Gray matter blood flow and volume are reduced in association with white matter hyperintensity lesion burden: a cross-sectional MRI study

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.

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Associations between white matter hyperintensity burden, cerebral blood flow and transit time in small vessel disease: an updated meta-analysis

10.1101/2020.10.06.20207373 ◽

2020 ◽

Author(s):

Catriona R Stewart ◽

Michael S Stringer ◽

Yulu Shi ◽

Michael J Thrippleton ◽

Joanna M Wardlaw

Keyword(s):

Blood Flow ◽

Cerebral Blood Flow ◽

White Matter ◽

Longitudinal Studies ◽

Small Vessel Disease ◽

Meta Analysis ◽

Small Vessel ◽

White Matter Hyperintensity ◽

Cross Sectional ◽

Vessel Disease

AbstractCerebral small vessel disease is a major contributor to stroke and dementia, characterised by white matter hyperintensities (WMH) on neuroimaging. WMH are associated with reduced cerebral blood flow (CBF) cross-sectionally, though longitudinal associations remain unclear. We updated a 2016 meta-analysis, identifying 30 studies, 27 cross-sectional (n=2956) and 3 longitudinal (n=440), published since 2016. Cross-sectionally, we meta-analysed 10 new studies with 24 previously reported studies, total 34 (n=2180), finding lower CBF to be associated with worse WMH burden (mean global CBF: standardised mean difference: −0.45, 95% confidence interval (CI): −0.64,-0.27). Longitudinally, the association of baseline CBF with WMH progression varied: the largest study (5 years, n=252) found no associations, while another small study (4.5 years, n=52) found that low CBF in the periventricular WMH penumbra predicted WMH progression. We could not meta-analyse longitudinal studies due to different statistical and methodological approaches. We found lower CBF within WMH compared to normal appearing white matter (novel meta-analysis; 5 cross-sectional studies; n=295; SMD: −1.51, 95% CI: −1.94,-1.07). These findings highlight that relationships between resting CBF and WMH are complex and that more longitudinal studies analysing regional CBF and subsequent WMH change are required to determine the role of CBF in small vessel disease progression.

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Association of Age at Onset With Gray Matter Volume and White Matter Microstructural Abnormalities in People With Multiple Sclerosis

Neurology ◽

10.1212/wnl.0000000000012869 ◽

2021 ◽

pp. 10.1212/WNL.0000000000012869

Author(s):

Raffaello Bonacchi ◽

Alessandro Meani ◽

Elisabetta Pagani ◽

Olga Marchesi ◽

Andrea Falini ◽

...

Keyword(s):

Multiple Sclerosis ◽

White Matter ◽

Gray Matter ◽

Linear Models ◽

Gray Matter Volume ◽

Age At Onset ◽

Healthy Controls ◽

Compensatory Mechanisms ◽

Cross Sectional ◽

Matter Volume

Objective:To investigate whether age at onset influences brain gray matter volume (GMV) and white matter (WM) microstructural abnormalities in adult multiple sclerosis (MS) patients, given its influence on clinical phenotype and disease course.Method:In this hypothesis-driven cross-sectional study, we enrolled 67 pediatric-onset MS (POMS) patients and 143 sex- and disease duration (DD)-matched randomly-selected adult-onset MS (AOMS) patients, together with 208 healthy controls. All subjects underwent neurological evaluation and 3T MRI acquisition. MRI variables were standardized based on healthy controls, to remove effects of age and sex. Associations with DD in POMS and AOMS patients were studied with linear models. Time to reach clinical and MRI milestones was assessed with product-limit approach.Results:At DD=1 year, GMV and WM fractional anisotropy (FA) were abnormal in AOMS but not in POMS patients. Significant interaction of age at onset (POMS vs AOMS) into the association with DD was found for GMV and WM FA. The crossing point of regression lines in POMS and AOMS patients was at 20 years of DD for GMV and 14 for WM FA. For POMS and AOMS patients, median DD was 29 and 19 years to reach Expanded Disability Status Scale=3 (p<0.001), 31 and 26 years to reach abnormal Paced Auditory Serial Addition Task-3 (p=0.01), 24 and 18 years to reach abnormal GMV (p=0.04), and 19 and 17 years to reach abnormal WM FA (p=0.36).Conclusions:Younger patients are initially resilient to MS-related damage. Then, compensatory mechanisms start failing with loss of WM integrity, followed by GM atrophy and finally disability.

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Trial of remote ischaemic preconditioning in vascular cognitive impairment (TRIC-VCI): protocol

BMJ Open ◽

10.1136/bmjopen-2020-040466 ◽

2020 ◽

Vol 10 (10) ◽

pp. e040466

Author(s):

Aravind Ganesh ◽

Philip Barber ◽

Sandra E Black ◽

Dale Corbett ◽

Thalia S Field ◽

...

Keyword(s):

Blood Flow ◽

Cerebral Blood Flow ◽

Cognitive Impairment ◽

White Matter ◽

Diffusion Tensor ◽

Vascular Cognitive Impairment ◽

White Matter Injury ◽

White Matter Hyperintensity ◽

Limb Ischaemia ◽

Ischaemic Brain

IntroductionCerebral small vessel disease (cSVD) accounts for 20%–25% of strokes and is the most common cause of vascular cognitive impairment (VCI). In an animal VCI model, inducing brief periods of limb ischaemia-reperfusion reduces subsequent ischaemic brain injury with remote and local protective effects, with hindlimb remote ischaemic conditioning (RIC) improving cerebral blood flow, decreasing white-matter injury and improving cognition. Small human trials suggest RIC is safe and may prevent recurrent strokes. It remains unclear what doses of chronic daily RIC are tolerable and safe, whether effects persist after treatment cessation, and what parameters are optimal for treatment response.Methods and analysisThis prospective, open-label, randomised controlled trial (RCT) with blinded end point assessment and run-in period, will recruit 24 participants, randomised to one of two RIC intensity groups: one arm treated once daily or one arm twice daily for 30 consecutive days. RIC will consistent of 4 cycles of blood pressure cuff inflation to 200 mm Hg for 5 min followed by 5 min deflation (total 35 min). Selection criteria include: age 60–85 years, evidence of cSVD on brain CT/MRI, Montreal Cognitive Assessment (MoCA) score 13–24 and preserved basic activities of living. Outcomes will be assessed at 30 days and 90 days (60 days after ceasing treatment). The primary outcome is adherence (completing ≥80% of sessions). Secondary safety/tolerability outcomes include the per cent of sessions completed and pain/discomfort scores from patient diaries. Efficacy outcomes include changes in cerebral blood flow (per arterial spin-label MRI), white-matter hyperintensity volume, diffusion tensor imaging, MoCA and Trail-Making tests.Ethics and disseminationResearch Ethics Board approval has been obtained. The results will provide information on feasibility, dose, adherence, tolerability and outcome measures that will help design a phase IIb RCT of RIC, with the potential to prevent VCI. Results will be disseminated through peer-reviewed publications, organisations and meetings.Trial registration numberNCT04109963.

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Association of Carotid Atherosclerosis With White Matter Hyperintensity in an Asymptomatic Japanese Population: A Cross-Sectional Study

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2021.665573 ◽

2021 ◽

Vol 8 ◽

Author(s):

Li Zhang ◽

Quan Zhou ◽

Li Hua Shao ◽

Jun Wen ◽

Jun Xia

Keyword(s):

White Matter ◽

Carotid Artery ◽

Japanese Population ◽

Carotid Atherosclerosis ◽

Smoking Status ◽

White Matter Hyperintensity ◽

Large Artery ◽

Cross Sectional ◽

Carotid Artery Plaque ◽

Plaque Score

Objective: A limited number of scholars concentrated on the relationship between carotid atherosclerosis (CAS) and white matter hyperintensity (WMH) (i.e., CAS-WMH relationship). The current research aimed to clarify the CAS-WMH relationship in Japanese population.Methods: All participants underwent MRI of head and ultrasonography of the carotid artery. WMH was diagnosed from MRI results. The carotid ultrasound findings, carotid artery plaque score (PS), and plaque number (PN) could be achieved to indicate the severity of CAS. We also employed multivariate logistic regression models to estimate the CAS-WMH relationship. Interaction and stratified analyses were undertaken on the basis of a number of factors (e.g., gender, age, smoking status, drinking habit, and history of chronic diseases).Results: A total of 1,904 Japanese subjects were included, and the prevalence of WMH was 54.8% (1,044/1,904). It was unveiled that frequency of CAS was greater in cases with WMH. In a fully adjusted model, high PS was associated with the frequency of WMH, followed by high PN. Further analyses revealed a dose-response relationship between PS and incidence of WMH.Conclusion: PS and PN exhibited the greatest influences on determining the frequency of WMH, highlighting the potentially important pathophysiological role of large artery atherosclerosis in intensifying WMH.

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Characterizing the white matter hyperintensity penumbra with cerebral blood flow measures

NeuroImage Clinical ◽

10.1016/j.nicl.2015.04.012 ◽

2015 ◽

Vol 8 ◽

pp. 224-229 ◽

Cited By ~ 47

Author(s):

N. Promjunyakul ◽

D. Lahna ◽

J.A. Kaye ◽

H.H. Dodge ◽

D. Erten-Lyons ◽

...

Keyword(s):

Blood Flow ◽

Cerebral Blood Flow ◽

White Matter ◽

White Matter Hyperintensity

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Quantifying the Link between Anatomical Connectivity, Gray Matter Volume and Regional Cerebral Blood Flow: An Integrative MRI Study

PLoS ONE ◽

10.1371/journal.pone.0014801 ◽

2011 ◽

Vol 6 (4) ◽

pp. e14801 ◽

Cited By ~ 26

Author(s):

Bálint Várkuti ◽

Mustafa Cavusoglu ◽

Alexander Kullik ◽

Björn Schiffler ◽

Ralf Veit ◽

...

Keyword(s):

Blood Flow ◽

Cerebral Blood Flow ◽

Gray Matter ◽

Regional Cerebral Blood Flow ◽

Gray Matter Volume ◽

Regional Cerebral Blood ◽

Anatomical Connectivity ◽

Matter Volume ◽

Mri Study

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Arterial stiffness and dementia pathology

Neurology ◽

10.1212/wnl.0000000000005259 ◽

2018 ◽

Vol 90 (14) ◽

pp. e1248-e1256 ◽

Cited By ~ 42

Author(s):

Timothy M. Hughes ◽

Lynne E. Wagenknecht ◽

Suzanne Craft ◽

Akiva Mintz ◽

Gerardo Heiss ◽

...

Keyword(s):

White Matter ◽

Arterial Stiffness ◽

Small Vessel Disease ◽

Brain Mri ◽

Volume Ratio ◽

Cognitive Testing ◽

White Matter Hyperintensity ◽

Cross Sectional ◽

Brain Volumes ◽

Atherosclerosis Risk In Communities

ObjectiveArterial stiffness has been associated with evidence of cerebral small vessel disease (cSVD) and fibrillar β-amyloid (Aβ) deposition in the brain. These complex relationships have not been examined in racially and cognitively diverse cohorts.MethodsThe Atherosclerosis Risk in Communities (ARIC)–Neurocognitive Study collected detailed cognitive testing for adjudication of dementia and mild cognitive impairment (MCI), brain MRI, and arterial stiffness by pulse wave velocity (PWV, carotid-femoral [cfPWV] and heart-carotid [hcPWV]). The ARIC-PET ancillary study added Aβ imaging using florbetapir ([18F]-AV-45) to obtain standardized uptake volume ratios and defined global Aβ-positivity as standardized uptake volume ratio >1.2. One-SD increase in PWV was related to brain volume, MRI-defined cSVD (e.g., cerebral microbleeds and white matter hyperintensity), and cortical Aβ deposition adjusted for age, body mass index, sex, race, and APOE ε4 status. We examined the cross-sectional relationships including interactions by race, APOE ε4 status, and cognition.ResultsAmong the 320 ARIC-PET participants (76 [5] years, 45% black, 27% MCI), greater central stiffness (hcPWV) was associated with greater Aβ deposition (odds ratio [OR] = 1.31, 95% confidence interval [CI] 1.01–1.71). Greater central stiffness (cfPWV) was significantly associated with having lower brain volumes in Alzheimer disease–susceptible regions (in mm3, β = −1.5 [0.7 SD], p = 0.03) and high white matter hyperintensity burden (OR = 1.6, 95% CI 1.2–2.1). Furthermore, cfPWV was associated with a higher odds of concomitant high white matter hyperintensity and Aβ-positive scans (OR = 1.4, 95% CI 1.1–2.1). These associations were strongest among individuals with MCI and did not differ by race or APOE ε4 status.ConclusionsArterial stiffness, measured by PWV, is an emerging risk factor for dementia through its repeated relationships with cognition, cSVD, and Aβ deposition.

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Baseline vs. cross-sectional MRI of concussion: distinct brain patterns in white matter and cerebral blood flow

Scientific Reports ◽

10.1038/s41598-020-58073-9 ◽

2020 ◽

Vol 10 (1) ◽

Cited By ~ 1

Author(s):

Nathan W. Churchill ◽

Michael G. Hutchison ◽

Simon J. Graham ◽

Tom A. Schweizer

Keyword(s):

Blood Flow ◽

Cerebral Blood Flow ◽

White Matter ◽

Cross Sectional

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Characteristics of reactive hyperemia in the cerebral circulation

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1984.246.1.h52 ◽

1984 ◽

Vol 246 (1) ◽

pp. H52-H58 ◽

Cited By ~ 7

Author(s):

J. K. Gourley ◽

D. D. Heistad

Keyword(s):

Blood Flow ◽

White Matter ◽

Cerebral Ischemia ◽

Gray Matter ◽

Cerebral Circulation ◽

Time Course ◽

Reactive Hyperemia ◽

Arterial Occlusion ◽

Maximal Peak ◽

Minimal Resistance

Reactive hyperemia has been characterized in many vascular beds, but little is known about quantitative characteristics of reactive hyperemia in the cerebral circulation. We measured velocity of blood flow and pial artery diameter to characterize the time course of reactive hyperemia and used microspheres to study regional blood flow in the brain. Cerebral ischemia was produced by raising intracranial pressure or by arterial occlusion with a cuff around the neck. Five seconds of ischemia produced virtually maximal peak reactive hyperemia, and 30 s of ischemia produced maximal peak reactive hyperemia. During reactive hyperemia after 30 s of cerebral ischemia, there was a three- to fourfold increase in cerebral blood flow. The magnitude of reactive hyperemia was greater in gray matter than in white matter. Minimal resistance during reactive hyperemia, after ischemia produced by arterial occlusion, is similar to minimal resistance during seizures or hypercapnia, which suggests that reactive hyperemia produces maximal vasodilatation. Oxygen saturation of cerebral venous blood increased almost twofold during reactive hyperemia, which indicates that factors in addition to venous (and presumably tissue) oxygen are important determinants of reactive hyperemia. In summary, 1) we have characterized the time course of reactive hyperemia in the cerebral circulation; 2) reactive hyperemia after arterial occlusion produces maximal cerebral vasodilatation; and 3) there is marked heterogeneity of the response, with much larger increases in flow in cortical gray matter than white matter.

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