Cerebral amyloid angiopathy and Alzheimer disease — one peptide, two pathways

Nature Reviews Neurology, Год журнала: 2019, Номер 16(1), С. 30 - 42

Опубликована: Дек. 11, 2019

Язык: Английский

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Perivascular spaces in the brain: anatomy, physiology and pathology

Nature Reviews Neurology, Год журнала: 2020, Номер 16(3), С. 137 - 153

Опубликована: Фев. 24, 2020

Язык: Английский

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Emerging concepts in sporadic cerebral amyloid angiopathy

Brain, Год журнала: 2017, Номер 140(7), С. 1829 - 1850

Опубликована: Фев. 27, 2017

Sporadic cerebral amyloid angiopathy is a common, well-defined small vessel disease and largely untreatable cause of intracerebral haemorrhage contributor to age-related cognitive decline. The term 'cerebral angiopathy' now encompasses not only specific cerebrovascular pathological finding, but also different clinical syndromes (both acute progressive), brain parenchymal lesions seen on neuroimaging set diagnostic criteria—the Boston criteria, which have resulted in increasingly detected during life. Over the past few years, it has become clear that, at pathophysiological level, appears be part protein elimination failure that this dysfunction feed-forward process, potentially leads worsening vascular amyloid-β accumulation, activation injury pathways impaired physiology. From standpoint, characterized by individual focal (microbleeds, cortical superficial siderosis, microinfarcts) large-scale alterations (white matter hyperintensities, structural connectivity, thickness), both subcortical. This review provides an interdisciplinary critical outlook various emerging changing concepts field, illustrating mechanisms associated with pathology neurological dysfunction.

Язык: Английский

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Pathophysiologic relationship between Alzheimer's disease, cerebrovascular disease, and cardiovascular risk: A review and synthesis

Alzheimer s & Dementia Diagnosis Assessment & Disease Monitoring, Год журнала: 2017, Номер 7(1), С. 69 - 87

Опубликована: Янв. 1, 2017

Abstract As the population ages due to demographic trends and gains in life expectancy, incidence prevalence of dementia increases, need understand etiology pathogenesis becomes ever more urgent. Alzheimer's disease (AD), most common form dementia, is a complex disease, mechanisms which are poorly understood. The we learn about AD, questions raised our current conceptual models disease. In absence cure or means by slow progress, it may be prudent apply knowledge intersection between cardiovascular cerebrovascular foster efforts delay onset AD. This review discusses understanding epidemiology, genetics, pathophysiology AD vascular causes proposes future directions for research prevention.

Язык: Английский

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Understanding the role of the perivascular space in cerebral small vessel disease

Cardiovascular Research, Год журнала: 2018, Номер 114(11), С. 1462 - 1473

Опубликована: Май 2, 2018

Small vessel diseases (SVDs) are a group of disorders that result from pathological alteration the small blood vessels in brain, including arteries, capillaries and veins. Of 35–36 million people estimated to suffer dementia worldwide, up 65% have an SVD component. Furthermore, causes 20–25% strokes, worsens outcome after stroke is leading cause disability, cognitive impairment poor mobility. Yet underlying cause(s) not fully understood. Magnetic resonance imaging has confirmed enlarged perivascular spaces (PVS) as hallmark feature SVD. In healthy tissue, these proposed form part complex brain fluid drainage system which supports interstitial exchange may also facilitate clearance waste products brain. The pathophysiological signature PVS what this infers about their function interaction with cerebral microcirculation, plus subsequent downstream effects on lesion development been established. Here we discuss potential be unique biomarker for related vascular We propose widening suggests presence peri-vascular cell debris other vicious cycle involving impaired cerebrovascular reactivity, blood-brain barrier dysfunction, inflammation ultimately proteins space, accumulation toxins, hypoxia, tissue damage. Here, outline current knowledge, questions hypotheses regarding understanding dynamics underpinning through common denominator

Язык: Английский

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Cerebrovascular disease in ageing and Alzheimer’s disease

Acta Neuropathologica, Год журнала: 2015, Номер 131(5), С. 645 - 658

Опубликована: Дек. 28, 2015

Cerebrovascular disease (CVD) and Alzheimer's (AD) have more in common than their association with ageing. They share risk factors overlap neuropathologically. Most patients AD Aβ amyloid angiopathy degenerative changes affecting capillaries, many ischaemic parenchymal abnormalities. Structural vascular contributes to the abnormalities some AD. However, stereotyped progression of hypoperfusion this disease, first precuneus cingulate gyrus, then frontal temporal cortex lastly occipital cortex, suggests that other are important, particularly early disease. Whilst demand for oxygen glucose falls late functional MRI, near infrared spectroscopy measure saturation haemoglobin by oxygen, biochemical analysis myelin proteins differential susceptibility reduced oxygenation all shown reduction blood flow is primarily a problem inadequate supply, not metabolic demand. Increasing evidence points non-structural dysfunction rather structural vessel walls as main cause cerebral Several mediators probably responsible. One emerging major contributor vasoconstrictor endothelin-1 (EDN1). there clearly an additive component clinical pathological effects AD, experimental observations suggest processes also interact mechanistically at cellular level manner exacerbates both. The elucidation mechanisms responsible interactions between CVD has led identification several novel therapeutic approaches potential ameliorate damage slow neurodegenerative

Язык: Английский

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Vascular basement membranes as pathways for the passage of fluid into and out of the brain

Acta Neuropathologica, Год журнала: 2016, Номер 131(5), С. 725 - 736

Опубликована: Март 14, 2016

In the absence of conventional lymphatics, drainage interstitial fluid and solutes from brain parenchyma to cervical lymph nodes is along basement membranes in walls cerebral capillaries tunica media arteries. Perivascular pathways are also involved entry CSF into by convective influx/glymphatic system. The objective this study differentiate vascular membrane which passes out pathway enters brain. Experiment 1: 0.5 µl soluble biotinylated or fluorescent Aβ, 1 15 nm gold nanoparticles was injected mouse hippocampus their distributions determined at 5 min transmission electron microscopy. Aβ distributed within extracellular spaces Nanoparticles did not enter capillary spaces. 2: 2 were CSF. Within min, groups present pial-glial on outer aspect cortical arteries between investing layer pia mater glia limitans. results previous research suggest that form but different layers involved. significance these findings for neuroimmunology, Alzheimer's disease, drug delivery concept Virchow-Robin space discussed.

Язык: Английский

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Neurofilaments: neurobiological foundations for biomarker applications

Brain, Год журнала: 2020, Номер 143(7), С. 1975 - 1998

Опубликована: Март 13, 2020

Interest in neurofilaments has risen sharply recent years with recognition of their potential as biomarkers brain injury or neurodegeneration CSF and blood. This is the context a growing appreciation for complexity neurobiology neurofilaments, new specialized roles synapses developing understanding mechanisms responsible turnover. Here we will review neurofilament proteins, describing current structure function, including recently discovered evidence synapses. We explore emerging degradation clearance methods future elucidation kinetics turnover humans. Primary pathogenesis human diseases be described. With this background, then critically supporting use concentration measures neuronal degeneration. Finally, reflect on major challenges studies intermediate filaments specific attention to identifying what needs learned more precise confident interpretation neurodegeneration.

Язык: Английский

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Convective influx/glymphatic system: tracers injected into the CSF enter and leave the brain along separate periarterial basement membrane pathways

Acta Neuropathologica, Год журнала: 2018, Номер 136(1), С. 139 - 152

Опубликована: Май 12, 2018

Tracers injected into CSF pass the brain alongside arteries and out again. This has been recently termed "glymphatic system" that proposes tracers enter along periarterial "spaces" leave walls of veins. The object present study is to test hypothesis that: (1) from cerebral cortex pial-glial basement membranes as there are no perivascular around cortical arteries, (2) smooth muscle cell form Intramural Peri-Arterial Drainage (IPAD) pathways for elimination interstitial fluid solutes brain. 2 μL 100 μM soluble, fluorescent fixable amyloid β (Aβ) were cisterna magna 6-10 24-30 month-old male mice their brains examined 5 30 min later. At min, immunocytochemistry confocal microscopy revealed Aβ on outer aspects colocalized with α-2 laminin in membranes. was colocalised collagen IV corresponding IPAD pathways. No evidence drainage veins found. Measurements depth penetration tracer taken 11 regions Maximum depths achieved pons caudoputamen. Conclusions drawn separate membrane exit route which accumulates angiopathy (CAA) Alzheimer's disease. Results this suggest may be a suitable delivery therapies neurological diseases, including CAA.

Язык: Английский

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Cognitive impact of COVID-19: looking beyond the short term

Alzheimer s Research & Therapy, Год журнала: 2020, Номер 12(1)

Опубликована: Дек. 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.

Язык: Английский

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