Perivascular Spaces, Glymphatic System and MR

Yu, Linya; Hu, Xiaofei; Li, Haitao; Zhao, Yi‐Lei

doi:10.3389/fneur.2022.844938

Cited by 48 publications

(53 citation statements)

References 105 publications

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“…They have a signal consistent with the cerebrospinal fluid and may be a marker of PVS dysfunction. 46 PVS are believed to be important conduits for the removal of metabolic waste and maintenance of homeostatic fluid circulation in the brain as part of the “glymphatic system.” 47 This has led to the suggestion that enlarged PVS reflect impairment of brain fluid and waste clearance. Increasing evidence suggests that they are another facet of SVD.…”

Section: Enlarged Perivascular Spaces; a New Player In Svd Pathogenesismentioning

confidence: 99%

Cerebral small vessel disease: Recent advances and future directions

Markus

Leeuw

2022

International Journal of Stroke

145

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Cerebral small vessel disease (SVD) causes lacunar stroke and intracerebral hemorrhage, and is the most common pathology underlying vascular cognitive impairment. Increasingly, the importance of other clinical features of SVD is being recognized including motor impairment, (vascular) parkinsonism, impaired balance, falls, and behavioral symptoms, such as depression, apathy, and personality change. Epidemiological data show a high prevalence of the characteristic magnetic resonance imaging (MRI) features of white matter hyperintensities and lacunar infarcts in community studies, and recent data suggest that it is also a major health burden in low- and middle-income countries. In this review, we cover advances in diagnosis, imaging, clinical presentations, pathogenesis, and treatment. The two most common pathologies underlying SVD are arteriolosclerosis caused by aging, hypertension, and other conventional vascular risk factors, and cerebral amyloid angiopathy (CAA) caused by vascular deposition of β-amyloid. We discuss the revised Boston criteria of CAA based on MRI features, which have been recently validated. Imaging is providing important insights into pathogenesis, including improved detection of tissue damage using diffusion tensor imaging (DTI) leading to its use to monitor progression and surrogate endpoints in clinical trials. Advanced MRI techniques can demonstrate functional or dynamic abnormalities of the blood vessels, while the high spatial resolution provided by ultrahigh field MRI at 7 T allows imaging of individual perforating arteries for the first time, and the measurement of flow velocity and pulsatility within these arteries. DTI and structural network analysis have highlighted the importance of network disruption in mediating the effect of different SVD pathologies in causing a number of symptoms, including cognitive impairment, apathy, and gait disturbance. Despite the public health importance of SVD, there are few proven treatments. We review the evidence for primary prevention, and recent data showing how intensive blood pressure lowering reduces white matter hyperintensities (WMH) progression and delays the onset of cognitive impairment. There are few treatments for secondary prevention, but a number of trials are currently evaluating novel treatment approaches. Recent advances have implicated molecular processes related to endothelial dysfunction, nitric oxide synthesis, blood–brain barrier integrity, maintenance and repair of the extracellular matrix, and inflammation. Novel treatment approaches are being developed to a number of these targets. Finally, we highlight the importance of large International collaborative initiatives in SVD to address important research questions and cover a number which have recently been established.

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Section: Enlarged Perivascular Spaces; a New Player In Svd Pathogenesismentioning

confidence: 99%

Cerebral small vessel disease: Recent advances and future directions

Markus

Leeuw

2022

International Journal of Stroke

145

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“…Interestingly, this finding points toward a size-selective nature of the PVS when clearing molecules from the brain. Moreover, this may suggest why large molecules found in AD, such as Aβ plaques, are deposited around blood vessels, as they simply cannot enter and be clear from the PVS ( Yu et al, 2022 ).…”

Section: Perivascular Spaces As a Biomarker For Alzheimer’s Diseasementioning

confidence: 99%

“…The Basal Ganglia and Centrum Semi-Ovale are currently implicated as the most accurate measures of PVS burden. Image from Yu et al (2022) .…”

Section: Perivascular Spaces As a Biomarker For Alzheimer’s Diseasementioning

confidence: 99%

Perivascular spaces as a potential biomarker of Alzheimer’s disease

et al. 2022

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Alzheimer’s disease (AD) is a highly damaging disease that affects one’s cognition and memory and presents an increasing societal and economic burden globally. Considerable research has gone into understanding AD; however, there is still a lack of effective biomarkers that aid in early diagnosis and intervention. The recent discovery of the glymphatic system and associated Perivascular Spaces (PVS) has led to the theory that enlarged PVS (ePVS) may be an indicator of AD progression and act as an early diagnostic marker. Visible on Magnetic Resonance Imaging (MRI), PVS appear to enlarge when known biomarkers of AD, amyloid-β and tau, accumulate. The central goal of ePVS and AD research is to determine when ePVS occurs in AD progression and if ePVS are causal or epiphenomena. Furthermore, if ePVS are indeed causative, interventions promoting glymphatic clearance are an attractive target for research. However, it is necessary first to ascertain where on the pathological progression of AD ePVS occurs. This review aims to examine the knowledge gap that exists in understanding the contribution of ePVS to AD. It is essential to understand whether ePVS in the brain correlate with increased regional tau distribution and global or regional Amyloid-β distribution and to determine if these spaces increase proportionally over time as individuals experience neurodegeneration. This review demonstrates that ePVS are associated with reduced glymphatic clearance and that this reduced clearance is associated with an increase in amyloid-β. However, it is not yet understood if ePVS are the outcome or driver of protein accumulation. Further, it is not yet clear if ePVS volume and number change longitudinally. Ultimately, it is vital to determine early diagnostic criteria and early interventions for AD to ease the burden it presents to the world; ePVS may be able to fulfill this role and therefore merit further research.

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“…Although much reduced compared to the BBB clearance, this system may compensate in case of the failure of other cerebral clearance pathways in pathological conditions, or it can be directly involved in vascular pathology such as amyloid angiopathy [ 51 ]. Additionally, the “glymphatic” system, the most recently described para-vascular drainage system [ 52 ], facilitates solutes clearance from the ISF via aquaporin 4 (AQP4) water channels and other insufficient explored mechanisms. In normal conditions, only some roles of the “glymphatic” system are described, such as waste clearance predominant during sleep [ 53 ]; however, emerging functions are expected to be discovered.…”

Section: Revising the Aβ Hypothesis And Dynamics—from The Anatomical−...mentioning

confidence: 99%

The “Cerebrospinal Fluid Sink Therapeutic Strategy” in Alzheimer’s Disease—From Theory to Design of Applied Systems

2022

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Alzheimer’s disease (AD) is a global health problem, with incidence and prevalence considered to increase during the next decades. However, no currently available effective treatment exists despite numerous clinical trials in progress. Moreover, although many hypotheses are accepted regarding the pathophysiological mechanisms of AD onset and evolution, there are still many unknowns about the disorder. A relatively new approach, based on the amyloid-beta dynamics among different biological compartments, is currently intensely discussed, as it seems to offer a promising solution with significant therapeutic impact. Known as the “cerebrospinal-fluid-sink therapeutic strategy”, part of the “three-sink therapeutic strategy”, this theoretical model focuses on the dynamics of amyloid-beta among the three main liquid compartments of the human body, namely blood, cerebrospinal fluid, and the (brain) interstitial fluid. In this context, this article aims to describe in detail the abovementioned hypothesis, by reviewing in the first part the most relevant anatomical and physiological aspects of amyloid-beta dynamics. Subsequently, explored therapeutic strategies based on the clearance of amyloid-beta from the cerebrospinal fluid level are presented, additionally highlighting their limitations. Finally, the originality and novelty of this work rely on the research experience of the authors, who focus on implantable devices and their utility in AD treatment.

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Perivascular Spaces, Glymphatic System and MR

Cited by 48 publications

References 105 publications

Cerebral small vessel disease: Recent advances and future directions

Cerebral small vessel disease: Recent advances and future directions

Perivascular spaces as a potential biomarker of Alzheimer’s disease

The “Cerebrospinal Fluid Sink Therapeutic Strategy” in Alzheimer’s Disease—From Theory to Design of Applied Systems

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