow in the circle of Willis, and the method can be used when there is need for subject-specific analysis.

Freezing of gait in idiopathic normal pressure hydrocephalus.

BACKGROUND: Reports of freezing of gait (FoG) in idiopathic normal pressure hydrocephalus (iNPH) are few and results are variable. This study's objective was to evaluate the frequency of FoG in a large cohort of iNPH patients, identify FoG-associated factors, and assess FoG's responsiveness to shunt surgery. METHODS: Videotaped standardized gait protocols with iNPH patients pre- and post-shunt surgery (n = 139; median age 75 (71-79) years; 48 women) were evaluated for FoG episodes by two observers (Cohens kappa = 0.9, p < 0.001). FoG episodes were categorized. Mini-mental state examination (MMSE) and MRI white matter hyperintensities (WMH) assessment using the Fazekas scale were performed. CSF was analyzed for Beta-amyloid, Tau, and Phospho-tau. Patients with and without FoG were compared. RESULTS: Twenty-two patients (16%) displayed FoG at baseline, decreasing to seven (8%) after CSF shunt surgery (p = 0.039). The symptom was most frequently exhibited during turning (n = 16, 73%). Patients displaying FoG were older (77.5 vs. 74.6 years; p = 0.029), had a slower walking speed (0.59 vs. 0.89 m/s; p < 0.001), a lower Tinetti POMA score (6.8 vs. 10.8; p < 0.001), lower MMSE score (21.3 vs. 24.0; p = 0.031), and longer disease duration (4.2 vs. 2.3 years; p < 0.001) compared to patients not displaying FoG. WMH or CSF biomarkers did not differ between the groups. CONCLUSIONS: FoG is occurring frequently in iNPH patients and may be considered a typical feature of iNPH. FoG in iNPH was associated with higher age, longer disease duration, worse cognitive function, and a more unstable gait. Shunt surgery seems to improve the symptom.

Cerebral arterial stiffness is linked to white matter hyperintensities and perivascular spaces in older adults - A 4D flow MRI study.

White matter hyperintensities (WMH), perivascular spaces (PVS) and lacunes are common MRI features of small vessel disease (SVD). However, no shared underlying pathological mechanism has been identified. We investigated whether SVD burden, in terms of WMH, PVS and lacune status, was related to changes in the cerebral arterial wall by applying global cerebral pulse wave velocity (gcPWV) measurements, a newly described marker of cerebral vascular stiffness. In a population-based cohort of 190 individuals, 66-85 years old, SVD features were estimated from T1-weighted and FLAIR images while gcPWV was estimated from 4D flow MRI data. Additionally, the gcPWV's stability to variations in field-of-view was analyzed. The gcPWV was 10.82 (3.94) m/s and displayed a significant correlation to WMH and white matter PVS volume (r = 0.29, p < 0.001; r = 0.21, p = 0.004 respectively from nonparametric tests) that persisted after adjusting for age, blood pressure variables, body mass index, ApoB/A1 ratio, smoking as well as cerebral pulsatility index, a previously suggested early marker of SVD. The gcPWV displayed satisfactory stability to field-of-view variations. Our results suggest that SVD is accompanied by changes in the cerebral arterial wall that can be captured by considering the velocity of the pulse wave transmission through the cerebral arterial network.

Cerebral Blood Flow Patterns in Patients With Low-Flow Carotid Artery Stenosis, a 4D-PCMRI Assessment.

BACKGROUND: Compromised cerebral blood flow can contribute to future ischemic events in patients with symptomatic carotid artery disease. However, there is limited knowledge of the effects on cerebral hemodynamics resulting from a reduced internal carotid artery (ICA) blood flow rate (BFR). PURPOSE: Investigate how reduced ICA-BFR, relates to BFR in the cerebral arteries. STUDY TYPE: Prospective. SUBJECTS: Thirty-eight patients, age 72 ± 6 years (11 female). FIELD STRENGTH/SEQUENCE: 3-Tesla, four-dimensional phase-contrast magnetic resonance imaging (4D-PCMRI). ASSESSMENT: Patients with ischemic stroke or transient ischemic attack were evaluated regarding the degree of stenosis. 4D-PCMRI was used to measure cerebral BFR in 38 patients with symptomatic carotid stenosis (≥50%). BFR in the cerebral arteries was assessed in two subgroups based on symptomatic ICA-BFR: reduced ICA-flow (<160 mL/minutes) and preserved ICA-flow (≥160 mL/minutes). BFR laterality was defined as a difference in the paired ipsilateral-contralateral arteries. STATISTICAL TESTS: Patients were grouped based on ICA-BFR (reduced vs. preserved). Statistical tests (independent sample t-test/paired t-test) were used to compare groups and hemispheres. Significance was determined at P < 0.05. RESULTS: The degree of stenosis was not significantly different, 80% (95% confidence interval [CI] = 73%-87%) in the reduced ICA-flow vs. 72% (CI = 66%-76%) in the preserved ICA-flow; P = 0.09. In the reduced ICA-flow group, a significantly reduced BFR was found in the ipsilateral middle cerebral artery and anterior cerebral artery (A1), while significantly increased in the contralateral A1. Retrograde BFR was found in the posterior communicating artery and ophthalmic artery. Significant BFR laterality was present in all paired arteries in the reduced ICA-flow group, contrasting the preserved ICA-flow group (P = 0.14-0.93). DATA CONCLUSIONS: 4D-PCMRI revealed compromised cerebral BFR due to carotid stenosis, not possible to detect by solely analyzing the degree of stenosis. In patients with reduced ICA-flow, collaterals were not sufficient to maintain symmetrical BFR distribution to the two hemispheres. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 3.

Cerebral Blood Flow Assessed with Phase-contrast Magnetic Resonance Imaging during Blood Pressure Changes with Noradrenaline and Labetalol: A Trial in Healthy Volunteers.

BACKGROUND: Adequate cerebral perfusion is central during general anesthesia. However, perfusion is not readily measured bedside. Clinicians currently rely mainly on mean arterial pressure (MAP) as a surrogate, even though the relationship between blood pressure and cerebral blood flow is not well understood. The aim of this study was to apply phase-contrast magnetic resonance imaging to characterize blood flow responses in healthy volunteers to commonly used pharmacologic agents that increase or decrease arterial blood pressure. METHODS: Eighteen healthy volunteers aged 30 to 50 yr were investigated with phase-contrast magnetic resonance imaging. Intra-arterial blood pressure monitoring was used. First, intravenous noradrenaline was administered to a target MAP of 20% above baseline. After a wash-out period, intravenous labetalol was given to a target MAP of 15% below baseline. Cerebral blood flow was measured using phase-contrast magnetic resonance imaging and defined as the sum of flow in the internal carotid arteries and vertebral arteries. Cardiac output (CO) was defined as the flow in the ascending aorta. RESULTS: Baseline median cerebral blood flow was 772 ml/min (interquartile range, 674 to 871), and CO was 5,874 ml/min (5,199 to 6,355). The median dose of noradrenaline was 0.17 µg · kg-1 · h-1 (0.14 to 0.22). During noradrenaline infusion, cerebral blood flow decreased to 705 ml/min (606 to 748; P = 0.001), and CO decreased to 4,995 ml/min (4,705 to 5,635; P = 0.01). A median dose of labetalol was 120 mg (118 to 150). After labetalol boluses, cerebral blood flow was unchanged at 769 ml/min (734 to 900; P = 0.68). CO increased to 6,413 ml/min (6,056 to 7,464; P = 0.03). CONCLUSIONS: In healthy, awake subjects, increasing MAP using intravenous noradrenaline decreased cerebral blood flow and CO. These data do not support inducing hypertension with noradrenaline to increase cerebral blood flow. Cerebral blood flow was unchanged when decreasing MAP using labetalol.

10-year mortality, causes of death and cardiovascular comorbidities in idiopathic normal pressure hydrocephalus.

OBJECTIVE: The objective was to investigate 10-year mortality, causes of death and cardiovascular comorbidity in idiopathic normal pressure hydrocephalus (iNPH) and to evaluate their mutual associations. METHODS: This prospective cohort study included 176 CSF-shunted iNPH patients, and 368 age- and sex-matched controls. At inclusion, participants were medically examined, had blood analyzed and answered a questionnaire. The vascular comorbidities investigated were smoking, diabetes, body mass index, blood pressure (BP), hyperlipidemia, kidney function, atrial fibrillation and, cerebro- and cardiovascular disease. RESULTS: Survival was observed for a mean period of 10.3 ± 0.84 years. Shunted iNPH patients had an increased risk of death compared to controls (hazard ratio (HR) = 2.5, 95% CI 1.86-3.36; p < 0.001). After 10 years, 50% (n = 88) of iNPH patients and 24% (n = 88) of the controls were dead (p < 0.001). The risk of dying from cardiovascular disease, falls and neurological diseases were higher in iNPH (p < 0.05). The most common cause of death in iNPH was cardiovascular diseases (14% vs 7% for controls). Seven out of nine iNPH dying from falls had subdural hematomas. Systolic BP (HR = 0.985 95% CI 0.972-0.997, p = 0.018), atrial fibrillation (HR = 2.652, 95% CI 1.506-4.872, p < 0.001) and creatinine (HR = 1.018, 95% CI 1.010-1.027, p < 0.001) were independently associated with mortality for iNPH. DISCUSSION: This long-term and population-matched cohort study indicates that in spite of CSF-shunt treatment, iNPH has shorter life expectancy. It may be important to treat iNPH in supplementary ways to reduce mortality. Both cardiovascular comorbidities and lethal falls are contributing to the excess mortality in iNPH and reducing these preventable risks should be an established part of the treatment plan.

Cerebral Microbleeds-Long-Term Outcome After Cerebrospinal Fluid Shunting in Idiopathic Normal Pressure Hydrocephalus.

BACKGROUND: Cerebral microbleeds (CMBs) are common in idiopathic normal pressure hydrocephalus (INPH) and have been suggested as radiological markers of a brain prone to bleeding. The presence of CMBs might be relevant when selecting patients for shunt surgery. OBJECTIVE: To evaluate whether CMBs increases long-term risk of hemorrhagic complications and mortality or affects outcomes after cerebrospinal fluid shunt surgery in a cohort of patients with INPH. METHODS: One hundred and forty nine shunted patients with INPH (mean age, 73 years) were investigated with MRI (T2* or susceptibility-weighted imaging sequences) preoperatively. CMBs were scored with the Microbleed Anatomic Rating Scale. Patients were observed for a mean of 6.5 years (range 2 weeks to 13 years) after surgery. Hemorrhagic events and death were noted. Improvement in gait was evaluated 3 to 6 months after surgery. RESULTS: At baseline, 74 patients (50%) had CMBs. During follow-up, 7 patients (5%) suffered a hemorrhagic stroke and 43 (29%) suffered a subdural hematoma/hygroma with a median time from surgery of 30.2 months (IQR 50). Overall, having CMBs was not associated with suffering a subdural hematoma/hygroma or hemorrhagic stroke during follow-up with 1 exception that an extensive degree of CMBs (≥50 CMB) was more common in patients suffering a hemorrhagic stroke ( P = .03). CMBs were associated with increased mortality ( P = .02, Kaplan-Meier, log-rank test). The presence of CMBs did not affect gait outcome ( P = .28). CONCLUSION: CMBs were associated with hemorrhagic stroke and mortality. CMBs do not seem to reduce the possibility of gait improvement after shunt surgery or contribute to the risk of hemorrhagic complications regarding subdural hematoma or hygroma.

Clinical Features of Idiopathic Normal Pressure Hydrocephalus: Critical Review of Objective Findings.

Background: Idiopathic normal pressure hydrocephalus (iNPH) is characterized by the classic clinical triad of gait, cognitive, and urinary dysfunction, albeit incomplete in a relevant proportion of patients. The clinical findings and evolution of these symptoms have been variably defined in the literature. Objectives: To evaluate how the phenomenology has been defined, assessed, and reported, we performed a critical review of the existing literature discussing the phenomenology of iNPH. The review also identified the instrumental tests most frequently used and the evolution of clinical and radiologic findings. Methods: The review was divided into 3 sections based on gait, cognitive, and urinary dysfunction. Each section performed a literature search using the terms "idiopathic normal pressure hydrocephalus" (iNPH), with additional search terms used by each section separately. The number of articles screened, duplicates, those meeting the inclusion criteria, and the number of articles excluded were recorded. Findings were subsequently tallied and analyzed. Results: A total of 1716 articles with the aforementioned search criteria were identified by the 3 groups. A total of 81 full-text articles were reviewed after the elimination of duplicates, articles that did not discuss phenomenological findings or instrumental testing of participants with iNPH prior to surgery, and articles with fewer than 10 participants. Conclusions: "Wide-based gait" was the most common gait dysfunction identified. Cognitive testing varied significantly across articles, and ultimately a specific cognitive profile was not identified. Urodynamic testing found detrusor overactivity and "overactive bladder" as the most common symptom of urinary dysfunction.

Placebo-Controlled Effectiveness of Idiopathic Normal Pressure Hydrocephalus Shunting: A Randomized Pilot Trial.

BACKGROUND: Multiple prospective nonrandomized studies have shown 60% to 70% of patients with idiopathic normal pressure hydrocephalus (iNPH) improve with shunt surgery, but multicenter placebo-controlled trial data are necessary to determine its effectiveness. OBJECTIVE: To evaluate the effectiveness of cerebrospinal fluid shunting in iNPH through comparison of open vs placebo shunting groups at 4 months using a pilot study. METHODS: Patients were randomized to a Codman Certas Plus valve (Integra LifeSciences) set at 4 (open shunt group) or 8 ("virtual off"; placebo group). Patients and assessors were blinded to treatment group. The primary outcome measure was 10-m gait velocity. Secondary outcome measures included functional scales for bladder control, activities of daily living, depression, and quality of life. Immediately after 4-month evaluation, all shunts were adjusted in a blinded fashion to an active setting and followed to 12 months after shunting. RESULTS: A total of 18 patients were randomized. At the 4-month evaluation, gait velocity increased by 0.28 ± 0.28 m/s in the open shunt group vs 0.04 ± 0.17 m/s in the placebo group. The estimated treatment difference was 0.22 m/s ([ P = .071], 95% CI -0.02 to 0.46). Overactive Bladder Short Form symptom bother questionnaire significantly improved in open shunt vs placebo ( P = .007). The 4-month treatment delay did not reduce the subsequent response to active shunting, nor did it increase the adverse advents rate at 12 months. CONCLUSION: This multicenter, randomized pilot study demonstrates the effectiveness, safety, and feasibility of a placebo-controlled trial in iNPH, and found a trend suggesting gait velocity improves more in the open shunt group than in the placebo group.

Vascular risk profiles for predicting outcome and long-term mortality in patients with idiopathic normal pressure hydrocephalus: comparison of clinical decision support tools.

OBJECTIVE: Vascular risk factors (VRFs) may act synergistically, and clinical decision support tools (CDSTs) have been developed that present vascular risk as a summarized score. Because VRFs are a major issue in patients with idiopathic normal pressure hydrocephalus (INPH), a CDST may be useful in the diagnostic workup. The objective was to compare 4 CDSTs to determine which one most accurately predicts short-term outcome and 10-year mortality after CSF shunt surgery in INPH patients. METHODS: One-hundred forty INPH patients who underwent CSF shunt surgery were included. For each patient, 4 CDST scores (Systematic Coronary Risk Evaluation-Older Persons [SCORE-OP], Framingham Risk Score [FRS], Revised Framingham Stroke Risk Profile, and Kiefer's Comorbidity Index [KCI]) were estimated. Short-term outcome (3 months after CSF shunt surgery) was defined on the basis of improvements in gait, Mini-Mental State Examination score, and modified Rankin Scale score. The 10-year mortality rate after surgery was noted. The CDSTs were compared by using Cox regression analysis, receiver operating characteristic curve analysis, and the chi-square test. RESULTS: For 3 CDSTs, increased score was associated with increased risk of 10-year mortality. A 1-point increase in the FRS indicated a 2% higher risk of death within 10 years (HR 1.02, 95% CI 1.003-1.035, p = 0.021); SCORE-OP, 5% (HR 1.05, 95% CI 1.019-1.087, p = 0.002); and KCI, 12% (HR 1.12, 95% CI 1.03-1.219, p = 0.008). FRS predicted short-term outcome of surgery (p = 0.024). When the cutoff value was set to 32.5%, the positive predictive value was 80% and the negative predictive value was 48% (p = 0.012). CONCLUSIONS: The authors recommend using FRS to predict short-term outcome and 10-year risk of mortality in INPH patients. The study indicated that extensive treatment of the risk factors of INPH may decrease risk of mortality. Clinical trial registration no.: NCT01850914 (ClinicalTrials.gov).

Prediction of cerebral perfusion pressure during carotid surgery - A computational fluid dynamics approach.

BACKGROUND: Maintaining cerebral perfusion pressure in the brain when a carotid artery is closed during vascular surgery is critical for avoiding intraoperative hypoperfusion and risk of ischemic stroke. Here we propose and evaluate a method based on computational fluid dynamics for predicting patient-specific cerebral perfusion pressures at carotid clamping during carotid endarterectomy. METHODS: The study consisted of 22 patients with symptomatic carotid stenosis who underwent carotid endarterectomy (73 ± 5 years, 59-80 years, 17 men). The geometry of the circle of Willis was obtained preoperatively from computed tomography angiography and corresponding flow rates from four-dimensional flow magnetic resonance imaging. The patients were also classified as having a present or absent ipsilateral posterior communicating artery based on computed tomography angiography. The predicted mean stump pressures from computational fluid dynamics were compared with intraoperatively measured stump pressures from carotid endarterectomy. FINDINGS: On group level, there was no difference between the predicted and measured stump pressures (-0.5 ± 13 mmHg, P = 0.86) and the pressures were correlated (r = 0.44, P = 0.039). Omitting two outliers, the correlation increased to r = 0.78 (P < 0.001) (-1.4 ± 8.0 mmHg, P = 0.45). Patients with a present ipsilateral posterior communicating artery (n = 8) had a higher measured stump pressure than those with an absent artery (n = 12) (P < 0.001). INTERPRETATION: The stump pressure agreement indicates that the computational fluid dynamics approach was promising in predicting cerebral perfusion pressures during carotid clamping, which may prove useful in the preoperative planning of vascular interventions.

5-Year Associations among Cerebral Arterial Pulsatility, Perivascular Space Dilation, and White Matter Lesions.

OBJECTIVE: High cerebral arterial pulsatility index (PI), white matter lesions (WMLs), enlarged perivascular spaces (PVSs), and lacunar infarcts are common findings in the elderly population, and considered indicators of small vessel disease (SVD). Here, we investigate the potential temporal ordering among these variables, with emphasis on determining whether high PI is an early or delayed manifestation of SVD. METHODS: In a population-based cohort, 4D flow MRI data for cerebral arterial pulsatility was collected for 159 participants at baseline (age 64-68), and for 122 participants at follow-up 5 years later. Structural MRI was used for WML and PVS segmentation, and lacune identification. Linear mixed-effects (LME) models were used to model longitudinal changes testing for pairwise associations, and latent change score (LCS) models to model multiple relationships among variables simultaneously. RESULTS: Longitudinal 5-year increases were found for WML, PVS, and PI. Cerebral arterial PI at baseline did not predict changes in WML or PVS volume. However, WML and PVS volume at baseline predicted 5-year increases in PI. This was shown for PI increases in relation to baseline WML and PVS volumes using LME models (R  ≥  0.24; p < 0.02 and R  ≥  0.23; p < 0.03, respectively) and LCS models ( ß  = 0.28; p = 0.015 and ß  = 0.28; p = 0.009, respectively). Lacunes at baseline were unrelated to PI. INTERPRETATION: In healthy older adults, indicators of SVD are related in a lead-lag fashion, in which the expression of WML and PVS precedes increases in cerebral arterial PI. Hence, we propose that elevated PI is a relatively late manifestation, rather than a risk factor, for cerebral SVD. ANN NEUROL 2022;92:871-881.

4D flow MRI hemodynamic biomarkers for cerebrovascular diseases.

Alterations in cerebral blood flow are common in several neurological diseases among the elderly including stroke, cerebral small vessel disease, vascular dementia, and Alzheimer's disease. 4D flow magnetic resonance imaging (MRI) is a relatively new technique to investigate cerebrovascular disease, and makes it possible to obtain time-resolved blood flow measurements of the entire cerebral arterial venous vasculature and can be used to derive a repertoire of hemodynamic biomarkers indicative of cerebrovascular health. The information that can be obtained from one single 4D flow MRI scan allows both the investigation of aberrant flow patterns at a focal location in the vasculature as well as estimations of brain-wide disturbances in blood flow. Such focal and global hemodynamic biomarkers show the potential of being sensitive to impending cerebrovascular disease and disease progression and can also become useful during planning and follow-up of interventions aiming to restore a normal cerebral circulation. Here, we describe 4D flow MRI approaches for analyzing the cerebral vasculature. We then survey key hemodynamic biomarkers that can be reliably assessed using the technique. Finally, we highlight cerebrovascular diseases where one or multiple hemodynamic biomarkers are of central interest.

Hemodynamic Disturbances in Posterior Circulation Stroke: 4D Flow Magnetic Resonance Imaging Added to Computed Tomography Angiography.

Objective: A clinically feasible, non-invasive method to quantify blood flow, hemodynamics, and collateral flow in the vertebrobasilar arterial tree is missing. The objective of this study was to evaluate the feasibility of quantifying blood flow and blood flow patterns using 4D flow magnetic resonance imaging (MRI) in consecutive patients after an ischemic stroke in the posterior circulation. We also explore if 4D-flow, analyzed in conjunction with computed tomography angiography (CTA), has potential as a diagnostic tool in posterior circulation stroke. Methods: Twenty-five patients (mean age 62 years; eight women) with acute ischemic stroke in the posterior circulation were investigated. At admission, all patients were examined with CTA followed by MRI (4D flow MRI and diffusion-weighted sequences) at median 4 days after the presenting event. Based on the classification of Caplan, patients were divided into proximal/middle (n = 16) and distal territory infarcts (n = 9). Absolute and relative blood flow rates were calculated for internal carotid arteries (ICA), vertebral arteries (VA), basilar artery (BA), posterior cerebral arteries (P1 and P2), and the posterior communicating arteries (Pcom). In a control group consisting of healthy elderly, the 90th and 10th percentiles of flow were calculated in order to define normal, increased, or decreased blood flow in each artery. "Major hemodynamic disturbance" was defined as low BA flow and either low P2 flow or high Pcom flow. Various minor hemodynamic disturbances were also defined. Blood flow rates were compared between groups. In addition, a comprehensive analysis of each patient's blood flow profile was performed by assessing relative blood flow rates in each artery in conjunction with findings from CTA. Results: There was no difference in total cerebral blood flow between patients and controls [604 ± 117 ml/min vs. 587 ± 169 ml/min (mean ± SD), p = 0.39] or in total inflow to the posterior circulation (i.e., the sum of total VA and Pcom flows, 159 ± 63 ml/min vs. 164 ± 52 ml/min, p = 0.98). In individual arteries, there were no significant differences between patients and controls in absolute or relative flow. However, patients had larger interindividual relative flow variance in BA, P1, and P2 (p = 0.01, <0.01, and 0.02, respectively). Out of the 16 patients that had proximal/middle territory infarcts, nine had CTA findings in VA and/or BA generating five with major hemodynamic disturbance identified with 4D flow MRI. For those without CTA findings, seven had no or minor 4D flow MRI hemodynamic disturbance. Among nine patients with distal territory infarcts, one had major hemodynamic disturbances, while the remaining had minor disturbances. Conclusion: 4D flow MRI contributed to the identification of the patients who had major hemodynamic disturbances from the vascular pathologies revealed on CTA. We thus conclude that 4D flow MRI could add valuable hemodynamic information when used in conjunction with CTA.

Posture-Dependent Collapse of the Optic Nerve Subarachnoid Space: A Combined MRI and Modeling Study.

Purpose: We hypothesize that a collapse of the optic nerve subarachnoid space (ONSAS) in the upright posture may protect the eyes from large translamina cribrosa pressure differences (TLCPD) believed to play a role in various optic nerve diseases (e.g., glaucoma). In this study, we combined magnetic resonance imaging (MRI) and mathematical modeling to investigate this potential ONSAS collapse and its effects on the TLCPD. Methods: First, we performed MRI on six healthy volunteers in 6° head-down tilt (HDT) and 13° head-up tilt (HUT) to assess changes in ONSAS volume (measured from the eye to the optic canal) with changes in posture. The volume change reflects optic nerve sheath (ONS) distensibility. Second, we used the MRI data and mathematical modeling to simulate ONSAS pressure and the potential ONSAS collapse in a 90° upright posture. Results: The MRI showed a 33% decrease in ONSAS volume from the HDT to HUT (P < 0.001). In the upright posture, the simulations predicted an ONSAS collapse 25 mm behind lamina cribrosa, disrupting the pressure communication between the ONSAS and the intracranial subarachnoid space. The collapse reduced the simulated postural increase in TLCPD by roughly 1 mm Hg, although this reduction was highly sensitive to ONS distensibility, varying between 0 and 4.8 mm Hg when varying the distensibility by ±â€…1 SD. Conclusions: The ONSAS volume along the optic nerve is posture dependent. The simulations supported the hypothesized ONSAS collapse in the upright posture and showed that even small changes in ONS stiffness/distensibility may affect the TLCPD.

Quantification and mapping of cerebral hemodynamics before and after carotid endarterectomy, using four-dimensional flow magnetic resonance imaging.

BACKGROUND: Carotid stenosis can profoundly affect cerebral hemodynamics, which cannot simply be inferred from the degree of stenosis. We quantified and mapped the distribution of the blood flow rate (BFR) in the cerebral arteries before and after carotid endarterectomy using four-dimensional (4D) phase-contrast (PC) magnetic resonance imaging (MRI). METHODS: Nineteen patients (age, 71 ± 6 years; 2 women) with symptomatic carotid stenosis (≥50%) undergoing carotid endarterectomy (CEA) were investigated using 4D PC-MRI before and after surgery. The BFR was measured in 17 cerebral arteries and the ophthalmic arteries. Collateral recruitment through the anterior and posterior communicating arteries, ophthalmic arteries, and leptomeningeal arteries was quantified. BFR laterality was significantly different between the paired contralateral and ipsilateral arteries. Subgroups were defined according to the presence of collateral recruitment. RESULTS: The total cerebral blood flow had increased by 15% (P < .01) after CEA. Before CEA, laterality was seen in the internal carotid artery, anterior cerebral artery, and middle cerebral artery (MCA). On the ipsilateral side, an increased BFR was found after CEA in the internal carotid artery (246 ± 62 mL/min vs 135 ± 80 mL/min; P < .001), anterior cerebral artery (87 ± mL/min vs 38 ± 58 mL/min; P < .01), and MCA (149 ± 43 mL/min vs 119 ± 34 mL/min; P < .01), resulting in a postoperative BFR distribution without signs of laterality. In the nine patients with preoperatively recruited collaterals, BFR laterality was found in the MCA before, but not after, CEA (P < .01). This laterality was not found in the 10 patients without collateral recruitment (P = .2). The degree of stenosis did not differ between the groups with and without collateral recruitment (P = .85). CONCLUSIONS: Using 4D PC-MRI, we have presented a comprehensive and noninvasive method to evaluate the cerebral hemodynamics due to carotid stenosis before and after CEA. MCA laterality, seen in the patients with collateral recruitment before CEA, pointed toward a hemodynamic disturbance in MCA territory for those patients. This methodologic advancement provides an insight into the pathophysiology of cerebral hemodynamics in patients with carotid stenosis.

Falls and Fear of Falling in Shunted Idiopathic Normal Pressure Hydrocephalus-The Idiopathic Normal Pressure Hydrocephalus Comorbidity and Risk Factors Associated With Hydrocephalus Study.

BACKGROUND: Gait and balance impairment are typical symptoms of idiopathic normal pressure hydrocephalus (INPH), implicating that falls may afflict these patients. OBJECTIVE: To investigate falls, related injuries, and associated psychological features, before and after shunt surgery for INPH and compared to the general population. METHODS: The study included 176 patients shunted for INPH and 368 age- and sex-matched controls. Falls, fear of falling (FOF), fall-related injuries (mild-severe), confidence in avoiding falls (Swedish Falls Efficacy Scale (FES(S)), quality of life (QoL; EuroQoL 5-dimension 5 level instrument), and symptoms of depression (Geriatric Depression Scale 15) were investigated. Pre- and postoperative observational times were 12 mo before surgery and 21 mo after (mean). Recurrent fallers fell ≥2 times. RESULTS: More INPH patients than controls were recurrent fallers (67% vs 11%; P < .001). They feared falling more often (FOF, mean ± standard deviation: 3.3 ± 1.1 vs 1.6 ± 0.9; P < .001) and had lower confidence in avoiding falls (FES(S) 78 ± 40 vs 126 ± 14; P < .001). After surgery, INPH patients improved in all parameters but they did not reach the levels of the controls. Among fallers there was no difference between patients and controls in the severity of injuries suffered. Low QoL and symptoms of depression were more common among recurrent fallers than one-time or nonfallers in both shunted patients and controls (P ≤ .001). CONCLUSION: Falls, FOF, and low confidence in avoiding falls are considerable problems in INPH that may be reduced by shunt surgery. We suggest that remaining risk of falling and preventative measures are routinely considered in postoperative follow-ups and rehabilitation planning.