A β42 is the predominant form of amyloid b -protein in the brains of short-term survivors of head injury

Gentleman, Stephen M.; Greenberg, B. D.; Savage, Mary J.; Noori, Muna; Newman, Suzanna J.; Roberts, G. W.; Griffin, W. Sue T.; Graham, David I.

doi:10.1097/00001756-199704140-00039

Cited by 102 publications

(59 citation statements)

References 4 publications

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“…In fact, a recent study using the carbon 11-labeled Pittsburgh Compound B positron emission tomography ligand demonstrated deposition of Aβ in cortical gray matter and striatum in patients with head injury followed for 1 year after TBI [53]. The predominant amyloid identified has been Aβ 1-42 [54,55], the most toxic form of this peptide [56][57][58]. Others have demonstrated elevated expression of the amyloid precursor protein in cortex from hours to years after TBI [59][60][61][62].…”

Section: Mechanistic Associationsmentioning

confidence: 99%

Chronic Neurodegeneration After Traumatic Brain Injury: Alzheimer Disease, Chronic Traumatic Encephalopathy, or Persistent Neuroinflammation?

2015

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It has long been suggested that prior traumatic brain injury (TBI) increases the subsequent incidence of chronic neurodegenerative disorders, including Alzheimer disease, Parkinson disease, and amyotrophic lateral sclerosis. Among these, the association with Alzheimer disease has the strongest support. There is also a long-recognized association between repeated concussive insults and progressive cognitive decline or other neuropsychiatric abnormalities. The latter was first described in boxers as dementia pugilistica, and has received widespread recent attention in contact sports such as professional American football. The term chronic traumatic encephalopathy was coined to attempt to define a "specific" entity marked by neurobehavioral changes and the extensive deposition of phosphorylated tau protein. Nearly lost in the discussions of post-traumatic neurodegeneration after traumatic brain injury has been the role of sustained neuroinflammation, even though this association has been well established pathologically since the 1950s, and is strongly supported by subsequent preclinical and clinical studies. Manifested by extensive microglial and astroglial activation, such chronic traumatic brain inflammation may be the most important cause of post-traumatic neurodegeneration in terms of prevalence. Critically, emerging preclinical studies indicate that persistent neuroinflammation and associated neurodegeneration may be treatable long after the initiating insult(s).

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Section: Mechanistic Associationsmentioning

confidence: 99%

Chronic Neurodegeneration After Traumatic Brain Injury: Alzheimer Disease, Chronic Traumatic Encephalopathy, or Persistent Neuroinflammation?

2015

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“…21 Even a single TBI may be associated with ab42 deposits in the postmortem brains of short-term (6 h to 7 days) or long-term (1-47 years) TBI survivors. 22,23 Further, positron emission tomography studies using carbon 11-labeled Pittsburgh Compound B ([ 11 C]PiB) showed increased amyloid deposition following acute TBI compared to controls. 24 Simoa is a novel technology that employs highly sensitive immunoassays and allows accurate measurements of candidate biomarkers found at low concentrations in blood.…”

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confidence: 99%

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

172

126

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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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“…2). As a support to this concept it has been shown that temporary hypoxia or energy deprivation is able to generate ß-amyloid without cognitive defects [40,88,89] in young adults following a sustained hypoxic coma or traumatic brain lesions [90,91].…”

Section: Atp and ßApp Processingmentioning

confidence: 99%

Mitochondrial Genome Lesions in the Pathogenesis of Sporadic Alzheimer’s Disease

Meier‐Ruge¹,

Bertoni–Freddari²

1999

Gerontology

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Background: The recent, magnificent results of molecular biology concerning β-amyloid (βA) metabolism in early onset Alzheimer’s disease (AD) have generated a series of new findings and, in turn, a new etiological concept. Attention on the early events in the pathogenesis of AD has been shifted from the chromosomal abnormalities in the nucleus of nerve cells onto genetic changes in the mitochondrial genome. This offers a new pathogenetic approach which also opens new pharmacological challenges particularly for the episodic forms of AD. Objective: Alterations occurring at the mitochondrial genome result in major consequences of oxidative phosphorylation and, if a specific threshold is exceeded, they may constitute important causative events in the apoptosis of selected nerve cells. The fact that the main source of mitochondrial metabolism is its glucose turnover allows monitoring brain changes in glucose metabolism by 18F-2 deoxyglucose positron emission tomography. In the demented brain, a low glucose turnover causes a cholinergic deficit by decreasing the synthetic rate of acetyl coenzyme A (AcCoA). AcCoA represents the key substrate for the acetylation of choline to acetylcholine by choline acetyltransferase. The consistent energy need for AcCoA synthesis appears obvious when considering that 1 molecule of glucose generates just 2 molecules of AcCoA, but 38 molecules of ATP. In the brain, AcCoA is exclusively synthesized in the glycolitic pathway. Generation of βA is increased if the synthetic rate of ATP drops below a critical threshold: under these conditions, the βA precursor protein (βAPP) is inserted only in part into synaptic membranes which have the highest βAPP turnover. In conditions of short ATP supply, βAPP is not split at the β region by an ATP-activated protease and this results in a substantial increase in uncleaved βA molecules. Conclusion: Peroxidative alterations in mitochondrial DNA are of importance in degenerative diseases of postmitotic tissues, particularly in degenerative diseases. This offers a new pharmacological approach for the treatment of AD. Neurotrophic factors and estrogen seem to be the first pharmacological leads.

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A β42 is the predominant form of amyloid b -protein in the brains of short-term survivors of head injury

Cited by 102 publications

References 4 publications

Chronic Neurodegeneration After Traumatic Brain Injury: Alzheimer Disease, Chronic Traumatic Encephalopathy, or Persistent Neuroinflammation?

Chronic Neurodegeneration After Traumatic Brain Injury: Alzheimer Disease, Chronic Traumatic Encephalopathy, or Persistent Neuroinflammation?

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

Mitochondrial Genome Lesions in the Pathogenesis of Sporadic Alzheimer’s Disease

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