Blood-Brain Barrier Opening with MRI-guided Focused Ultrasound Elicits Meningeal Venous Permeability in Humans with Early Alzheimer Disease DOI
Rashi I. Mehta, Jeffrey Carpenter, Rupal I. Mehta

et al.

Radiology, Journal Year: 2021, Volume and Issue: 298(3), P. 654 - 662

Published: Jan. 5, 2021

Background Opening of the blood-brain barrier (BBB) induced with MRI-guided focused ultrasound has been shown in experimental animal models to reduce amyloid-β plaque burden, improve memory performance, and facilitate delivery therapeutic agents brain. However, physiologic effects this procedure humans Alzheimer disease (AD) require further investigation. Purpose To assess imaging ultrasound–induced BBB opening hippocampus human participants early AD evaluate fluid flow patterns after by using serial contrast-enhanced MRI. Materials Methods Study recruited a Health Insurance Portability Accountability Act–compliant, prospective, ongoing phase II clinical trial (ClinicalTrials.gov identifier, NCT03671889) underwent three separate procedures that used 220-kHz transducer concomitant intravenous microbubble contrast agent administered at 2-week intervals targeting entorhinal cortex between October 2018 May 2019. Posttreatment gadolinium-based enhancement were evaluated 3.0-T Results Three women (aged 61, 72, 73 years) consecutively enrolled successfully completed repeated cortex. Postprocedure was clearly identified within targeted brain volumes, indicating immediate spatially precise opening. Parenchymal resolved 24 hours all treatments, confirming closure. Transient perivenous consistently observed during acute Notably, reappeared perivenular regions This marker is consistent blood-meningeal permeability persisted for 24–48 before spontaneous resolution. No evidence intracranial hemorrhage or other adverse effect identified. Conclusion safely performed hippocampi without any effects. MRI reveals unique spatiotemporal pattern suggests immunologic healing response downstream from sites. © RSNA, 2021 Online supplemental material available article. See also editorial Klibanov issue.

Language: Английский

Small vessel disease: mechanisms and clinical implications DOI
Joanna M. Wardlaw, Colin Smith, Martin Dichgans

et al.

The Lancet Neurology, Journal Year: 2019, Volume and Issue: 18(7), P. 684 - 696

Published: May 13, 2019

Language: Английский

Citations

1228
Perivascular spaces in the brain: anatomy, physiology and pathology DOI
Joanna M. Wardlaw, Helene Benveniste,

Maiken Nedergaard

et al.

Nature Reviews Neurology, Journal Year: 2020, Volume and Issue: 16(3), P. 137 - 153

Published: Feb. 24, 2020

Language: Английский

Citations

610
Vascular Cognitive Impairment and Dementia DOI Creative Commons
Costantino Iadecola, Marco Duering, Vladimir Hachinski

et al.

Journal of the American College of Cardiology, Journal Year: 2019, Volume and Issue: 73(25), P. 3326 - 3344

Published: June 24, 2019

Language: Английский

Citations

551
Neurovascular and Cognitive Dysfunction in Hypertension DOI Open Access
Costantino Iadecola, Rebecca F. Gottesman

Circulation Research, Journal Year: 2019, Volume and Issue: 124(7), P. 1025 - 1044

Published: March 28, 2019

Hypertension has emerged as a leading cause of age-related cognitive impairment. Long known to be associated with dementia caused by vascular factors, hypertension more recently been linked also Alzheimer disease-the major in older people. Thus, although midlife is risk factor for late-life dementia, may promote the neurodegenerative pathology underlying disease. The mechanistic bases these harmful effects remain established. well alter structure and function cerebral blood vessels, but how cerebrovascular lead impairment disease not understood. Furthermore, critical questions concern whether treatment prevents impairment, pressure threshold treatment, antihypertensive agents used. Recent advances neurovascular biology, epidemiology, brain imaging, biomarker development have started provide new insights into issues. In this review, we will examine progress made date, and, after evaluation evidence, highlight still outstanding seek path forward future studies.

Language: Английский

Citations

402
Fluid transport in the brain DOI
Martin Kaag Rasmussen, Humberto Mestre, Maiken Nedergaard

et al.

Physiological Reviews, Journal Year: 2021, Volume and Issue: 102(2), P. 1025 - 1151

Published: May 5, 2021

The brain harbors a unique ability to, figuratively speaking, shift its gears. During wakefulness, the is geared fully toward processing information and behaving, while homeostatic functions predominate during sleep. blood-brain barrier establishes stable environment that optimal for neuronal function, yet imposes physiological problem; transcapillary filtration forms extracellular fluid in other organs reduced to minimum brain. Consequently, depends on special [the cerebrospinal (CSF)] flushed into along perivascular spaces created by astrocytic vascular endfeet. We describe this pathway, coined term glymphatic system, based dependency endfeet their adluminal expression of aquaporin-4 water channels facing CSF-filled spaces. Glymphatic clearance potentially harmful metabolic or protein waste products, such as amyloid-β, primarily active sleep, when drivers, cardiac cycle, respiration, slow vasomotion, together efficiently propel CSF inflow periarterial brain's space contains an abundance proteoglycans hyaluronan, which provide low-resistance hydraulic conduit rapidly can expand shrink sleep-wake cycle. system brain, meets requisites maintain homeostasis similar peripheral organs, considering blood-brain-barrier paths formation egress CSF.

Language: Английский

Citations

331
Cognitive impact of COVID-19: looking beyond the short term DOI Creative Commons
J. Scott Miners, Patrick G. Kehoe, Seth Love

et al.

Alzheimer s Research & Therapy, Journal Year: 2020, Volume and Issue: 12(1)

Published: Dec. 1, 2020

COVID-19 is primarily a respiratory disease but up to two thirds of hospitalised patients show evidence central nervous system (CNS) damage, predominantly ischaemic, in some cases haemorrhagic and occasionally encephalitic. It unclear how much the ischaemic damage mediated by direct or inflammatory effects virus on CNS vasculature secondary extracranial cardiorespiratory disease. Limited data suggest that causative SARS-CoV-2 may enter via nasal mucosa olfactory fibres, haematogenous spread, capable infecting endothelial cells, pericytes probably neurons. Extracranially, targets cells pericytes, causing cell dysfunction, vascular leakage immune activation, sometimes leading disseminated intravascular coagulation. remains be confirmed whether cerebral are similarly targeted. Several aspects likely impact cognition. Cerebral white matter particularly vulnerable also critically important for cognitive function. There accumulating hypoperfusion accelerates amyloid-β (Aβ) accumulation linked tau TDP-43 pathology, inducing phosphorylation α-synuclein at serine-129, ischaemia increase risk development Lewy body Current therapies understandably focused supporting function, preventing thrombosis reducing activation. Since angiotensin-converting enzyme (ACE)-2 receptor SARS-CoV-2, ACE inhibitors angiotensin blockers predicted ACE-2 expression, it was initially feared their use might exacerbate COVID-19. Recent meta-analyses have instead suggested these medications protective. This perhaps because entry deplete ACE-2, tipping balance towards II-ACE-1-mediated classical RAS activation: exacerbating promoting inflammation. relevant APOE ε4 individuals, who seem increased COVID-19, lowest activity. leave an unexpected legacy long-term neurological complications significant number survivors. Cognitive follow-up will important, especially develop cerebrovascular during acute illness.

Language: Английский

Citations

219
The glymphatic system: Current understanding and modeling DOI Creative Commons
Tomas Bohr, Poul G. Hjorth, Sebastian C. Holst

et al.

iScience, Journal Year: 2022, Volume and Issue: 25(9), P. 104987 - 104987

Published: Aug. 20, 2022

We review theoretical and numerical models of the glymphatic system, which circulates cerebrospinal fluid interstitial around brain, facilitating solute transport. Models enable hypothesis development predictions transport, with clinical applications including drug delivery, stroke, cardiac arrest, neurodegenerative disorders like Alzheimer's disease. sort existing into broad categories by anatomical function: Perivascular flow, transport in brain parenchyma, interfaces to perivascular spaces, efflux routes, links neuronal activity. Needs opportunities for future work are highlighted wherever possible; new models, expanded novel experiments inform could all have tremendous value advancing field.

Language: Английский

Citations

175
Pathophysiology of blood brain barrier dysfunction during chronic cerebral hypoperfusion in vascular cognitive impairment DOI Creative Commons

Vismitha Rajeev,

David Y. Fann,

Quynh Nhu Dinh

et al.

Theranostics, Journal Year: 2022, Volume and Issue: 12(4), P. 1639 - 1658

Published: Jan. 1, 2022

The prevalence of cerebrovascular disease increases with age, placing the elderly at a greater lifetime risk for dementia. Vascular cognitive impairment (VCI) encompasses spectrum deficits from mild to VCI and its most severe form, vascular dementia (VaD), is becoming major public health concern worldwide. As growing efforts are being taken understand VaD in animal models humans, pathogenesis actively explored. It postulated that chronic cerebral hypoperfusion (CCH) cause VCI. CCH activates molecular cellular injury cascade leads breakdown blood brain barrier (BBB) neurodegeneration. BBB tightly regulates movement substances between brain, thereby regulating microenvironment within parenchyma. Here we illustrate how damage causal through increased activation pathways related excitotoxicity, oxidative stress, inflammation matrix metalloproteinases lead downstream perivascular damage, leukocyte infiltration white matter changes brain. Thus, CCH-induced may initiate contribute vicious cycle, resulting progressive neuropathological This review outlines mechanisms govern during highlights clinical evidence identifying at-risk patients.

Language: Английский

Citations

160
Cognitive impairment in sporadic cerebral small vessel disease: A systematic review and meta‐analysis DOI Creative Commons
Olivia KL Hamilton, Ellen V. Backhouse, Esther Janssen

et al.

Alzheimer s & Dementia, Journal Year: 2020, Volume and Issue: 17(4), P. 665 - 685

Published: Nov. 13, 2020

Abstract This paper is a proposal for an update on the characterization of cognitive impairments associated with sporadic cerebral small vessel disease (SVD). We pose series questions about nature SVD‐related and provide answers based comprehensive review meta‐analysis published data from 69 studies. Although SVD thought primarily to affect executive function processing speed, we hypothesize that affects all major domains ability. also identify low levels education as potentially modifiable risk factor impairment. Therefore, propose use assessments measurement educational level both in clinics research settings, suggest several recommendations future research.

Language: Английский

Citations

141
Age-related immune alterations and cerebrovascular inflammation DOI Creative Commons
Carson Finger, Inés Moreno‐González, Antonia Gutiérrez

et al.

Molecular Psychiatry, Journal Year: 2021, Volume and Issue: 27(2), P. 803 - 818

Published: Oct. 28, 2021

Abstract Aging is associated with chronic systemic inflammation, which contributes to the development of many age-related diseases, including vascular disease. The world’s population aging, leading an increasing prevalence both stroke and dementia. inflammatory response ischemic critical pathophysiology recovery. Age a predictor poor outcomes after stroke. immune altered in aged individuals, disparate between young patients. In this review, we describe current knowledge effects aging on system cerebral vasculature how these changes alter dementia animal human studies. Potential implications alterations inflammation disease outcome are highlighted.

Language: Английский

Citations

116