Recent findings from several studies have shown that paramagnetic rim lesions identified using susceptibility-based MRI could represent potential diagnostic and prognostic biomarkers in multiple ...sclerosis (MS). Here, we perform a systematic review and meta-analysis of the existing literature to assess their pooled prevalence at lesion-level and patient-level.
Both database searching (PubMed and Embase) and handsearching were conducted to identify studies allowing the lesion-level and/or patient-level prevalence of rim lesions or chronic active lesions to be calculated. Pooled prevalence was estimated using the DerSimonian-Laird random-effects model. Subgroup analysis and meta-regression were performed to explore possible sources of heterogeneity. PROSPERO registration: CRD42020192282.
29 studies comprising 1230 patients were eligible for analysis. Meta-analysis estimated pooled prevalences of 9.8% (95% CI: 6.6-14.2) and 40.6% (95% CI: 26.2-56.8) for rim lesions at lesion-level and patient-level, respectively. Pooled lesion-level and patient-level prevalences for chronic active lesions were 12.0% (95% CI: 9.0-15.8) and 64.8% (95% CI: 54.3-74.0), respectively. Considerable heterogeneity was observed across studies (I2>75%). Subgroup analysis revealed a significant difference in patient-level prevalence between studies conducted at 3T and 7T (p = 0.0312). Meta-regression analyses also showed significant differences in lesion-level prevalence with respect to age (p = 0.0018, R2 = 0.20) and disease duration (p = 0.0018, R2 = 0.48). Other moderator analyses demonstrated no significant differences according to MRI sequence, gender and expanded disability status scale (EDSS).
In this study, we show that paramagnetic rim lesions may be present in an important proportion of MS patients, notwithstanding significant variation in their assessment across studies. In view of their possible clinical relevance, we believe that clear guidelines should be introduced to standardise their assessment across research centres to in turn facilitate future analyses.
Patients undergo interventions to achieve a 'normal' brain temperature; a parameter that remains undefined for humans. The profound sensitivity of neuronal function to temperature implies the brain ...should be isothermal, but observations from patients and non-human primates suggest significant spatiotemporal variation. We aimed to determine the clinical relevance of brain temperature in patients by establishing how much it varies in healthy adults. We retrospectively screened data for all patients recruited to the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) High Resolution Intensive Care Unit Sub-Study. Only patients with direct brain temperature measurements and without targeted temperature management were included. To interpret patient analyses, we prospectively recruited 40 healthy adults (20 males, 20 females, 20-40 years) for brain thermometry using magnetic resonance spectroscopy. Participants were scanned in the morning, afternoon, and late evening of a single day. In patients (n = 114), brain temperature ranged from 32.6 to 42.3°C and mean brain temperature (38.5 ± 0.8°C) exceeded body temperature (37.5 ± 0.5°C, P < 0.0001). Of 100 patients eligible for brain temperature rhythm analysis, 25 displayed a daily rhythm, and the brain temperature range decreased in older patients (P = 0.018). In healthy participants, brain temperature ranged from 36.1 to 40.9°C; mean brain temperature (38.5 ± 0.4°C) exceeded oral temperature (36.0 ± 0.5°C) and was 0.36°C higher in luteal females relative to follicular females and males (P = 0.0006 and P < 0.0001, respectively). Temperature increased with age, most notably in deep brain regions (0.6°C over 20 years, P = 0.0002), and varied spatially by 2.41 ± 0.46°C with highest temperatures in the thalamus. Brain temperature varied by time of day, especially in deep regions (0.86°C, P = 0.0001), and was lowest at night. From the healthy data we built HEATWAVE-a 4D map of human brain temperature. Testing the clinical relevance of HEATWAVE in patients, we found that lack of a daily brain temperature rhythm increased the odds of death in intensive care 21-fold (P = 0.016), whilst absolute temperature maxima or minima did not predict outcome. A warmer mean brain temperature was associated with survival (P = 0.035), however, and ageing by 10 years increased the odds of death 11-fold (P = 0.0002). Human brain temperature is higher and varies more than previously assumed-by age, sex, menstrual cycle, brain region, and time of day. This has major implications for temperature monitoring and management, with daily brain temperature rhythmicity emerging as one of the strongest single predictors of survival after brain injury. We conclude that daily rhythmic brain temperature variation-not absolute brain temperature-is one way in which human brain physiology may be distinguished from pathophysiology.
White matter hyperintensities are frequent on neuroimaging of older people and are a key feature of cerebral small vessel disease. They are commonly attributed to chronic hypoperfusion, although ...whether low cerebral blood flow is cause or effect is unclear. We systematically reviewed studies that assessed cerebral blood flow in small vessel disease patients, performed meta-analysis and sensitivity analysis of potential confounders. Thirty-eight studies (n = 4006) met the inclusion criteria, including four longitudinal and 34 cross-sectional studies. Most cerebral blood flow data were from grey matter. Twenty-four cross-sectional studies (n = 1161) were meta-analysed, showing that cerebral blood flow was lower in subjects with more white matter hyperintensity, globally and in most grey and white matter regions (e.g. mean global cerebral blood flow: standardised mean difference−0.71, 95% CI −1.12, −0.30). These cerebral blood flow differences were attenuated by excluding studies in dementia or that lacked age-matching. Four longitudinal studies (n = 1079) gave differing results, e.g., more baseline white matter hyperintensity predated falling cerebral blood flow (3.9 years, n = 575); cerebral blood flow was low in regions that developed white matter hyperintensity (1.5 years, n = 40). Cerebral blood flow is lower in subjects with more white matter hyperintensity cross-sectionally, but evidence for falling cerebral blood flow predating increasing white matter hyperintensity is conflicting. Future studies should be longitudinal, obtain more white matter data, use better age-correction and stratify by clinical diagnosis.
Cerebrovascular reactivity (CVR) magnetic resonance imaging (MRI) probes cerebral haemodynamic changes in response to a vasodilatory stimulus. CVR closely relates to the health of the vasculature and ...is therefore a key parameter for studying cerebrovascular diseases such as stroke, small vessel disease and dementias. MRI allows
measurement of CVR but several different methods have been presented in the literature, differing in pulse sequence, hardware requirements, stimulus and image processing technique. We systematically reviewed publications measuring CVR using MRI up to June 2020, identifying 235 relevant papers. We summarised the acquisition methods, experimental parameters, hardware and CVR quantification approaches used, clinical populations investigated, and corresponding summary CVR measures. CVR was investigated in many pathologies such as steno-occlusive diseases, dementia and small vessel disease and is generally lower in patients than in healthy controls. Blood oxygen level dependent (BOLD) acquisitions with fixed inspired CO
gas or end-tidal CO
forcing stimulus are the most commonly used methods. General linear modelling of the MRI signal with end-tidal CO
as the regressor is the most frequently used method to compute CVR. Our survey of CVR measurement approaches and applications will help researchers to identify good practice and provide objective information to inform the development of future consensus recommendations.
Growing evidence suggests that increased intracranial pulsatility is associated with cerebral small vessel disease (SVD). We systematically reviewed papers that assessed intracranial pulsatility in ...subjects with SVD. We included 27 cross-sectional studies (
=3356): 20 used Doppler ultrasound and 7 used phase-contrast MRI. Most studies measured pulsatility in the internal carotid or middle cerebral arteries (ICA, MCA), whereas few assessed veins or cerebrospinal fluid (CSF). Methods to reduce bias and risk factor adjustment were poorly reported. Substantial variation between studies in assessment of SVD and of pulsatility indices precluded a formal meta-analysis. Eight studies compared pulsatility by SVD severity (
=26-159, median = 74.5): arterial pulsatility index was generally higher in more severe SVD (e.g. MCA: standardized mean difference = 3.24, 95% confidence interval 2.40, 4.07), although most did not match for age. Seventeen studies (
=9-700; median = 110) performed regression or correlation analysis, of which most showed that increased pulsatility was associated with SVD after adjustment for age. In conclusion, most studies support a cross-sectional association between higher pulsatility in large intracranial arteries and SVD. Future studies should minimize bias, adjust for potential confounders, include pulsatility in veins and CSF, and examine longitudinal relationship between pulsatility and SVD. Agreement on reliable measures of intracranial pulsatility would be helpful.
Cerebral small vessel disease (cSVD) comprises pathological processes of the small vessels in the brain that may manifest clinically as stroke, cognitive impairment, dementia, or gait disturbance. It ...is generally accepted that endothelial dysfunction, including blood-brain barrier (BBB) failure, is pivotal in the pathophysiology. Recent years have seen increasing use of imaging, primarily dynamic contrast-enhanced magnetic resonance imaging, to assess BBB leakage, but there is considerable variability in the approaches and findings reported in the literature. Although dynamic contrast-enhanced magnetic resonance imaging is well established, challenges emerge in cSVD because of the subtle nature of BBB impairment. The purpose of this work, authored by members of the HARNESS Initiative, is to provide an in-depth review and position statement on magnetic resonance imaging measurement of subtle BBB leakage in clinical research studies, with aspects requiring further research identified. We further aim to provide information and consensus recommendations for new investigators wishing to study BBB failure in cSVD and dementia.
The brain’s vasculature is essential for brain health and its dysfunction contributes to the onset and development of many dementias and neurological disorders. While numerous in vivo imaging ...techniques exist to investigate cerebral haemodynamics in humans, phase-contrast magnetic resonance imaging (MRI) has emerged as a reliable, non-invasive method of quantifying blood flow within intracranial vessels. In recent years, an advanced form of this method, known as 4D flow, has been developed and utilised in patient studies, where its ability to capture complex blood flow dynamics within any major vessel across the acquired volume has proved effective in collecting large amounts of information in a single scan. While extremely promising as a method of examining the vascular system’s role in brain-related diseases, the collection of 4D data can be time-consuming, meaning data quality has to be traded off against the acquisition time. Here, we review the available literature to examine 4D flow’s capabilities in assessing physiological and pathological features of the cerebrovascular system. Emerging techniques such as dynamic velocity-encoding and advanced undersampling methods, combined with increasingly high-field MRI scanners, are likely to bring 4D flow to the forefront of cerebrovascular imaging studies in the years to come.
Cerebral small vessel disease (SVD) is common during ageing and can present as stroke, cognitive decline, neurobehavioural symptoms, or functional impairment. SVD frequently coexists with ...neurodegenerative disease, and can exacerbate cognitive and other symptoms and affect activities of daily living. Standards for Reporting Vascular Changes on Neuroimaging 1 (STRIVE-1) categorised and standardised the diverse features of SVD that are visible on structural MRI. Since then, new information on these established SVD markers and novel MRI sequences and imaging features have emerged. As the effect of combined SVD imaging features becomes clearer, a key role for quantitative imaging biomarkers to determine sub-visible tissue damage, subtle abnormalities visible at high-field strength MRI, and lesion-symptom patterns, is also apparent. Together with rapidly emerging machine learning methods, these metrics can more comprehensively capture the effect of SVD on the brain than the structural MRI features alone and serve as intermediary outcomes in clinical trials and future routine practice. Using a similar approach to that adopted in STRIVE-1, we updated the guidance on neuroimaging of vascular changes in studies of ageing and neurodegeneration to create STRIVE-2.
Cerebral small vessel disease (SVD) contributes to 25% of ischemic strokes and 45% of dementias. We aimed to investigate the role of cerebral blood flow (CBF) and intracranial pulsatility in SVD. We ...scanned 60 patients with minor ischemic stroke, representing a range of white matter hyperintensities (WMH). We rated WMH and perivascular spaces (PVS) using semi-quantitative scales and measured WMH volume. We measured flow and pulsatility in the main cerebral vessels and cerebrospinal fluid (CSF) using phase-contrast MRI. We investigated the association between flow, pulsatility and SVD features. In 56/60 patients (40 male, 67.8±8.3 years) with complete data, median WMH volume was 10.7 mL (range 1.4–75.0 mL), representing median 0.77% (0.11–5.17%) of intracranial volume. Greater pulsatility index (PI) in venous sinuses was associated with larger WMH volume (e.g. superior sagittal sinus, β = 1.29, P < 0.01) and more basal ganglia PVS (e.g. odds ratio = 1.38, 95% confidence interval 1.06, 1.79, per 0.1 increase in superior sagittal sinus PI) independently of age, sex and blood pressure. CSF pulsatility and CBF were not associated with SVD features. Our results support a close association of SVD features with increased intracranial pulsatility rather than with low global CBF, and provide potential targets for mechanistic research, treatment and prevention of SVD.
PDF
