Potential Value of Cerebrospinal Fluid Progranulin in the Identification of Postoperative Delirium in Geriatrics Patients Undergoing Knee Replacement: The Perioperative Neurocognitive Disorder and Biomarker LifestylE Study

Objective: The aim of this study was to investigate whether progranulin (PGRN) levels in cerebrospinal fluid (CSF) were associated with postoperative delirium (POD) in geriatric patients undergoing knee replacement.Method: A total of 600 Han Chinese patients aged 65–90 years and who underwent unilateral total knee arthroplasty were included in the Perioperative Neurocognitive Disorder And Biomarker LifestylE (PNDABLE) study from June 2020 to November 2020. All participants were assessed using the Confusion Assessment Method and the Memorial Delirium Assessment Scale on postoperative days 1–7 (or before discharge) by an anesthesiologist. CSF PGRN and CSF biomarkers of POD were measured by ELISA. We analyzed the risk and protective factors of POD using the multivariate logistic regression, and the associations between CSF PGRN and CSF biomarkers of POD using multiple linear regression. We also explored whether the influence of CSF PGRN on POD was mediated by POD core pathology in linear regression models.Results: Postoperative delirium incidence was 9.7% (53/545). There were significant differences in preoperative CSF PGRN between patients with POD and non-POD (NPOD). As for CSF biomarkers, CSF Aβ40, T-tau, and P-tau were risk factors for POD, while CSF PGRN, Aβ42, and Aβ42/Aβ40 were protective factors for POD, as shown by the multivariate logistic regression analysis. CSF PGRN was positively associated with CSF Aβ42 and was negatively associated with CSF Aβ40, T-tau, and P-tau in patients with POD. We found that the AUC was 0.795 (95% CI = 0.706, 0.867) for PGRN between POD and NPOD groups. We found the influence of CSF PGRN on POD was mediated by POD core pathology. The effect was considered partial mediation with the proportion of mediation varying from 44.92 to 62.07%.Conclusion: Cerebrospinal fluid PGRN may be a reasonably good prognostic factor for POD development. Overall, amyloid pathology and tau protein might partially mediate the influence of PGRN on POD.Clinical Trial Registration:www.clinicaltrials.gov, identifier ChiCTR2000033439.

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Preoperative Circulating MiR-210, a Risk Factor for Postoperative Delirium Among Elderly Patients with Gastric Cancer Undergoing Curative Resection

Current Pharmaceutical Design ◽

10.2174/1381612826666200617163857 ◽

2020 ◽

Vol 26 (40) ◽

pp. 5213-5219

Author(s):

Yun Chen ◽

Jinwei Zheng ◽

Junping Chen

Keyword(s):

Gastric Cancer ◽

Logistic Regression ◽

Risk Factor ◽

Elderly Patients ◽

Curative Resection ◽

Postoperative Delirium ◽

Area Under The Curve ◽

Multivariate Logistic Regression Model ◽

Multivariate Logistic Regression ◽

Clinicopathologic Characteristics

Background: Postoperative delirium (POD) is a very common complication in elderly patients with gastric cancer (GC) and associated with poor prognosis. MicroRNAs (miRNAs) serve as key post-transcriptional regulators of gene expression via targeting mRNAs and play important roles in the nervous system. This study aimed to investigate the potential predictive role of miRNAs for POD. Methods: Elderly GC patients who were scheduled to undergo elective curative resection were consequently enrolled in this study. POD was assessed at 1 day before surgery and 1-7 days after surgery following the guidance of the 5th edition of Diagnostic and Statistical Manual of Mental Disorders (DSM V, 2013). The demographics, clinicopathologic characteristics and preoperative circulating miRNAs by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) were compared between patients with or without POD. Risk factors for POD were assessed via univariate and multivariate logistic regression analyses. Results: A total of 370 participants were enrolled, of which 63 had suffered from POD within postoperative 7 days with an incidence of 17.0%. Preoperative miR-210 was a predictor for POD with an area under the curve (AUC) of 0.921, a cut-off value of 1.67, a sensitivity of 95.11%, and a specificity of 92.06%, (P<0.001). In the multivariate logistic regression model, the relative expression of serum miR-210 was an independent risk factor for POD (OR: 3.37, 95%CI: 1.98–5.87, P=0.003). Conclusions: In conclusion, the present study highlighted that preoperative miR-210 could serve as a potential predictor for POD in elderly GC patients undergoing curative resection.

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Predictive Value of Cerebrospinal Fluid Biomarkers for Tap Test Responsiveness in Patients with Suspected Idiopathic Normal Pressure Hydrocephalus

10.21203/rs.3.rs-173474/v1 ◽

2021 ◽

Author(s):

Rongrong Hua ◽

Chunyan Liu ◽

Xing Liu ◽

Jinwu Zhu ◽

Jie Zhang ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Normal Pressure Hydrocephalus ◽

Predictive Value ◽

Test Group ◽

Normal Pressure ◽

Idiopathic Normal Pressure Hydrocephalus ◽

Binary Logistic Regression Analysis ◽

Csf Biomarkers ◽

Tap Test ◽

T Tau

Abstract Background: The value of cerebrospinal fluid (CSF) biomarkers for idiopathic normal pressure hydrocephalus (iNPH) needs to be determined. This prospective study aimed to reveal the correlation between CSF biomarkers and clinical symptoms of iNPH, and its predictive value for tap test responsiveness.Methods: Thirty-nine suspected iNPH patients were recruited, contributed qualified CSF, and accepted a tap test and unified pre- and post-test evaluation of neurological function. Results: The analysis of biomarkers from their CSF showed a decrease of tau and its phosphorylated form, especially in the tap test (+) group. In addition, the responsiveness of the tap test was also related to the number of combined symptoms (p<0.01). A correlation was also found between the end pressure or pressure difference of CSF and tap test responsiveness (p<0.05). The results of binary logistic regression analysis showed that P (tap test responsiveness) = 1/1 + e ^ - (-5.505+55.314 * ratio of p/T-tau - 1.586 * numbers of combined symptoms). The combined indicators (-5.505+0.553* percentage of p/T-tau - 1.586 * numbers of combined symptoms) gave the highest sensitivity and specificity, which were 94.12% and 72.73%, respectively.Conclusions: It may be accessed in judgment of tap test responsiveness, which is beneficial for the feasibility of clinical application.

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0057 Actigraphy-Based Circadian Measures and Cerebrospinal Fluid Biomarkers of Neurodegeneration in Alzheimer’s Disease with Mild Cognitive Impairment

SLEEP ◽

10.1093/sleep/zsaa056.055 ◽

2020 ◽

Vol 43 (Supplement_1) ◽

pp. A23-A23

Author(s):

R Mehra ◽

R Bhambra ◽

J Bena ◽

L Bekris ◽

J Leverenz ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebrospinal Fluid ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Csf Biomarkers ◽

Significance Level ◽

Unit Increase ◽

T Tau ◽

Age And Sex

Abstract Introduction Although recent data implicates sleep and circadian disruption to neurodegeneration in Alzheimer’s Disease (AD), the association of objective circadian biomarkers and neurodegeneration remains understudied. We hypothesize that actigraphy-based circadian measures are associated with cerebrospinal fluid (CSF) biomarkers of neurodegeneration in those mild cognitive impairment due to AD (MCI-AD). Methods Eighteen patients with CSF biomarker-confirmed MCI-AD underwent actigraphy monitoring generating the following circadian measures: amplitude, F-ratio and mesor and morning collection of CSF biomarkers of neurodegeneration (Aβ42,t-tau,p-tau). Linear models were used to evaluate the association of circadian and CSF measures; logarithmic transformations were performed on neurodegenerative markers for greater normality. Analysis was performed using SAS software. A significance level of 0.05 was assumed for all tests. Results Eighteen MCI-AD patients who were 68± 6.2 years, 44% female, with median AHI=12 and underwent actigraphy monitoring for 8.2+/-3.2 days were included. There was no significant association of circadian measures and Aβ42 nor with mesor and neurodegeneration biomarkers. Amplitude was associated with both p-tau and t-tau, such that each 10 unit increase in amplitude resulted in a predicted increase in p-tau of 8% (95% CI:1%-15%, p=0.018) and an increase of 13% (3%-23%; p=0.01) in t-tau. F-ratio was positively associated with p-tau and t-tau; each 1000 unit increase in F-ratio resulted in a predicted 12% (4%-22%; p=0.007) increase in P-tau and 20%(6%-35%; p=0.005) increase in t-tau. Associations of these circadian measures and CSF levels of p-tau and t-tau remained statistically significant after adjustment for age and sex. Conclusion Among patients with symptomatic MCI stages of AD, objective measures of circadian rhythm disruption are associated with CSF-based biomarkers of neurodegeneration even after consideration of age and sex. Future investigation should clarify directionality of this association and potential utility of circadian-based interventions in the mitigation of AD progression. Support N/A

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Cerebrospinal fluid profiles with increasing number of cerebral microbleeds in a continuum of cognitive impairment

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x15606141 ◽

2015 ◽

Vol 36 (3) ◽

pp. 621-628 ◽

Cited By ~ 23

Author(s):

Sara Shams ◽

Tobias Granberg ◽

Juha Martola ◽

Xiaozhen Li ◽

Mana Shams ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebrospinal Fluid ◽

Cognitive Impairment ◽

Serum Albumin ◽

Amyloid Β ◽

Cerebral Microbleeds ◽

Csf Biomarkers ◽

Barrier Dysfunction ◽

T Tau

Cerebral microbleeds (CMBs) are hypothesised to have an important yet unknown role in the dementia disease pathology. In this study we analysed increasing number of CMBs and their independent associations with routine cerebrospinal fluid (CSF) biomarkers in a continuum of cognitive impairment. A total of 1039 patients undergoing dementia investigation were analysed and underwent lumbar puncture, and an MRI scan. CSF samples were analysed for amyloid β (Aβ) 42, total tau (T-tau), tau phosphorylated at threonine 18 (P-tau) and CSF/serum albumin ratios. Increasing number of CMBs were independently associated with low Aβ42 levels, in the whole cohort, Alzheimer’s disease and mild cognitive impairment ( p < 0.05). CSF/serum albumin ratios were high with multiple CMBs ( p < 0.001), reflecting accompanying blood–brain barrier dysfunction. T-tau and P-tau levels were lower in Alzheimer’s patients with multiple CMBs when compared to zero CMBs, but did not change in the rest of the cohort. White matter hyperintensities were associated with low Aβ42 in the whole cohort and Alzheimer’s disease ( p < 0.05). Aβ42 is the routine CSF-biomarker mainly associated with CMBs in cognitive impairment, and there is an accumulative effect with increasing number of CMBs.

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Predictive Factors of Chronic Post-Surgical Pain at 6 Months Following Knee Replacement: Influence of Postoperative Pain Trajectory and Genetics

January 2018 - Pain Physician ◽

10.36076/ppj/2019.19.e729 ◽

2016 ◽

Vol 5;19 (5;19) ◽

pp. E729-E741

Author(s):

Dr Célia Lloret-Linares

Keyword(s):

Logistic Regression ◽

Postoperative Pain ◽

Knee Replacement ◽

Predictive Factors ◽

High Intensity ◽

Walking Ability ◽

Single Center ◽

Multivariate Logistic Regression ◽

Postsurgical Pain ◽

Chronic Postsurgical Pain

Background: The frequency of chronic postsurgical pain (CPSP) after knee replacement remains high, but might be decreased by improvements to prevention. Objectives: To identify pre- and postsurgical factors predictive of CPSP 6 months after knee replacement. Study Design: Single-center prospective observational study. Setting: An orthopedic unit in a French hospital. Methods: Consecutive patients referred for total or unicompartmental knee arthroplasty from March to July 2013 were prospectively invited to participate in this study. For each patient, we recorded preoperative pain intensity, anxiety and depression levels, and sensitivity and pain thresholds in response to an electrical stimulus. We analyzed OPRM1 and COMT single-nucleotide polymorphisms. Acute postoperative pain (APOP) in the first 5 days after surgery was modeled by a pain trajectory. Changes in the characteristics and consequences of the pain were monitored 3 and 6 months after surgery. Bivariate analysis and multivariate logistic regression were conducted to identify predictors of CPSP. Results: We prospectively evaluated 104 patients in this study, 74 (28.8%) of whom reported CPSP at 6 months. Three preoperative factors were found to be associated with the presence of CPSP in multivariate logistic regression analysis: high school diploma level (OR = 3.83 [1.20 – 12.20]), consequences of pain in terms of walking ability, as assessed with the Brief Pain Inventory short form “walk” item (OR = 4.06 [1.18 – 13.94]), and a lack of physical activity in adulthood (OR = 4.01 [1.33 – 12.10]). One postoperative factor was associated with the presence of CPSP: a high-intensity APOP trajectory. An association of borderline statistical significance was found with the A allele of the COMT gene (OR = 3.4 [0.93 – 12.51]). Two groups of patients were identified on the basis of their APOP trajectory: high (n = 28, 26%) or low (n = 80, 74%) intensity. Patients with high-intensity APOP trajectory had higher anxiety levels and were less able to walk before surgery (P < 0.05). Limitations: This was a single-center study and the sample may have been too small for the detection of some factors predictive of CPSP or to highlight the role of genetic factors. Conclusion: Our findings suggest that several preoperative and postoperative characteristics could be used to facilitate the identification of patients at high risk of CPSP after knee surgery. All therapeutic strategies decreasing APOP, such as anxiety management or performing knee replacement before the pain has a serious effect on ability to walk, may help to decrease the risk of CPSP. Further prospective studies testing specific management practices, including a training program before surgery, are required. Key words: Chronic postsurgical pain, opioids, arthroplasty, pain trajectory, genetics, COMT, predictive factors

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Cerebrospinal Fluid Biomarkers for Dementia with Lewy Bodies

International Journal of Alzheimer s Disease ◽

10.4061/2010/536538 ◽

2010 ◽

Vol 2010 ◽

pp. 1-17 ◽

Cited By ~ 7

Author(s):

Elizabeta B. Mukaetova-Ladinska ◽

Rachael Monteith ◽

Elaine K. Perry

Keyword(s):

Cerebrospinal Fluid ◽

Dementia With Lewy Bodies ◽

Lewy Bodies ◽

Low Frequency ◽

Csf Biomarkers ◽

Term Care ◽

Clinical Criteria ◽

Cerebrospinal Fluid Biomarkers ◽

The Uk ◽

T Tau

More than 750,000 of the UK population suffer from some form of cognitive impairment and dementia. Of these, 5–20% will have Dementia with Lewy Bodies (DLB). Clinico-pathological studies have shown that it is the low frequency of DLB clinical core features that makes the DLB diagnosis hardly recognisable during life, and easily misdiagnosed for other forms of dementia. This has an impact on the treatment and long-term care of the affected subjects. Having a biochemical test, based on quantification of a specific DLB biomarker within Cerebrospinal Fluid (CSF) could be an effective diagnostic method to improve the differential diagnosis. Although some of the investigated DLB CSF biomarkers are well within the clinical criteria for sensitivity and specificity (90%), they all seem to be confounded by the contradictory data for each of the major groups of biomarkers (-synuclein, tau and amyloid proteins). However, a combination of CSF measures appear to emerge, that may well be able to differentiate DLB from other dementias: -synuclein reduction in early DLB, a correlation between CSF -synuclein and A42 measures (characteristic for DLB only), and t-tau and p-tau181 profile (differentiating AD from DLB).

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Neuronal and Glia-Related Biomarkers in Cerebrospinal Fluid of Patients with Acute Ischemic Stroke

Journal of Central Nervous System Disease ◽

10.4137/jcnsd.s13821 ◽

2014 ◽

Vol 6 ◽

pp. JCNSD.S13821 ◽

Cited By ~ 48

Author(s):

Clara Hjalmarsson ◽

Maria Bjerke ◽

Björn Andersson ◽

Kaj Blennow ◽

Henrik Zetterberg ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Ischemic Stroke ◽

White Matter ◽

Acute Ischemic Stroke ◽

Experimental Studies ◽

Csf Biomarkers ◽

Stroke Severity ◽

Neurofilament Light ◽

Age Related ◽

T Tau

Background Cerebral ischemia promotes morphological reactions of the neurons, astrocytes, oligodendrocytes, and microglia in experimental studies. Our aim was to examine the profile of CSF (cerebrospinal fluid) biomarkers and their relation to stroke severity and degree of white matter lesions (WML). Methods A total of 20 patients (mean age 76 years) were included within 5–10 days after acute ischemic stroke (AIS) onset. Stroke severity was assessed using NIHSS (National Institute of Health stroke scale). The age-related white matter changes (ARWMC) scale was used to evaluate the extent of WML on CT-scans. The concentrations of specific CSF biomarkers were analyzed. Results Patients with AIS had significantly higher levels of NFL (neurofilament, light), T-tau, myelin basic protein (MBP), YKL-40, and glial fibrillary acidic protein (GFAP) compared with controls; T-Tau, MBP, GFAP, and YKL-40 correlated with clinical stroke severity, whereas NFL correlated with severity of WML (tested by Mann–Whitney test). Conclusions Several CSF biomarkers increase in AIS, and they correlate to clinical stroke severity. However, only NFL was found to be a marker of degree of WML.

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Cerebrospinal Fluid Biomarkers and Prediction of Conversion in Patients with Mild Cognitive Impairment: 4-Year Follow-Up in a Routine Clinical Setting

The Scientific World JOURNAL ◽

10.1100/tsw.2009.106 ◽

2009 ◽

Vol 9 ◽

pp. 961-966 ◽

Cited By ~ 19

Author(s):

Alessia Lanari ◽

Lucilla Parnetti

Keyword(s):

Cerebrospinal Fluid ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Clinical Setting ◽

Cognitive Disorders ◽

Correct Prediction ◽

Csf Biomarkers ◽

Routine Clinical Setting ◽

T Tau

Mild cognitive impairment (MCI) is a very common syndrome in elderly people, with a high risk of conversion to dementia. Several investigations have shown the usefulness of cerebrospinal fluid (CSF) biomarkers (Aβ42, total tau [T-tau], and phosphorylated tau [P-tau]) in predicting the progression to Alzheimer's disease (AD). We report a 4-year follow-up of MCI patients who underwent CSF evaluation for biomarker assessment, in order to further evaluate the usefulness of CSF analysis in predicting the conversion to dementia in a routine clinical setting. We identified 55 patients with MCI among the consecutive patients, referred from 2001 to 2003 to our Memory Clinic for cognitive disorders, who underwent a complete diagnostic assessment, including lumbar puncture (n = 273). At the end of the follow-up, 31 MCI patients (56%) did not progress to dementia (stable MCI), while 24 (44%) developed a dementia condition. At baseline, the mean levels of CSF Aβ42, T-tau, and P-tau were significantly altered in MCI patients who were converting to dementia with respect to those with stable MCI. All MCI patients with the three altered CSF biomarkers developed dementia within 1 year. Among the stable MCI patients, none showed all three pathological values and only one subject had the pathological value of P-tau. Early diagnosis of dementia and, specifically, a correct prediction of MCI outcome represent a primary goal. To this respect, the role of CSF biomarkers seems to be crucial in a routine clinical setting.

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Comparison between plasma and cerebrospinal fluid biomarkers for the early diagnosis and association with survival in prion disease

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2020-323826 ◽

2020 ◽

Vol 91 (11) ◽

pp. 1181-1188 ◽

Cited By ~ 1

Author(s):

Samir Abu-Rumeileh ◽

Simone Baiardi ◽

Anna Ladogana ◽

Corrado Zenesini ◽

Anna Bartoletti-Stella ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Diagnostic Accuracy ◽

Prion Disease ◽

Single Molecule ◽

Clinical Care ◽

Csf Biomarkers ◽

Neurofilament Light Chain ◽

Neurofilament Light ◽

Lower Accuracy ◽

T Tau

ObjectiveTo compare the diagnostic accuracy and the prognostic value of blood and cerebrospinal fluid (CSF) tests across prion disease subtypes.MethodsWe used a single-molecule immunoassay to measure tau and neurofilament light chain (NfL) protein levels in the plasma and assessed CSF total(t)-tau, NfL and protein 14-3-3 levels in patients with prion disease (n=336), non-prion rapidly progressive dementias (n=106) and non-neurodegenerative controls (n=37). We then evaluated each plasma and CSF marker for diagnosis and their association with survival, taking into account the disease subtype, which is a strong independent prognostic factor in prion disease.ResultsPlasma tau and NfL concentrations were higher in patients with prion disease than in non-neurodegenerative controls and non-prion rapidly progressive dementias. Plasma tau showed higher diagnostic value than plasma NfL, but a lower accuracy than the CSF proteins t-tau and 14-3-3. In the whole prion cohort, both plasma (tau and NfL) and CSF (t-tau, 14-3-3 and NfL) markers were significantly associated with survival and showed similar prognostic values. However, the intrasubtype analysis revealed that only CSF t-tau in sporadic Creutzfeldt-Jakob disease (sCJD) MM(V)1, plasma tau and CSF t-tau in sCJD VV2, and plasma NfL in slowly progressive prion diseases were significantly associated with survival after accounting for covariates.ConclusionsPlasma markers have lower diagnostic accuracy than CSF biomarkers. Plasma tau and NfL and CSF t-tau are significantly associated with survival in prion disease in a subtype-specific manner and can be used to improve clinical trial stratification and clinical care.

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Plasma Catecholamine Profile of Subarachnoid Hemorrhage Patients with Neurogenic Cardiomyopathy

Cerebrovascular Diseases Extra ◽

10.1159/000431155 ◽

2015 ◽

Vol 5 (2) ◽

pp. 57-67 ◽

Cited By ~ 12

Author(s):

Michael Moussouttas ◽

Elizabeth Mearns ◽

Arthur Walters ◽

Matthew DeCaro

Keyword(s):

Logistic Regression ◽

Subarachnoid Hemorrhage ◽

Linear Regression ◽

Roc Curves ◽

Clinical Severity ◽

Plasma Catecholamine ◽

Clinical Grade ◽

Regression Analyses ◽

Linear Regression Models ◽

Multivariate Logistic Regression

Purpose: To investigate the connection between sympathetic function and neurogenic cardiomyopathy (NC), and to determine whether NC is mediated primarily by circulating adrenal epinephrine (EPI) or neuronally transmitted norepinephrine (NE), following subarachnoid hemorrhage (SAH). Methods: This is a prospective observational investigation of consecutive severe-grade SAH patients. All participants had transthoracic echocardiography and serological assays for catecholamine levels - dopamine (DA), NE and EPI - within 48 h of hemorrhage onset. Clinical and serological independent predictors of NC were determined using multivariate logistic regression analyses, and the accuracy of predictors was assessed by receiver operating characteristic (ROC) curves. Multivariate linear regression analyses were used to evaluate correlations among the catecholamines. Results: The investigation included a total of 94 subjects: the mean age was 55 years, 81% were female and 57% were Caucasian. NC was identified in approximately 10% (9/94) of cases. Univariate analyses revealed associations between NC and worse clinical severity (p = 0.019), plasma DA (p = 0.018) and NE levels (p = 0.024). Plasma NE correlated with DA levels (ρ = 0.206, p = 0.046) and EPI levels (ρ = 0.392, p < 0.001), but was predicted only by plasma EPI in bivariate [parameter estimate (PE) = 1.95, p < 0.001] and multivariate (PE = 1.89, p < 0.001) linear regression models. Multivariate logistic regression analyses consistently demonstrated the predictive value of clinical grade for NC (p < 0.05 for all analyses) except in models incorporating plasma NE, where NC was independently predicted by NE level (OR 1.25, 95% CI 1.01-1.55) over clinical grade (OR 4.19, 95% CI 0.874-20.1). ROC curves similarly revealed the greater accuracy of plasma NE [area under the curve (AUC) 0.727, 95% CI 0.56-0.90, p = 0.02] over clinical grade (AUC 0.704, 95% CI 0.55-0.86, p = 0.05) for identifying the presence or absence of NC. Conclusions: Following SAH, the development of NC is primarily related to elevated plasma NE levels. Findings implicate a predominantly neurogenic process mediated by neuronal NE (and not adrenal EPI), but cannot exclude synergy between the catecholamines.

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