Hypoxia Due to Cardiac Arrest Induces a Time-Dependent Increase in Serum Amyloid β Levels in Humans

Zetterberg, Henrik; Mörtberg, Erik; Song, Linan; Chang, Lei; Provuncher, Gail K.; Patel, Purvish P.; Ferrell, Evan P.; Fournier, David R.; Kan, Cheuk W.; Campbell, Todd; Meyer, Ray E.; Rivnak, Andrew J.; Pink, Brian; Minnehan, Kaitlin A.; Piech, Tomasz; Rissin, David M.; Duffy, David C.; Rubertsson, Sten; Wilson, David H.; Blennow, Kaj

doi:10.1371/journal.pone.0028263

Cited by 155 publications

(166 citation statements)

References 24 publications

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“…In addition, cardiac systolic dysfunction could affect Aβ generation and clearance in the brain as a result of reduced cerebral blood flow [99][100][101][102] . Regional cerebral blood flow and glucose uptake or metabolism are consistently decreased in Aβ-positive patients with AD 103 , and correlate inversely with AD severity 104 .…”

Section: Cardiovascular Diseasementioning

confidence: 99%

A systemic view of Alzheimer disease — insights from amyloid-β metabolism beyond the brain

et al. 2017

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The global burden of Alzheimer disease (AD), already the most common type of dementia, is expected to increase still further owing to population ageing. AD not only causes severe distress for patients and caregivers, but also results in a large economic burden on society. Current major challenges in AD include the lack of reliable biomarkers for its early diagnosis, as well as the lack of effective preventive strategies and treatments 1,2 . Thus, increased understanding of the molecular patho genesis of AD could lead to the development of improved diagnostic and therapeutic strategies.AD is conventionally regarded as a CNS disorder. However, increasing experimental, epidemiological and clinical evidence has suggested that manifestations of AD extend beyond the brain. These systemic alterations might not be simply secondary effects of the cerebral degeneration seen in AD, but could reflect under lying processes linked to progression of the disease. AD pathogenesis is complex, involving abnormal amyloid-β (Aβ) metabolism, tau hyperphosphorylation, oxidative stress, reactive glial and microglial changes, and other pathological events. Given that Aβ is a major hallmark of AD and a fertile area of research in this disease, this Review focuses on the systemic role of Aβ in AD. We discuss the communication between peripheral and central pools of Aβ, and describe interactions between systemic abnormalities and AD pathogenesis in the brain. We review emerging findings of associations between systemic abnormalities and Aβ metabolism, and describe how these associations might interact with or reflect on the central pathways of Aβ production and clearance. On the basis of these findings, we suggest that interactions between the brain and the periphery might have a crucial role in the development and progression of AD. Aβ biogenesis and catabolismA steady accrual of data from laboratories and clinics is providing increasing support for the concept that an imbalance between the production and clearance of Aβ is a very early (and often initiating) factor in AD 3 . Normal metabolism of Aβ and maintenance of the homeostatic balance between Aβ production and clearance is, therefore, essential to maintain brain health. In fact, physiological metabolism of Aβ occurs not only in the brain but also in the periphery, and communication between these regions is possible (FIG. 1). Central and peripheral production of AβAβ is derived from the proteolytic cleavage of amyloid precursor protein (APP), which is expressed not only in brain cells, including neurons, astrocytes and microglia, but also in peripheral organs and tissues, such as the Abstract | Alzheimer disease (AD) is the most common type of dementia, and is currently incurable; existing treatments for AD produce only a modest amelioration of symptoms. Research into this disease has conventionally focused on the CNS. However, several peripheral and systemic abnormalities are now understood to be linked to AD, and our understanding of how these alterations contribute to AD is becom...

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Section: Cardiovascular Diseasementioning

confidence: 99%

A systemic view of Alzheimer disease — insights from amyloid-β metabolism beyond the brain

et al. 2017

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“…It is interesting that prolonged elevation of peripheral Ab42 was noted in a subset of patients with hypoxia after cardiac arrest, and that this was correlated with unfavorable outcome. 27 Experimental data indicate that TBI in triple transgenic AD model mice causes accumulation and aggregation of Ab oligomers in the brain, which may contribute to developing AD later in life. 40 Genetic factors, such as presence of an ApoE4 allele 44 or neprilysin gene transfer (GT) repeat polymorphism 45 may potentially explain the bimodal distribution of Ab42 after TBI.…”

Section: Discussionmentioning

confidence: 99%

“…25 Simoa detected increases of serum tau and Ab42 after hypoxic brain injury. 26,27 Plasma tau was increased in hockey players after concussion, 8 and in military personnel who sustained a TBI. 28 There was a correlation between tau and severity of postconcussive symptoms (r = 0.37; p = 0.003).…”

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confidence: 96%

Increases of Plasma Levels of Glial Fibrillary Acidic Protein, Tau, and Amyloid β up to 90 Days after Traumatic Brain Injury

Bogoslovsky

Wilson

Yao

et al. 2017

Journal of Neurotrauma

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172

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Glial fibrillary acidic protein (GFAP), microtubule-associated protein tau, and amyloid b peptide (Ab42) have been proposed as diagnostic and prognostic biomarkers in traumatic brain injury (TBI). Single molecule array (Simoa) is a novel technology that employs highly sensitive immunoassays for accurate measurements of candidate biomarkers found at low concentration in biological fluids. Our objective was to trace the trajectory of tau, GFAP, and Ab42 levels in plasma from the acute through subacute stages after TBI, compared with controls. Samples from 34 TBI subjects enrolled in the Citicoline Brain Injury Treatment Trial (COBRIT) were studied. Injury severity was assessed by Glasgow Coma Scale (GCS) and admission CT. Glasgow Outcome Scale Extended (GOSE) was assessed 6 months after injury. Plasma was collected within 24 h (Day 0), and 30 and 90 days after the TBI. Plasma collected from 69 healthy volunteers was used for comparison. At every time point, increases were noted in plasma GFAP ( p < 0.0001 for all comparisons), tau ( p < 0.0001, p < 0.0001, and p = 0.0044, at Days 0, 30, and 90, respectively), and Ab42 ( p < 0.001, p < 0.0001, and p = 0.0203, respectively) in TBI cases compared with controls. The levels were maximal at Day 0 for GFAP and tau and at Day 30 for Ab42. Area under curve (AUC) analyses for Day 0 GFAP and tau were excellent for discrimination of complicated mild TBI (cmTBI) from controls (0.936 and 0.901, correspondingly). Discriminant component analysis (DCA) for all three biomarkers at Days 0 and 30 differentiated controls from cmTBI (91.1% and 89.7% correctly classified, at each time point). Duration of post-traumatic amnesia (PTA) correlated weakly with tau levels at 30 days (Spearman's r = 0.40; 95% CI 0.0003-0.60, p = 0.044). The Marshall CT Grade on admission correlated weakly with Day 30 tau levels (Spearman's r = 0.41; 95% CI 0.04-0.68, p = 0.027). Day 30 Ab42 correlated with GOSE (standardized b -0.486, p = 0.042). GFAP, tau and Ab42 were increased up to 90 days after TBI compared with controls. Total tau levels correlated with clinical and radiological variables of TBI severity. Plasma Ab42 correlated with clinical outcome. Combination of all three biomarkers at Days 0 and 30 can be used to differentiate controls from cmTBI populations, and may be useful as biomarkers of TBI in both acute and subacute phases.

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“…Ischaemia in animal models, or its simulation by deprivation of oxygen and glucose in vitro , is associated with increased production of Aβ (reviewed in 12). Transient global cerebral ischaemia due to cardiac arrest in man was shown to cause a significant rise in serum Aβ42, lasting several days 61. Serum Aβ42 also rose in people who had sustained diffuse traumatic brain injury 37, in which there is invariably brain swelling and reduced perfusion; the rise in serum Aβ42 was accompanied by a decline in Aβ42 in the cerebrospinal fluid, arguing against nonspecific “leakage” of Aβ42 from damaged brain tissue.…”

Section: Introductionmentioning

confidence: 98%

Pathophysiology of Hypoperfusion of the Precuneus in Early Alzheimer's Disease

2015

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The earliest decline in cerebral perfusion in Alzheimer's disease (AD) is in the medial parietal cortex (precuneus). We have analyzed precuneus in post‐mortem tissue from 70 AD and 37 control brains to explore the pathophysiology of the hypoperfusion: the contribution of arteriolosclerotic small vessel disease (SVD) and cerebral amyloid angiopathy (CAA), and of the vasoconstrictors endothelin‐1 (EDN1) and angiotensin II (Ang II), and the association with Aβ. The myelin‐associated glycoprotein:proteolipid protein‐1 ratio (MAG:PLP1) was used as an indicator of oxygenation of the precuneus prior to death. MAG:PLP1 was reduced ∼50% in early AD (Braak stage III–IV). Although MAG:PLP1 remained low in advanced AD (stage V–VI), the reduction was less pronounced, possibly reflecting falling oxygen demand. Reduction in cortical MAG:PLP1 correlated with elevation in vascular endothelial growth factor (VEGF), another marker of hypoperfusion. Cortical MAG:PLP1 declined nonsignificantly with increasing SVD and CAA, but significantly with the concentration of EDN1, which was elevated approximately 75% in AD. In contrast, with reduction in cortical MAG:PLP1, Ang II level and angiotensin‐converting enzyme (ACE) activity declined, showing a normal physiological response to hypoperfusion. MAG:PLP1 was reduced in the parietal white matter (WM) in AD but here the decline correlated positively (ie, physiologically) with WM EDN1. However, the decline of MAG:PLP1 in the WM was associated with increasing cortical EDN1 and perhaps reflected vasoconstriction of perforating arterioles, which traverse the cortex to perfuse the WM. EDN1 in the cortex correlated highly significantly with both soluble and insoluble Aβ42, shown previously to upregulate neuronal endothelin‐converting enzyme‐2 (ECE2), but not with Aβ40. Our findings demonstrate reduced oxygenation of the precuneus in early AD and suggest that elevated EDN1, resulting from Aβ42‐mediated upregulation of ECE2, is a contributor.

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Hypoxia Due to Cardiac Arrest Induces a Time-Dependent Increase in Serum Amyloid β Levels in Humans

Cited by 155 publications

References 24 publications

A systemic view of Alzheimer disease — insights from amyloid-β metabolism beyond the brain

A systemic view of Alzheimer disease — insights from amyloid-β metabolism beyond the brain

Increases of Plasma Levels of Glial Fibrillary Acidic Protein, Tau, and Amyloid β up to 90 Days after Traumatic Brain Injury

Pathophysiology of Hypoperfusion of the Precuneus in Early Alzheimer's Disease

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