Blockade of the extracellular signal-regulated kinase pathway by U0126 attenuates neuronal damage following circulatory arrest

AbstractObjectivesThe extracellular signal-regulated kinase pathway of the mitogen-activated protein kinase signal transduction cascade has been implicated in the neuronal and endothelial dysfunction witnessed following cerebral ischemia-reperfusion injury. Extracellular signal-regulated kinase is activated by mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2. We evaluated the ability of a mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2–specific inhibitor (U0126) to block extracellular signal-regulated kinase activation and mitigate ischemic neuronal damage in a model of deep hypothermic circulatory arrest.MethodsPiglets underwent normal flow cardiopulmonary bypass (control, n = 4), deep hypothermic circulatory arrest (n = 6), and deep hypothermic circulatory arrest with U0126 (n = 5) at 20°C for 60 minutes. The deep hypothermic circulatory arrest with U0126 group was given 200 μg/kg of U0126 45 minutes prior to initiation of bypass followed by 100 μg/kg at reperfusion. Following 24 hours of post–cardiopulmonary bypass recovery, brains were harvested. Eleven distinct cortical regions were evaluated for neuronal damage using hematoxylin and eosin staining. A section of ischemic cortex was further evaluated by immunohistochemistry with rabbit polyclonal antibody against phosphorylated extracellular signal-regulated kinase 1/2.ResultsThe deep hypothermic circulatory arrest and deep hypothermic circulatory arrest with U0126 groups displayed diffuse ischemic changes. However, the deep hypothermic circulatory arrest with U0126 group possessed significantly lower neuronal damage scores in the right frontal watershed zone of cerebral cortex, basal ganglia, and thalamus (P ≤ .05) and an overall trend toward neuroprotection versus the deep hypothermic circulatory arrest group. This neuroprotection was accompanied by nearly complete blockade of phosphorylated extracellular signal-regulated kinase in the cerebral vascular endothelium.ConclusionsIn this experimental model of deep hypothermic circulatory arrest, U0126 blocked extracellular signal-regulated kinase activation and provided a significant neuroprotective effect. These results support targeting of the extracellular signal-regulated kinase pathway for inhibition as a novel therapeutic approach to mitigate neuronal damage following deep hypothermic circulatory arrest

Partial Volume Correction in Quantitative Amyloid Imaging.

Amyloid imaging is a valuable tool for research and diagnosis in dementing disorders. As positron emission tomography (PET) scanners have limited spatial resolution, measured signals are distorted by partial volume effects. Various techniques have been proposed for correcting partial volume effects, but there is no consensus as to whether these techniques are necessary in amyloid imaging, and, if so, how they should be implemented. We evaluated a two-component partial volume correction technique and a regional spread function technique using both simulated and human Pittsburgh compound B (PiB) PET imaging data. Both correction techniques compensated for partial volume effects and yielded improved detection of subtle changes in PiB retention. However, the regional spread function technique was more accurate in application to simulated data. Because PiB retention estimates depend on the correction technique, standardization is necessary to compare results across groups. Partial volume correction has sometimes been avoided because it increases the sensitivity to inaccuracy in image registration and segmentation. However, our results indicate that appropriate PVC may enhance our ability to detect changes in amyloid deposition

Clinical and Biomarker Changes in Dominantly Inherited Alzheimer's Disease

BACKGROUND: The order and magnitude of pathologic processes in Alzheimer's disease are not well understood, partly because the disease develops over many years. Autosomal dominant Alzheimer's disease has a predictable age at onset and provides an opportunity to determine the sequence and magnitude of pathologic changes that culminate in symptomatic disease. METHODS: In this prospective, longitudinal study, we analyzed data from 128 participants who underwent baseline clinical and cognitive assessments, brain imaging, and cerebrospinal fluid (CSF) and blood tests. We used the participant's age at baseline assessment and the parent's age at the onset of symptoms of Alzheimer's disease to calculate the estimated years from expected symptom onset (age of the participant minus parent's age at symptom onset). We conducted cross-sectional analyses of baseline data in relation to estimated years from expected symptom onset in order to determine the relative order and magnitude of pathophysiological changes. RESULTS: Concentrations of amyloid-beta (Aβ)(42) in the CSF appeared to decline 25 years before expected symptom onset. Aβ deposition, as measured by positron-emission tomography with the use of Pittsburgh compound B, was detected 15 years before expected symptom onset. Increased concentrations of tau protein in the CSF and an increase in brain atrophy were detected 15 years before expected symptom onset. Cerebral hypometabolism and impaired episodic memory were observed 10 years before expected symptom onset. Global cognitive impairment, as measured by the Mini-Mental State Examination and the Clinical Dementia Rating scale, was detected 5 years before expected symptom onset, and patients met diagnostic criteria for dementia at an average of 3 years after expected symptom onset. CONCLUSIONS: We found that autosomal dominant Alzheimer's disease was associated with a series of pathophysiological changes over decades in CSF biochemical markers of Alzheimer's disease, brain amyloid deposition, and brain metabolism as well as progressive cognitive impairment. Our results require confirmation with the use of longitudinal data and may not apply to patients with sporadic Alzheimer's disease. (Funded by the National Institute on Aging and others; DIAN ClinicalTrials.gov number, NCT00869817.)

Utility of perfusion PET measures to assess neuronal injury in Alzheimer's disease

Introduction: 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) is commonly used to estimate neuronal injury in Alzheimer's disease (AD). Here, we evaluate the utility of dynamic PET measures of perfusion using 11C-Pittsburgh compound B (PiB) to estimate neuronal injury in comparison to FDG PET. Methods: FDG, early frames of PiB images, and relative PiB delivery rate constants (PiB-R1) were obtained from 110 participants from the Dominantly Inherited Alzheimer Network. Voxelwise, regional cross-sectional, and longitudinal analyses were done to evaluate the correlation between images and estimate the relationship of the imaging biomarkers with estimated time to disease progression based on family history. Results: Metabolism and perfusion images were spatially correlated. Regional PiB-R1 values and FDG, but not early frames of PiB images, significantly decreased in the mutation carriers with estimated year to onset and with increasing dementia severity. Discussion: Hypometabolism estimated by PiB-R1 may provide a measure of brain perfusion without increasing radiation exposure

Serum neurofilament dynamics predicts neurodegeneration and clinical progression in presymptomatic Alzheimer's disease

Neurofilament light chain (NfL) is a promising fluid biomarker of disease progression for various cerebral proteopathies. Here we leverage the unique characteristics of the Dominantly Inherited Alzheimer Network and ultrasensitive immunoassay technology to demonstrate that NfL levels in the cerebrospinal fluid (n = 187) and serum (n = 405) are correlated with one another and are elevated at the presymptomatic stages of familial Alzheimer's disease. Longitudinal, within-person analysis of serum NfL dynamics (n = 196) confirmed this elevation and further revealed that the rate of change of serum NfL could discriminate mutation carriers from non-mutation carriers almost a decade earlier than cross-sectional absolute NfL levels (that is, 16.2 versus 6.8 years before the estimated symptom onset). Serum NfL rate of change peaked in participants converting from the presymptomatic to the symptomatic stage and was associated with cortical thinning assessed by magnetic resonance imaging, but less so with amyloid-β deposition or glucose metabolism (assessed by positron emission tomography). Serum NfL was predictive for both the rate of cortical thinning and cognitive changes assessed by the Mini-Mental State Examination and Logical Memory test. Thus, NfL dynamics in serum predict disease progression and brain neurodegeneration at the early presymptomatic stages of familial Alzheimer's disease, which supports its potential utility as a clinically useful biomarker

Relating Stool Microbial Metabolite Levels, Inflammatory Markers and Dietary Behaviors to Screening Colonoscopy Findings in a Racially/Ethnically Diverse Patient Population

Colorectal cancer (CRC) is the third leading cause of cancer death for both men and women in the United States, yet it is treatable and preventable. African Americans have higher incidence of CRC than other racial/ethnic groups, however, it is unclear whether this disparity is primarily due to environmental or biological factors. Short chain fatty acids (SCFAs) are metabolites produced by bacteria in the colon and are known to be inversely related to CRC progression. The aim of this study is to investigate how stool SCFA levels, markers of inflammation in stool and dietary intake relate to colonoscopy findings in a diverse patient population. Stool samples from forty-eight participants were analyzed for SCFA levels and inflammatory markers (lysozyme, secretory IgA, lactoferrin). Additionally, participants completed the National Cancer Institute’s Diet History Questionnaire II (DHQ II) to report dietary intake over the past year. Subsequently, the majority of participants underwent screening colonoscopy. Our results showed that African Americans had higher total levels of SCFAs in stool than other racial/ethnic groups, significantly lower intake of non-starchy vegetables and similar inflammatory marker expression and colonoscopy outcomes, compared to others. This work is an initial exploration into the biological and clinical factors that may ultimately inform personalized screening approaches and clinical decision-making to improve colorectal cancer disparities for African Americans