Cerebral Blood Flow Measured by Arterial Spin Labeling MRI as a Preclinical Marker of Alzheimer's Disease

Wierenga, Christina E.; Hays, Chelsea C.; Zlatar, Zvinka Z.

doi:10.3233/jad-141467

Cited by 188 publications

(180 citation statements)

References 63 publications

(97 reference statements)

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“…For example, extravasation of plasma proteins into the brain parenchyma causes glial activation (40,41), and the accompanying edema can cause narrowing of vessels, resulting in cerebral blood flow (CBF) disturbances (42). Glial activation (43,44) and CBF disruption (45,46) are early events in AD development that can directly contribute to neuronal dysfunction (12,38,47).…”

Section: Discussionmentioning

confidence: 99%

Activation of the factor XII-driven contact system in Alzheimer’s disease patient and mouse model plasma

Zamolodchikov

Chen

Conti

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

144

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Alzheimer's disease (AD) is characterized by accumulation of the β-amyloid peptide (Aβ), which likely contributes to disease via multiple mechanisms. Increasing evidence implicates inflammation in AD, the origins of which are not completely understood. We investigated whether circulating Aβ could initiate inflammation in AD via the plasma contact activation system. This proteolytic cascade is triggered by the activation of the plasma protein factor XII (FXII) and leads to kallikrein-mediated cleavage of high molecular-weight kininogen (HK) and release of proinflammatory bradykinin. Aβ has been shown to promote FXII-dependent cleavage of HK in vitro. In addition, increased cleavage of HK has been found in the cerebrospinal fluid of patients with AD. Here, we show increased activation of FXII, kallikrein activity, and HK cleavage in AD patient plasma. Increased contact system activation is also observed in AD mouse model plasma and in plasma from wild-type mice i.v. injected with Aβ42. Our results demonstrate that Aβ42-mediated contact system activation can occur in the AD circulation and suggest new pathogenic mechanisms, diagnostic tests, and therapies for AD.Alzheimer's disease | factor XII | high molecular-weight kininogen | plasma kallikrein A lzheimer's disease (AD) is a progressive neurodegenerative disorder with a complex and still poorly defined etiology. Although multiple factors are likely involved in AD onset and development, a growing body of evidence implicates both neuroinflammation and peripheral inflammation in the disease (1-3). Pathways capable of triggering inflammatory processes are therefore of particular interest to AD etiology and pathogenesis. One such pathway is the contact activation system, which is initiated when the plasma protein factor XII (FXII) is exposed to negatively charged surfaces (contact activation). Contact-activated FXII (FXIIa) triggers plasma kallikrein-mediated cleavage of high molecular-weight kininogen (HK) to release bradykinin, which promotes inflammatory processes including increased bloodbrain barrier permeability, edema, and cytokine expression (4) via interaction with receptors B 1 and B 2 (5). In AD, a possible surface for FXII activation could be the AD-associated peptide beta-amyloid (Aβ), which has been shown to stimulate FXII-dependent plasma kallikrein activity (6, 7) and kallikrein-mediated HK cleavage (6, 8) in vitro.Although the contact activation system is primarily thought to function in the circulation, there is evidence for its dysregulation in AD brain tissue: FXII is found in Aβ plaques (9), increased plasma kallikrein activity is observed in the AD brain parenchyma (10), and elevated levels of cleaved HK are found in cerebrospinal fluid (CSF) of patients with AD (11). To our knowledge, FXII activation and HK cleavage in the periphery of AD patients have not been demonstrated.Here, we show increased levels of FXIIa, HK cleavage, and kallikrein activity in the plasma of AD patients compared with nondemented (ND) control plasma. Furthermore, plasma...

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Section: Discussionmentioning

confidence: 99%

Activation of the factor XII-driven contact system in Alzheimer’s disease patient and mouse model plasma

Zamolodchikov

Chen

Conti

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

144

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“…Moreover, NIR light therapy has potential application in other brain conditions such as post-traumatic stress disorder, depression and anxiety, As we have reviewed here and elsewhere, [94] the rationale for using pharmacotherapy to increase cerebral blood flow to the brain is due to mounting evidence connecting brain hypoperfusion to MCI and some researchers consider the reduced brain blood flow as the likely the cause of this dyscognitive condition. [164][165][166][167][168][169] Cerebral hypoperfusion secondary to vascular risk factors during aging delivers suboptimal amounts of glucose and oxygen to hypometabolic brain cells.…”

Section: Low Level Laser Therapymentioning

confidence: 99%

Cerebral Perfusion Enhancing Interventions: A New Strategy for the Prevention of Alzheimer Dementia

Torre

2016

Brain Pathology

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Cardiovascular and cerebrovascular diseases are major risk factors in the development of cognitive impairment and Alzheimer's disease (AD). These cardio-cerebral disorders promote a variety of vascular risk factors which in the presence of advancing age are prone to markedly reduce cerebral perfusion and create a neuronal energy crisis. Long-term hypoperfusion of the brain evolves mainly from cardiac structural pathology and brain vascular insufficiency. Brain hypoperfusion in the elderly is strongly associated with the development of mild cognitive impairment (MCI) and both conditions are presumed to be precursors of Alzheimer dementia. A therapeutic target to prevent or treat MCI and consequently reduce the incidence of AD aims to elevate cerebral perfusion using novel pharmacological agents. As reviewed here, the experimental pharmaca include the use of Rho kinase inhibitors, neurometabolic energy boosters, sirtuins and vascular growth factors. In addition, a compelling new technique in laser medicine called photobiomodulation is reviewed. Photobiomodulation is based on the use of low level laser therapy to stimulate mitochondrial energy production non-invasively in nerve cells. The use of novel pharmaca and photobiomodulation may become important tools in the treatment or prevention of cognitive decline that can lead to dementia.

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“…Cerebral blood flow (CBF), or the rate of delivery of arterial blood to the capillary bed in a volume of tissue, is an indirect measure of neural function that can reliably distinguish between normal controls and those with AD, identify those at risk for MCI and AD, and predict conversion to MCI and AD (Hays, Zlatar, & Wierenga, 2016; Wierenga, Hays, & Zlatar, 2014). While some evidence suggests that AD-risk is associated with lower CBF, particularly in medial temporal lobe (MTL) regions, other studies support higher CBF among those at risk (Hays et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Temporal gradient during famous face naming is associated with lower cerebral blood flow and gray matter volume in aging

et al. 2017

Self Cite

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Objective Evidence suggests that famous face naming may be a cognitive ability especially sensitive to the early pathological processes of Alzheimer’s disease (AD) and that those at risk for AD may demonstrate a Ribot temporal gradient (RTG), characterized by better performance for naming remote famous faces than for naming recent famous faces. Reductions in cerebral blood flow (CBF) and gray matter volume (GMV) have been implicated in the neuropathological cascade of AD and show utility as biomarkers of AD risk. We examined whether a RTG during famous face naming was associated with lower CBF and/or GMV among a group of cognitively normal older adults. Methods Voxel-wise independent samples t-tests were employed to contrast resting CBF values between those who exhibited a RTG (RTG+) during a famous face naming task and those who did not (RTG−) among a sample of 52 cognitively normal older adults (25 RTG−, 27 RTG+; mean age=73). Groups were also compared on GMV using a voxel-wise general linear model. Results Significant group differences in CBF and GMV were found, whereby the RTG+ group demonstrated reduced CBF and GMV within medial temporal lobe regions (hippocampus, parahippocampal gyrus), relative to the RTG− group. Conclusions This represents the first study to show that cognitively intact older adults who demonstrate a RTG during famous face naming exhibit vascular dysregulation and structural changes similar to that seen in AD risk. Findings suggest that famous face naming ability may be particularly sensitive to the very early brain changes associated with AD.

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Cerebral Blood Flow Measured by Arterial Spin Labeling MRI as a Preclinical Marker of Alzheimer's Disease

Cited by 188 publications

References 63 publications

Activation of the factor XII-driven contact system in Alzheimer’s disease patient and mouse model plasma

Activation of the factor XII-driven contact system in Alzheimer’s disease patient and mouse model plasma

Cerebral Perfusion Enhancing Interventions: A New Strategy for the Prevention of Alzheimer Dementia

Temporal gradient during famous face naming is associated with lower cerebral blood flow and gray matter volume in aging

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