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1.
  • Csajbok, Ludvig Z, 1964, et al. (författare)
  • Apolipoprotein E polymorphism in aneurysmal subarachnoid haemorrhage in West Sweden.
  • 2016
  • Ingår i: Acta neurologica Scandinavica. - : Hindawi Limited. - 1600-0404 .- 0001-6314. ; 133:6, s. 466-474
  • Tidskriftsartikel (refereegranskat)abstract
    • Aneurysmal subarachnoid haemorrhage (aSAH) is associated with high morbidity and mortality despite novel treatments. Genetic variability may explain outcome differences. Apolipoprotein E (ApoE) is a glycoprotein with a major role in brain lipoprotein metabolism. It has three isoforms encoded by distinct alleles: APOEε2, APOEε3 and APOEε4. The APOEε4 allele is associated with Alzheimer's disease and worse outcome after traumatic brain injury and ischaemic stroke. This prospective blinded study explored the influence of the APOEε4 polymorphism on the risk of aSAH, risk of cerebral vasospasm (CVS) and 1-year neurological outcome.
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  • Ali, Muhammad, et al. (författare)
  • Leveraging large multi-center cohorts of Alzheimer disease endophenotypes to understand the role of Klotho heterozygosity on disease risk.
  • 2022
  • Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 17:5
  • Tidskriftsartikel (refereegranskat)abstract
    • Two genetic variants in strong linkage disequilibrium (rs9536314 and rs9527025) in the Klotho (KL) gene, encoding a transmembrane protein, implicated in longevity and associated with brain resilience during normal aging, were recently shown to be associated with Alzheimer disease (AD) risk in cognitively normal participants who are APOE ε4 carriers. Specifically, the participants heterozygous for this variant (KL-SVHET+) showed lower risk of developing AD. Furthermore, a neuroprotective effect of KL-VSHET+ has been suggested against amyloid burden for cognitively normal participants, potentially mediated via the regulation of redox pathways. However, inconsistent associations and a smaller sample size of existing studies pose significant hurdles in drawing definitive conclusions. Here, we performed a well-powered association analysis between KL-VSHET+ and five different AD endophenotypes; brain amyloidosis measured by positron emission tomography (PET) scans (n = 5,541) or cerebrospinal fluid Aβ42 levels (CSF; n = 5,093), as well as biomarkers associated with tau pathology: the CSF Tau (n = 5,127), phosphorylated Tau (pTau181; n = 4,778) and inflammation: CSF soluble triggering receptor expressed on myeloid cells 2 (sTREM2; n = 2,123) levels. Our results found nominally significant associations of KL-VSHET+ status with biomarkers for brain amyloidosis (e.g., CSF Aβ positivity; odds ratio [OR] = 0.67 [95% CI, 0.55-0.78], β = 0.72, p = 0.007) and tau pathology (e.g., biomarker positivity for CSF Tau; OR = 0.39 [95% CI, 0.19-0.77], β = -0.94, p = 0.007, and pTau; OR = 0.50 [95% CI, 0.27-0.96], β = -0.68, p = 0.04) in cognitively normal participants, 60-80 years old, who are APOE e4-carriers. Our work supports previous findings, suggesting that the KL-VSHET+ on an APOE ε4 genotype background may modulate Aβ and tau pathology, thereby lowering the intensity of neurodegeneration and incidence of cognitive decline in older controls susceptible to AD.
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4.
  • Anderson, Kevin J., et al. (författare)
  • Ischemia-induced upregulation of excitatory amino acid transport sites
  • 1993
  • Ingår i: Brain Research. - 0006-8993. ; 622:1-2, s. 93-98
  • Tidskriftsartikel (refereegranskat)abstract
    • The response of excitatory amino acid transporter binding sites in the rat brain to 10 min of cerebral ischemia induced by bilateral common carotid occlusion combined with hypotension was examined. We observed a transient increase in the density of transporter binding sites that was first noticeable at 5 min post-recovery and persisted for 48 h. The increase in binding sites was found throughout the brain, but was most prevalent in hippocampus and other cortical regions. We conclude that delayed neuronal death following transient cerebral ischemia may not be due to a decrease in the number of excitatory amino acid transport sites.
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5.
  • Andersson, Annika, et al. (författare)
  • Development of parallel reaction monitoring assays for cerebrospinal fluid proteins associated with Alzheimer's disease
  • 2019
  • Ingår i: Clinica Chimica Acta. - : Elsevier B.V.. - 0009-8981 .- 1873-3492. ; 494, s. 79-93
  • Tidskriftsartikel (refereegranskat)abstract
    • Detailed knowledge of protein changes in cerebrospinal fluid (CSF) across healthy and diseased individuals would provide a better understanding of the onset and progression of neurodegenerative disorders. In this study, we selected 20 brain-enriched proteins previously identified in CSF by antibody suspension bead arrays (SBA) to be potentially biomarkers for Alzheimer's disease (AD) and verified these using an orthogonal approach. We examined the same set of 94 CSF samples from patients affected by AD (including preclinical and prodromal), mild cognitive impairment (MCI), non-AD dementia and healthy individuals, which had previously been analyzed by SBA. Twenty-eight parallel reaction monitoring (PRM) assays were developed and 13 of them could be validated for protein quantification. Antibody profiles were verified by PRM. For seven proteins, the antibody profiles were highly correlated with the PRM results (r > 0.7) and GAP43, VCAM1 and PSAP were identified as potential markers of preclinical AD. In conclusion, we demonstrate the usefulness of targeted mass spectrometry as a tool for the orthogonal verification of antibody profiling data, suggesting that these complementary methods can be successfully applied for comprehensive exploration of CSF protein levels in neurodegenerative disorders.
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6.
  • Andersson, Emma, et al. (författare)
  • A prospective outcome study observing patients with severe traumatic brain injury over 10-15 years
  • 2017
  • Ingår i: Acta Anaesthesiologica Scandinavica. - : Wiley. - 0001-5172 .- 1399-6576. ; 61:5, s. 502-512
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Severe traumatic brain injury (sTBI) can be divided into primary and secondary injuries. Intensive care protocols focus on preventing secondary injuries. This prospective cohort study was initiated to investigate outcome, including mortality, in patients treated according to the Lund Concept after a sTBI covering 10-15 years post-trauma. Methods: Patients were included during 2000-2004 when admitted to the neurointensive care unit, Sahlgrenska University Hospital. Inclusion criteria were: Glasgow coma scale score of 8, need for artificial ventilation and intracranial monitoring. Glasgow Outcome Scale (GOS) was used to evaluate outcome both at 1-year and 10-15 years post-trauma. Results: Ninety-five patients, (27 female and 68 male), were initially included. Both improvement and deterioration were noted between 1- and 10-15 years post-injury. Mortality rate (34/95) was higher in the studied population vs. a matched Swedish population, (Standard mortality rate (SMR) 9.5; P < 0.0001). When dividing the cohort into Good (GOS 4-5) and Poor (GOS 2-3) outcome at 1-year, only patients with Poor outcome had a higher mortality rate than the matched population (SMR 7.3; P < 0.0001). Further, good outcome (high GOS) at 1-year was associated with high GOS 10-15 years post-trauma (P < 0.0001). Finally, a majority of patients demonstrated symptoms of mental fatigue. Conclusion: This indicates that patients with severe traumatic brain injury with Good outcome at 1-year have similar survival probability as a matched Swedish population and that high Glasgow outcome scale at 1-year is related to good long-term outcome. Our results further emphasise the advantage of the Lund concept.
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7.
  • Andersson, Emma, et al. (författare)
  • Acute-Phase Neurofilament Light and Glial Fibrillary Acidic Proteins in Cerebrospinal Fluid Predict Long-Term Outcome After Severe Traumatic Brain Injury
  • 2024
  • Ingår i: NEUROCRITICAL CARE. - 1541-6933 .- 1556-0961.
  • Tidskriftsartikel (refereegranskat)abstract
    • Background This study investigated trajectory profiles and the association of concentrations of the biomarkers neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) in ventricular cerebrospinal fluid (CSF) with clinical outcome at 1 year and 10-15 years after a severe traumatic brain injury (sTBI).Methods This study included patients with sTBI at the Neurointensive Care Unit at Sahlgrenska University Hospital, Gothenburg, Sweden. The injury was regarded as severe if patients had a Glasgow Coma Scale <= 8 corresponding to Reaction Level Scale >= 4. CSF was collected from a ventricular catheter during a 2-week period. Concentrations of NfL and GFAP in CSF were analyzed with enzyme-linked immunosorbent assay. The Glasgow Outcome Scale (GOS) was used to assess the 1-year and 10-15-year outcomes. After adjustment for age and previous neurological diseases, logistic regression was performed for the outcomes GOS 1 (dead) or GOS 2-5 (alive) and GOS 1-3 (poor) or GOS 4-5 (good) versus the independent continuous variables (NfL and GFAP).Results Fifty-three patients with sTBI were investigated; forty-seven adults are presented in the article, and six children (aged 7-18 years) are described in Supplement 1. The CSF concentrations of NfL gradually increased over 2 weeks post trauma, whereas GFAP concentrations peaked on days 3-4. Increasing NfL and GFAP CSF concentrations increased the odds of GOS 1-3 outcome 1 year after trauma (odds ratio [OR] 1.73, 95% confidence interval [CI] 1.07-2.80, p = 0.025; and OR 1.61, 95% CI 1.09-2.37, p = 0.016, respectively). Similarly, increasing CSF concentrations of NfL and GFAP increased the odds for GOS 1-3 outcome 10-15 years after trauma (OR 2.04, 95% CI 1.05-3.96, p = 0.035; and OR 1.60, 95% CI 1.02-2.00, p = 0.040).Conclusions This study shows that initial high concentrations of NfL and GFAP in CSF are both associated with higher odds for GOS 1-3 outcome 1 year and 10-15 years after an sTBI, implicating its potential usage as a prognostic marker in the future.
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8.
  • Bergström, Sofia, et al. (författare)
  • Multi-cohort profiling reveals elevated CSF levels of brain-enriched proteins in Alzheimer's disease
  • 2021
  • Ingår i: Annals of Clinical and Translational Neurology. - : Wiley. - 2328-9503. ; 8:7, s. 1456-1470
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective: Decreased amyloid beta (A beta) 42 together with increased tau and phospho-tau in cerebrospinal fluid (CSF) is indicative of Alzheimer's disease (AD). However, the molecular pathophysiology underlying the slowly progressive cognitive decline observed in AD is not fully understood and it is not known what other CSF biomarkers may be altered in early disease stages. Methods: We utilized an antibody-based suspension bead array to analyze levels of 216 proteins in CSF from AD patients, patients with mild cognitive impairment (MCI), and controls from two independent cohorts collected within the AETIONOMY consortium. Two additional cohorts from Sweden were used for biological verification. Results: Six proteins, amphiphysin (AMPH), aquaporin 4 (AQP4), cAMP-regulated phosphoprotein 21 (ARPP21), growth-associated protein 43 (GAP43), neurofilament medium polypeptide (NEFM), and synuclein beta (SNCB) were found at increased levels in CSF from AD patients compared with controls. Next, we used CSF levels of A beta 42 and tau for the stratification of the MCI patients and observed increased levels of AMPH, AQP4, ARPP21, GAP43, and SNCB in the MCI subgroups with abnormal tau levels compared with controls. Further characterization revealed strong to moderate correlations between these five proteins and tau concentrations. Interpretation: In conclusion, we report six extensively replicated candidate biomarkers with the potential to reflect disease development. Continued evaluation of these proteins will determine to what extent they can aid in the discrimination of MCI patients with and without an underlying AD etiology, and if they have the potential to contribute to a better understanding of the AD continuum.
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12.
  • Danielson, Mattias, et al. (författare)
  • Neuroinflammatory markers associate with cognitive decline after major surgery: Findings of an explorative study
  • 2020
  • Ingår i: Annals of Neurology. - : Wiley. - 0364-5134 .- 1531-8249. ; 87:3, s. 370-382
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective Long-term cognitive decline is an adverse outcome after major surgery associated with increased risk for mortality and morbidity. We studied the cerebrospinal fluid (CSF) and serum biochemical inflammatory response to a standardized orthopedic surgical procedure and the possible association with long-term changes in cognitive function. We hypothesized that the CSF inflammatory response pattern after surgery would differ in patients having long-term cognitive decline defined as a composite cognitive z score of >= 1.0 compared to patients without long-term cognitive decline at 3 months postsurgery. Methods Serum and CSF biomarkers of inflammation and blood-brain barrier (BBB) integrity were measured preoperatively and up to 48 hours postoperatively, and cognitive function was assessed preoperatively and at 2 to 5 days and 3 months postoperatively. Results Surgery was associated with a pronounced increase in inflammatory biomarkers in both CSF and blood throughout the 48-hour study period. A principal component (PC) analysis was performed on 52 inflammatory biomarkers. The 2 first PC (PC1 and PC2) construct outcome variables on CSF biomarkers were significantly associated with long-term cognitive decline at 3 months, but none of the PC construct serum variables showed a significant association with long-term cognitive decline at 3 months. Patients both with and patients without long-term cognitive decline showed early transient increases of the astroglial biomarkers S-100B and glial fibrillary acidic protein in CSF, and in BBB permeability (CSF/serum albumin ratio). Interpretation Surgery rapidly triggers a temporal neuroinflammatory response closely associated with long-term cognitive outcome postsurgery. The findings of this explorative study require validation in a larger surgical patient cohort.
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13.
  • Danielsson, Mattias, et al. (författare)
  • Association between cerebrospinal fluid biomarkers of neuronal injury or amyloidosis and cognitive decline after major surgery.
  • 2021
  • Ingår i: British journal of anaesthesia. - : Elsevier BV. - 1471-6771 .- 0007-0912. ; 126:2, s. 467-76
  • Tidskriftsartikel (refereegranskat)abstract
    • Postoperative neurocognitive decline is a frequent complication in adult patients undergoing major surgery with increased risk for morbidity and mortality. The mechanisms behind cognitive decline after anaesthesia and surgery are not known. We studied the association between CSF and blood biomarkers of neuronal injury or brain amyloidosis and long-term changes in neurocognitive function.In patients undergoing major orthopaedic surgery (knee or hip replacement), blood and CSF samples were obtained before surgery and then at 4, 8, 24, 32, and 48 h after skin incision through an indwelling spinal catheter. CSF and blood concentrations of total tau (T-tau), neurofilament light, neurone-specific enolase and amyloid β (Aβ1-42) were measured. Neurocognitive function was assessed using the International Study of Postoperative Cognitive Dysfunction (ISPOCD) test battery 1-2 weeks before surgery, at discharge from the hospital (2-5 days after surgery), and at 3 months after surgery.CSF and blood concentrations of T-tau, neurone-specific enolase, and Aβ1-42 increased after surgery. A similar increase in serum neurofilament light was seen with no overall changes in CSF concentrations. There were no differences between patients having a poor or good late postoperative neurocognitive outcome with respect to these biomarkers of neuronal injury and Aβ1-42.The findings of the present explorative study showed that major orthopaedic surgery causes a release of CSF markers of neural injury and brain amyloidosis, suggesting neuronal damage or stress. We were unable to detect an association between the magnitude of biomarker changes and long-term postoperative neurocognitive dysfunction.
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14.
  • Deming, Y., et al. (författare)
  • The MS4A gene cluster is a key modulator of soluble TREM2 and Alzheimer's disease risk
  • 2019
  • Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 11:505
  • Tidskriftsartikel (refereegranskat)abstract
    • Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) in cerebrospinal fluid (CSF) has been associated with Alzheimer's disease (AD). TREM2 plays a critical role in microglial activation, survival, and phagocytosis; however, the pathophysiological role of sTREM2 in AD is not well understood. Understanding the role of sTREM2 in AD may reveal new pathological mechanisms and lead to the identification of therapeutic targets. We performed a genome-wide association study (GWAS) to identify genetic modifiers of CSF sTREM2 obtained from the Alzheimer's Disease Neuroimaging Initiative. Common variants in the membrane-spanning 4-domains subfamily A (MS4A) gene region were associated with CSF sTREM2 concentrations (rs1582763; P = 1.15 x 10(-15)); this was replicated in independent datasets. The variants associated with increased CSF sTREM2 concentrations were associated with reduced AD risk and delayed age at onset of disease. The single-nucleotide polymorphism rs1582763 modified expression of the MS4A4A and MS4A6A genes in multiple tissues, suggesting that one or both of these genes are important for modulating sTREM2 production. Using human macrophages as a proxy for microglia, we found that MS4A4A and TREM2 colocalized on lipid rafts at the plasma membrane, that sTREM2 increased with MS4A4A overexpression, and that silencing of MS4A4A reduced sTREM2 production. These genetic, molecular, and cellular findings suggest that MS4A4A modulates sTREM2. These findings also provide a mechanistic explanation for the original GWAS signal in the MS4A locus for AD risk and indicate that TREM2 may be involved in AD pathogenesis not only in TREM2 risk-variant carriers but also in those with sporadic disease.
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15.
  • Dutkiewicz, Robert, et al. (författare)
  • Dementia and CSF-biomarkers for Alzheimer's disease predict mortality after acute hip fracture
  • 2020
  • Ingår i: Acta Anaesthesiologica Scandinavica. - : Wiley. - 0001-5172 .- 1399-6576. ; 64:1, s. 93-103
  • Tidskriftsartikel (refereegranskat)abstract
    • Background Mortality is high after an acute hip fracture (AHF) surgery. Are cognitive impairment and/or altered levels of Alzheimer's Disease (AD)-biomarkers in cerebrospinal fluid (CSF) predictors of mortality in AHF-patients, as retrospective studies indicate? Methods Prospective single-center study including 373 AHF-patients, operated in spinal anesthesia. Cognitive status was evaluated by clinical dementia rating (CDR); CSF was analyzed for AD-biomarker concentrations (total tau (T-tau), phosphorylated tau (P-tau), amyloid beta ratio (A beta 42/A beta 40). CDR and biomarker levels were related to mortality up to one-year post-surgery, using univariate logistic regression analysis. Results Survival analyses showed that mortality was associated to the degree of dementia. In the entire patient cohort 30-, 90-, and 365-day mortality rates were 7.2%, 15.5%, and 25.5%, respectively, but only 2.7%, 5.5%, and 12.6%, for cognitively intact vs 16.3%, 31.7%, and 42.3% for demented patients (OR = 2.2-2.8 [CI = 1.6-4.9]; P = .0001). High CSF T-tau (OR = 1.19 [CI = 1.05-1.33]; P = .004) and low A beta 42/A beta 40-ratio (OR = 0.85 [CI = 0.74-0.97]; P = .017) were associated with increased 90-day mortality. Analysis of 4 subgroups (Cognitive impairment +/- and Biomarkers +/-) showed significant associations of dementia and CSF biomarker concentrations to mortality after an AHF. Even cognitively intact patients presenting with abnormal AD-biomarkers showed an increased 90-day mortality which, however, was statistically insignificant. Conclusions Cognitive impairment and altered CSF biomarker concentrations indicative of AD pathology can predict increased mortality in patients with an AHF, and so probably even before clinical dementia diagnosis by early biomarker analysis; a notion that may have substantial clinical implications by improving perioperative treatment and postoperative rehabilitation.
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16.
  • Erichsen Andersson, Annette, 1966, et al. (författare)
  • Reduction of early surgical site and other care related infections in 3553 hip fracture patients : lessons learned from the 5-year Safe Hands project
  • 2022
  • Ingår i: Antimicrobial Resistance and Infection Control. - : Springer Science and Business Media LLC. - 2047-2994. ; 11:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Surgical site infection (SSI) after acute hip fracture surgery is a devastating complication associated with increased suffering and mortality. The aim of the study was to investigate early SSI, sepsis, pneumonia and urinary tract infections over five years, before and after the implementation of the Safe Hands project. Methods: This was a single-centre observational study with a 5-year longitudinal design, investigating the effects of an infection-prevention intervention targeting the clinical care pathway of individuals with acute hip fracture. Statistical analyses were based on routinely collected patient outcome data comprising 3553 patients. The study conforms to the criteria of the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE). Results: The incidence of early SSIs decreased from 2.5% in years 1–2 to 1.1% in years 4–5. Similar results were observed for sepsis (2.7% to 1.3%) and urinary tract infections (14.2% to 4.2%). The multivariable regression results suggest that, for every observed year, the odds of early SSIs decreased. Male gender, procedure time, sepsis and preoperative skin damage increased the odds significantly. Conclusions: Our preventive bundle, based on partnership between researchers, managers and clinicians and a strong commitment to change from the involved professions, appear to be effective in reducing the frequency of potentially devastating SSIs and other hospital acquired infections after hip fracture surgery. The use of external and internal facilitators was crucial to enable individual and organisational learning and overcoming barriers to improvements. Trial registration: Clinical Trials.gov ID: NCT02983136 Registered 6 December 2016—Retrospectively registered.
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17.
  • Falk Erhag, Hanna, et al. (författare)
  • The Association Between the Clinical Frailty Scale and Adverse Health Outcomes in Older Adults in Acute Clinical Settings : A Systematic Review of the Literature
  • 2023
  • Ingår i: Clinical Interventions in Aging. - : Dove Medical Press. - 1176-9092 .- 1178-1998. ; 18, s. 249-261
  • Forskningsöversikt (refereegranskat)abstract
    • Background: Frail older adults experience higher rates of adverse health outcomes. Therefore, assessing pre-hospital frailty early in the course of care is essential to identify the most vulnerable patients and determine their risk of deterioration. The Clinical Frailty Scale (CFS) is a frailty assessment tool that evaluates pre-hospital mobility, energy, physical activity, and function to generate a score that ranges from very fit to terminally ill.Purpose: To synthesize the evidence of the association between the CFS degree and all-cause mortality, all-cause readmission, length of hospital stay, adverse discharge destination, and functional decline in patients > 65 years in acute clinical settings.Design: Systematic review with narrative synthesis.Methods: Electronic databases (PubMed, EMBASE, CINAHL, Scopus) were searched for prospective or retrospective studies reporting a relationship between pre-hospital frailty according to the CFS and the outcomes of interest from database inception to April 2020.Results: Our search yielded 756 articles, of which 29 studies were included in this review (15 were at moderate risk and 14 at low risk of bias). The included studies represented 26 cohorts from 25 countries (N = 44166) published between 2011 and 2020. All included studies showed that pre-hospital frailty according to the CFS is an independent predictor of all adverse health outcomes included in the review.Conclusion: A primary purpose of the CFS is to grade clinically increased risk (i.e. risk stratification). Our results report the accumulated knowledge on the risk-predictive performance of the CFS and highlight the importance of routinely including frailty assessments, such as the CFS, to estimate biological age, improve risk assessments, and assist clinical decision-making in older adults in acute care. Further research into the potential of the CFS and whether implementing the CFS in routine practice will improve care and patients’ quality of life is warranted.
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18.
  • Falk Erhag, Hanna, et al. (författare)
  • The Association Between the Clinical Frailty Scale and Adverse Health Outcomes in Older Adults in Acute Clinical Settings - A Systematic Review of the Literature
  • 2023
  • Ingår i: Clinical Interventions in Aging. - 1178-1998. ; 18, s. 249-261
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Frail older adults experience higher rates of adverse health outcomes. Therefore, assessing pre-hospital frailty early in the course of care is essential to identify the most vulnerable patients and determine their risk of deterioration. The Clinical Frailty Scale (CFS) is a frailty assessment tool that evaluates pre-hospital mobility, energy, physical activity, and function to generate a score that ranges from very fit to terminally ill.Purpose: To synthesize the evidence of the association between the CFS degree and all-cause mortality, all-cause readmission, length of hospital stay, adverse discharge destination, and functional decline in patients >65 years in acute clinical settings. Design: Systematic review with narrative synthesis.Methods: Electronic databases (PubMed, EMBASE, CINAHL, Scopus) were searched for prospective or retrospective studies reporting a relationship between pre-hospital frailty according to the CFS and the outcomes of interest from database inception to April 2020. Results: Our search yielded 756 articles, of which 29 studies were included in this review (15 were at moderate risk and 14 at low risk of bias). The included studies represented 26 cohorts from 25 countries (N = 44166) published between 2011 and 2020. All included studies showed that pre-hospital frailty according to the CFS is an independent predictor of all adverse health outcomes included in the review.Conclusion: A primary purpose of the CFS is to grade clinically increased risk (i.e. risk stratification). Our results report the accumulated knowledge on the risk-predictive performance of the CFS and highlight the importance of routinely including frailty assessments, such as the CFS, to estimate biological age, improve risk assessments, and assist clinical decision-making in older adults in acute care. Further research into the potential of the CFS and whether implementing the CFS in routine practice will improve care and patients' quality of life is warranted.
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19.
  • Fernandes Gomes, Bárbara, et al. (författare)
  • α-Synuclein seed amplification assay as a diagnostic tool for parkinsonian disorders.
  • 2023
  • Ingår i: Parkinsonism & related disorders. - 1873-5126. ; 117
  • Tidskriftsartikel (refereegranskat)abstract
    • Synucleinopathies such as Parkinson's disease (PD) and multiple system atrophy (MSA) can be challenging to diagnose due to the symptom overlap with, for example, atypical parkinsonisms like progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Seed amplification assays (SAA), developed for the detection of α-synuclein (αSyn) aggregates in CSF, have been successful when used as a biomarker evaluation for synucleinopathies. In this study, we investigated the potential of this assay to not only detect αSyn seeds in CSF, but also discriminate between movement disorders.The αSyn-SAA was tested in a Scandinavian cohort composed of 129 CSF samples from patients with PD (n=55), MSA (n=27), CBD (n=7), and PSP (n=16), as well as healthy controls (HC, n=24).The αSyn seed amplification assay (αSyn-SAA) was able to correctly identify all PD samples as positive (sensitivity of 100%) while also discriminating the PD group from HC (70.8% specificity, p<0.0001) and tauopathies [CBD (71% specificity) and PSP (75% specificity), p<0.0001)]. The αSyn-SAA was also able to identify almost all MSA samples as positive for αSyn aggregation (sensitivity of 92.6%). In general, this assay is able to discriminate between the synucleinopathies and tauopathies analyzed herein (p<0.0001) despite the overlapping symptoms in these diseases.These findings suggest the αSyn-SAA is a useful diagnostic tool for differentiating between different parkinsonian disorders, although further optimization may be needed.
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20.
  • Frödin, Maria, et al. (författare)
  • A co-created nurse-driven catheterisation protocol can reduce bladder distension in acute hip fracture patients - results from a longitudinal observational study
  • 2022
  • Ingår i: BMC Nursing. - : Springer Science and Business Media LLC. - 1472-6955. ; 21
  • Tidskriftsartikel (refereegranskat)abstract
    • Abstract Background: Urinary retention is common in elderly patients undergoing acute hip fracture surgery. Avoiding overfilling the urinary bladder is important to avoid detrusor muscle damage and associated motility problems. The aim of this study was to analyse associations between the co-creation of a nurse-driven urinary catheterisation protocol and the incidence of bladder distension in patients undergoing hip fracture surgery. Methods: This is a single-centre implementation intervention with a retrospective longitudinal observation design, using five measures points, spanning from June 2015 to March 2020. The intervention was theory driven and the participants, together with the facilitators and researcher, co-created a nurse-driven urinary catheterisation protocol. Data were retrieved from the hip fracture register. Uni- and multivariable logistic regressions were used for analyses of changes in bladder distension and urinary volume of ≥500 ml over the years. Results: A total of 3078 patients were included over a five-year period. The implementation intervention was associated with a reduction in the proportion of patients with bladder distension of 31.5% (95% confidence interval 26.0–37.0), from year 1 to year 5. The multivariable analysis indicated a 39% yearly reduction in bladder distension, OR 0.61 (95% confidence interval 0.57–0.64, p < 0001). There was a reduction in the proportion of patients with a bladder volume of ≥500 ml of 42.8% (95% confidence interval 36.2–49.4), from year 1 to year 5. The multivariable analysis found a 41% yearly reduction in patients with a bladder volume of ≥500 ml, OR 0.59 (95% confidence interval 0.55–0.64, p < 0.0001). The intervention was associated with improved documentation of both catheter indications and removal plans. Conclusion: The use of predefined catheter indications and a tighter bladder scanning schedule were associated with a reduction in the incidence of both bladder distension and urine volume ≥ 500 ml in hip fracture patients. Registered nurses can play an active role in the facilitation of timely and appropriate catheter treatment in patients with hip fractures. Trial registration: Clinical Trial Registry ISRCTN 17022695 registered retrospectively on 23 December 2021, in the end of the study, after data collection.
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21.
  • Frödin, Maria, et al. (författare)
  • Effectiveness of implementing a preventive urinary catheter care bundle in hip fracture patients
  • 2022
  • Ingår i: Journal of Infection Prevention. - : SAGE Publications. - 1757-1774 .- 1757-1782. ; 23:2, s. 41-48
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Urinary catheter (UC)–associated infections are one of the most common preventable healthcare-associated infections (HAIs) and they frequently occur in older, frail populations. Aim: The study aim was to describe the incidence of UC-associated infection in elderly patients undergoing hip fracture surgery after implementing a preventive care bundle. Methods: A longitudinal prospective study using a before-and-after design. The bundle was theory driven and involved the co-creation of a standard operational procedure, education and practical training sessions. Prospectively collected registry data were analysed. Univariable statistics and multivariable logistic regressions were used for analyses. Results: 2,408 patients with an acute hip fracture were included into the study. There was an overall reduction in UC catheter associated-associated urinary tract infections, from 18.5% (n = 75/406) over time to 4.2% (n = 27/647). When adjusting for all identified confounders, patients in phase 4 were 74% less likely to contract an UC-associated infection (OR, 0.26; 95% CI, 0.15–0.45, p < 0.0001). Discussion: Bundled interventions can reduce UC-associated infections substantially, even in elderly frail patients. Partnership and co-creation as implementation strategies appear to be promising in the fight against HAI.
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22.
  • Frödin, Maria, et al. (författare)
  • Interactive Interventions can Improve Hand Hygiene and Aseptic Techniques During Perioperative Care – Experience From the “Safe Hands” Project
  • 2023
  • Ingår i: Journal of Perianesthesia Nursing. - : Elsevier BV. - 1089-9472. ; 38:2, s. 284-290
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose This paper evaluates a theory-driven, interactive hand hygiene (HH) intervention, the Safe Hands project, based on theories of organizational learning and culture including leadership support, dialogue and co-creation. Design This prospective quasi-experimental study used unobtrusive overt observations to evaluate adherence to HH recommendations after implementing an infection-prevention intervention. Methods The primary outcome was differences in HH practices “Before aseptic/clean procedure” (WHO moment 2), “After body fluid exposure risk” (WHO moment 3) and performance of aseptic techniques. One operating room (OR) department served as the study hospital and the other as the control hospital, both at Swedish university hospitals. Adherence to HH guidelines was measured 4 times during 2015 to 2017. Findings The intervention site displayed a significant improvement in adherence to HH guidelines and aseptic techniques. WHO 2; from 23.8% to 36.2%, (P = .014), WHO 3; from 22.2% to 42.3%, (P = .002), and aseptic techniques; from 17.5% to 31.6%, (P = .003). No changes in adherence were identified at the control site. The use of contaminated gloves decreased post intervention at the study operating department. Conclusions This study shows that implementing tailored interventions that are underpinned by theories from organizational learning and culture can improve adherence to hand hygiene in a complex setting as the OR up to 6 months post-intervention. The interprofessional co-creation of standards operating procedures addressing specific care procedures and emphasizing the importance of aseptic techniques can be an acceptable and feasible way to reduce the risks of contaminating medical devices and patients during perioperative care.
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23.
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24.
  • Gonzalez-Ortiz, Fernando, et al. (författare)
  • Association of Serum Brain-Derived Tau With Clinical Outcome and Longitudinal Change in Patients With Severe Traumatic Brain Injury.
  • 2023
  • Ingår i: JAMA network open. - 2574-3805. ; 6:7
  • Tidskriftsartikel (refereegranskat)abstract
    • Blood-based measurements of total tau (T-tau) are commonly used to examine neuronal injury in patients with traumatic brain injury (TBI), but current assays do not differentiate between brain-derived tau (BD-tau) and tau produced in peripheral tissues. A novel assay for BD-tau has recently been reported that selectively quantifies nonphosphorylated tau of central nervous system origin in blood samples.To examine the association of serum BD-tau with clinical outcomes in patients with severe TBI (sTBI) and its longitudinal changes over 1 year.This prospective cohort study was conducted at the neurointensive unit at the Sahlgrenska University Hospital, Gothenburg, Sweden, between September 1, 2006, and July 1, 2015. The study included 39 patients with sTBI followed up for up to 1 year. Statistical analysis was performed between October and November 2021.Serum BD-tau, T-tau, phosphorylated tau231 (p-tau231), and neurofilament light chain (NfL) measured on days 0, 7, and 365 after injury.Associations of serum biomarkers with clinical outcome and longitudinal change in sTBI. Severity of sTBI was evaluated using the Glasgow Coma Scale at hospital admission, while clinical outcome was assessed with the Glasgow Outcome Scale (GOS) at 1-year follow-up. Participants were classified as having a favorable outcome (GOS score, 4-5) or unfavorable outcome (GOS score, 1-3).Among the 39 patients (median age at admission, 36 years [IQR, 22-54 years]; 26 men [66.7%]) in the study on day 0, the mean (SD) serum BD-tau level was higher among patients with unfavorable outcomes vs those with favorable outcomes (191.4 [190.8] pg/mL vs 75.6 [60.3] pg/mL; mean difference, 115.9 pg/mL [95% CI, 25.7-206.1 pg/mL]), while the other markers had smaller between-group mean differences (serum T-tau, 60.3 pg/mL [95% CI, -22.0 to 142.7 pg/mL]; serum p-tau231, 8.3 pg/mL [95% CI, -6.4 to 23.0 pg/mL]; serum NfL, -5.4 pg/mL [95% CI, -99.0 to 88.3 pg/mL]). Similar results were recorded on day 7. Longitudinally, baseline serum BD-tau concentrations showed slower decreases in the whole cohort (42.2% on day 7 [from 138.6 to 80.1 pg/mL] and 93.0% on day 365 [from 138.6 to 9.7 pg/mL]) compared with serum T-tau (81.5% on day 7 [from 57.3 to 10.6 pg/mL] and 99.0% on day 365 [from 57.3 to 0.6 pg/mL]) and p-tau231 (92.5% on day 7 [from 20.1 to 1.5 pg/mL] and 95.0% on day 365 [from 20.1 to 1.0 pg/mL]). These results did not change when considering clinical outcome, where T-tau decreased twice as fast as BD-tau in both groups. Similar results were obtained for p-tau231. Furthermore, the biomarker levels on day 365 were lower, compared with day 7, for BD-tau but not T-tau or p-tau231. Serum NfL had a different trajectory to the tau biomarkers, with levels increasing by 255.9% on day 7 compared with day 0 (from 86.8 to 308.9 pg/mL) but decreasing by 97.0% by day 365 vs day 7 (from 308.9 to 9.2 pg/mL).This study suggests that serum BD-tau, T-tau, and p-tau231 have differential associations with clinical outcome and 1-year longitudinal change in patients with sTBI. Serum BD-tau demonstrated utility as a biomarker to monitor outcomes in sTBI and can provide valuable information regarding acute neuronal damage.
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25.
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26.
  • Hård af Segerstad, Mathias, et al. (författare)
  • Inhaled prostacyclin for the prevention of increased pulmonary vascular resistance in cemented hip hemiarthroplasty—A randomised trial
  • 2019
  • Ingår i: Acta Anaesthesiologica Scandinavica. - : Wiley. - 0001-5172 .- 1399-6576. ; 63:9, s. 1152-1161
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Bone cementation may cause pulmonary vasoconstriction and ventilation/perfusion abnormalities in patients undergoing cemented hip hemiarthroplasty. In this randomised trial, we tested the hypothesis that intra-operative inhalation of prostacyclin could attenuate the increase in pulmonary vascular resistance index (PVRI, primary endpoint) when compared to inhaled saline in this group of patients. Methods: Twenty-two patients with displaced femoral neck fractures were allocated to receive inhaled aerosolised prostacyclin (20 ng/kg/min) (n = 11) or inhaled saline (NaCl, 9 mg/mL) (n = 11). All patients received total intravenous anaesthesia and were catheterised with radial and pulmonary artery fast response thermodilution catheters, for measurements of arterial and pulmonary arterial pressures, cardiac output, right ventricular ejection fraction and effective pulmonary arterial elastance. Haemodynamic measurements were performed after induction of anaesthesia, during surgery before and immediately after bone cementation and prosthesis insertion, 10 and 20 min after insertion and during skin closure. Results: During the surgical procedure, PVRI increased both in the saline (44%, P < 0.001) and the prostacyclin (36%, P = 0.019) groups, with a less pronounced increase in the prostacyclin group (P = 0.031). Effective pulmonary arterial elastance increased both in the saline (44%, P < 0.001) and the prostacyclin groups (29%, P = 0.032), with a trend for a less pronounced increase in the prostacyclin group (P = 0.084). Right ventricular ejection fraction decreased significantly in both groups with no difference between the groups. Conclusion: Inhalation of prostacyclin attenuates the increase in pulmonary vascular resistance in patients undergoing cemented hip hemiarthroplasty and could potentially attenuate/prevent haemodynamic instability induced by an increase in right ventricular afterload seen in this procedure. © 2019 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
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27.
  • Hård af Segerstad, Mathias, et al. (författare)
  • Pulmonary haemodynamics and right ventricular function in cemented vs uncemented total hip arthroplasty-A randomized trial
  • 2019
  • Ingår i: Acta Anaesthesiologica Scandinavica. - : Wiley. - 0001-5172. ; 63:3, s. 298-305
  • Tidskriftsartikel (refereegranskat)abstract
    • Background Bone cement implantation syndrome (BCIS) is a feared complication in orthopaedic surgery with a huge impact on post-operative morbidity. In this randomized trial, we evaluated the effects of bone cement on pulmonary and systemic haemodynamics in patients receiving either cemented or uncemented hip arthroplasty for isolated femoral neck fracture. Methods Twenty-two patients were randomized to receive either cemented (n = 10) or uncemented (n = 12) total hip arthroplasty. Surgery was performed under total intravenous anaesthesia in the lateral position. All patients were catheterized with radial- and pulmonary artery catheters, for continuous measurements of mean arterial pressure (MAP), pulmonary arterial pressure (PAP), cardiac output, right ventricular (RV) end-diastolic volume (RVEDV) and RV ejection fraction (RVEF). Haemodynamic measurements and blood gas analyses were performed after induction of anaesthesia, during surgery before and immediately after bone cementation and prosthesis insertion, 10 and 20 minutes after insertion and during skin closure. Results Pulmonary vascular resistance index (PVRI) increased during and after prosthesis insertion by 45% and 20% in the cemented and uncemented group, respectively (P < 0.005). Systolic and mean PAP increased by 18% and 17% in the cemented group, which was not seen in the uncemented group (P < 0.001). There was a trend for a more pronounced fall in RVEF in the cemented group, while there were no differences in cardiac output or stroke volume between groups. Conclusion The use of bone cement in total hip arthroplasty increases pulmonary vascular resistance and the afterload of the RV with potentially negative effects on RV performance.
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28.
  • Jernås, Margareta, 1961, et al. (författare)
  • Changes in adipose tissue gene expression and plasma levels of adipokines and acute-phase proteins in patients with critical illness.
  • 2009
  • Ingår i: Metabolism: clinical and experimental. - : Elsevier BV. - 1532-8600. ; 58:1, s. 102-8
  • Tidskriftsartikel (refereegranskat)abstract
    • Insulin resistance develops rapidly during critical illness. The release of adipokines from adipose tissue is thought to play a key role in the development of insulin resistance, as are elevated levels of acute-phase proteins. The aim of this study was to identify changes in adipose tissue gene expression and plasma levels of adipokines and acute-phase proteins during critical illness. From 8 patients with subarachnoidal hemorrhage, consecutive blood samples and adipose tissue biopsies were obtained at 3 time points, twice during intensive care (1-2 days [IC1] and 7-9 days after subarachnoidal hemorrhage) and once after 8 months (recovery). The patients received a continuous insulin infusion to maintain normal glucose levels reflecting insulin resistance. The DNA microarray analysis showed increased zink-alpha2 glycoprotein (ZAG) and phospholipase A2, group IIA messenger RNA levels during intensive care compared with recovery (P < .05). Real-time polymerase chain reaction confirmed the increased expression of ZAG and phospholipase A2, group IIA. Plasma levels of ZAG, serum amyloid A, and C-reactive protein were higher at 7 to 9 days after subarachnoidal hemorrhage compared with either IC1 or recovery (P = .0001); and plasma levels of retinol-binding protein 4 and adiponectin were lower at IC1 compared with recovery (P = .05). The described changes in adipose tissue gene expression and plasma levels of adipokines and acute-phase proteins may influence the development of insulin resistance during critical illness.
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29.
  • Kanberg, Nelly, et al. (författare)
  • Neurochemical signs of astrocytic and neuronal injury in acute COVID-19 normalizes during long-term follow-up.
  • 2021
  • Ingår i: EBioMedicine. - : Elsevier BV. - 2352-3964. ; 70
  • Tidskriftsartikel (refereegranskat)abstract
    • Neurologic manifestations are well-recognized features of coronavirus disease 2019 (COVID-19). However, the longitudinal association of biomarkers reflecting CNS impact and neurological symptoms is not known. We sought to determine whether plasma biomarkers of CNS injury were associated with neurologic sequelae after COVID-19.Patients with confirmed acute COVID-19 were studied prospectively. Neurological symptoms were recorded during the acute phase of the disease and at six months follow-up, and blood samples were collected longitudinally. Healthy age-matched individuals were included as controls. We analysed plasma concentrations of neurofilament light-chain (NfL), glial fibrillary acidic protein (GFAp), and growth differentiation factor 15 (GDF-15).One hundred patients with mild (n=24), moderate (n=28), and severe (n=48) COVID-19 were followed for a median (IQR) of 225 (187-262) days. In the acute phase, patients with severe COVID-19 had higher concentrations of NfL than all other groups (all p < 0·001), and higher GFAp than controls (p < 0·001). GFAp was also significantly increased in moderate disease (p < 0·05) compared with controls. NfL (r=0·53, p < 0·001) and GFAp (r=0·39, p < 0·001) correlated with GDF-15 during the acute phase. After six months, NfL and GFAp concentrations had normalized, with no persisting group differences. Despite this, 50 patients reported persistent neurological symptoms, most commonly fatigue (n=40), "brain-fog" (n=29), and changes in cognition (n=25). We found no correlation between persistent neurological symptoms and CNS injury biomarkers in the acute phase.The normalization of CNS injury biomarkers in all individuals, regardless of previous disease severity or persisting neurological symptoms, indicates that post COVID-19 neurological sequelae are not accompanied by ongoing CNS injury.The Swedish State Support for Clinical Research, SciLifeLab Sweden, and the Knut and Alice Wallenberg Foundation have provided funding for this project.
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30.
  • Konsberg, Ylva, et al. (författare)
  • Progressive changes in pulmonary gas exchange during invasive respiratory support for COVID-19 associated acute respiratory failure: A retrospective study of the association with 90-day mortality.
  • 2024
  • Ingår i: Acta anaesthesiologica Scandinavica. - 1399-6576.
  • Tidskriftsartikel (refereegranskat)abstract
    • Ratio of arterial pressure of oxygen and fraction of inspired oxygen (P/F ratio) together with the fractional dead space (Vd/Vt) provides a global assessment of pulmonary gas exchange. The aim of this study was to assess the potential value of these variables to prognosticate 90-day survival in patients with COVID-19 associated ARDS admitted to the Intensive Care Unit (ICU) for invasive ventilatory support.In this single-center observational, retrospective study, P/F ratios and Vd/Vt were assessed up to 4weeks after ICU-admission. Measurements from the first 2weeks were used to evaluate the predictive value of P/F ratio and Vd/Vt for 90-day mortality and reported by the adjusted hazard ratio (HR) and 95% confidence intervals [95%CI] by Cox proportional hazard regression.Almost 20,000 blood gases in 130 patients were analyzed. The overall 90-day mortality was 30% and using the data from the first ICU week, the HR was 0.85 [0.77-0.94] for every 10mmHg increase in P/F ratio and 1.61 [1.20-2.16] for every 0.1 increase in Vd/Vt. In the second week, the HR for 90-day mortality was 0.82 [0.75-0.89] for every 10mmHg increase in P/F ratio and 1.97 [1.42-2.73] for every 0.1 increase in Vd/Vt.The progressive changes in P/F ratio and Vd/Vt in the first 2weeks of invasive ventilatory support for COVID-19 ARDS were significant predictors for 90-day mortality.
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31.
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32.
  • Kristiansson, J., et al. (författare)
  • Prolonged vasopressor support during hip-fracture surgery is a risk factor for enhanced mortality
  • 2019
  • Ingår i: Acta Anaesthesiologica Scandinavica. - : Wiley. - 0001-5172. ; 63:1, s. 46-54
  • Tidskriftsartikel (refereegranskat)abstract
    • Background Hip fracture is a common injury in the elderly population and is associated with high morbidity and mortality. Intraoperative hypotension is commonly noted, and is often treated with vasopressors (VP), however, to what extent is unknown. We set out to examine retrospectively how many hip fracture-patients received VP perioperatively and further to investigate if VP treatment is connected to increased mortality. Method Data on VP treatment were captured from medical and anaesthesia journals, and if so, data were investigated to find potential confounders. Patients were divided into (a) no VP, (b) VP by injection, (c) VP by infusion <3 hours, and (d) VP by infusion >= 3 hours to achieve stratification. Results Nine hundred and ninety-seven patients were included. About 80.4% received VP treatment. The 30-day mortality rates in subgroups were 3.6%, 5.4%, 6.4% and 19.1% respectively. The 90-day mortality rates were 6.7%, 10.3%, 11.6% and 30.3% respectively. Finally, the same patient groups had 365-day mortality rates of 12.8%, 20.0%, 23.3% and 44.9% respectively. We found a significant increase in mortality (30-90-365 days) in patients receiving VP infusion >= 3 hours, after adjusting for confounding factors. There was no increased mortality in patients treated by injection and by infusion Conclusion Vasopressor treatment is common during hip fracture surgery. Patients treated with VP infusion >= 3 hours have increased mortality, while patients treated with injections or infusion
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33.
  • Kristiansson, Johan, et al. (författare)
  • The influence of time-to-surgery on mortality after a hip fracture
  • 2020
  • Ingår i: Acta Anaesthesiologica Scandinavica. - : Wiley. - 0001-5172 .- 1399-6576. ; 64:3, s. 347-353
  • Tidskriftsartikel (refereegranskat)abstract
    • Background The effect of time-to-surgery on mortality in acute hip fracture (AHF) patients has been debated and studies are inconsistent regarding from what time limit mortality starts to increase. At Sahlgrenska University Hospital/Molndal, surgery is recommended within 24 hours leaving little time for pre-operative optimization. However, internationally the definition of early surgery varies between 24 and 48 hours and over. This retrospective study was initiated to investigate the relation between time-to-surgery and 30-day mortality. Method Data of AHF patients from January 2007 through December 2016 were collected. The variables analysed were: age, gender, American Society of Anesthesiologists physical status classification, surgical method (prosthesis or osteosynthesis) and time-to-surgery, along with 30-day mortality. Primary outcome was 30-day mortality related to time-to-surgery divided into groups. Secondary outcome was 30-day mortality related to time-to-surgery analysed hour-by-hour. Results From 10,844 eligible patients, 9,270 patients were included into the study. Mean time-to-surgery was 19.4 hours and overall 30-day mortality was 7.6%. Adjusted Cox regression analysis revealed an increased mortality rate in patients with time-to-surgery >48 hours. In the hour-by-hour analysis, significant mortality increase was observed at 39 hours of time-to-surgery. Patients with time-to-surgery >24 hours did not have increased mortality compared to patients with time-to-surgery In AHF patients, a time-to-surgery exceeding 39-48 hours was associated with increased mortality. Patients with surgeries performed before 39-48 hours did not have increased mortality and this time may, in some patients, be used for optimization prior surgery even if time-to-surgery exceeds 24 hours.
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34.
  • Lehmann-Werman, Roni, et al. (författare)
  • Identification of tissue-specific cell death using methylation patterns of circulating DNA
  • 2016
  • Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 113:13, s. E1826-E1834
  • Tidskriftsartikel (refereegranskat)abstract
    • Minimally invasive detection of cell death could prove an invaluable resource in many physiologic and pathologic situations. Cell-free circulating DNA (cfDNA) released from dying cells is emerging as a diagnostic tool for monitoring cancer dynamics and graft failure. However, existing methods rely on differences in DNA sequences in source tissues, so that cell death cannot be identified in tissues with a normal genome. We developed a method of detecting tissue-specific cell death in humans based on tissue-specific methylation patterns in cfDNA. We interrogated tissue-specific methylome databases to identify cell type-specific DNA methylation signatures and developed a method to detect these signatures in mixed DNA samples. We isolated cfDNA from plasma or serum of donors, treated the cfDNA with bisulfite, PCR-amplified the cfDNA, and sequenced it to quantify cfDNA carrying the methylation markers of the cell type of interest. Pancreatic beta-cell DNA was identified in the circulation of patients with recently diagnosed type-1 diabetes and islet-graft recipients; oligodendrocyte DNA was identified in patients with relapsing multiple sclerosis; neuronal/glial DNA was identified in patients after traumatic brain injury or cardiac arrest; and exocrine pancreas DNA was identified in patients with pancreatic cancer or pancreatitis. This proof-of-concept study demonstrates that the tissue origins of cfDNA and thus the rate of death of specific cell types can be determined in humans. The approach can be adapted to identify cfDNA derived from any cell type in the body, offering a minimally invasive window for diagnosing and monitoring a broad spectrum of human pathologies as well as providing a better understanding of normal tissue dynamics.
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35.
  • Morenas-Rodriguez, E., et al. (författare)
  • Soluble TREM2 in CSF and its association with other biomarkers and cognition in autosomal-dominant Alzheimer acute accent s disease: a longitudinal observational study
  • 2022
  • Ingår i: LANCET NEUROLOGY. - 1474-4422. ; 21:4, s. 329-341
  • Tidskriftsartikel (refereegranskat)abstract
    • Background Therapeutic modulation of TREM2-dependent microglial function might provide an additional strategy to slow the progression of Alzheimer's disease. Although studies in animal models suggest that TREM2 is protective against Alzheimer's pathology, its effect on tau pathology and its potential beneficial role in people with Alzheimer's disease is still unclear. Our aim was to study associations between the dynamics of soluble TREM2, as a biomarker of TREM2 signalling, and amyloid beta (A beta) deposition, tau-related pathology, neuroimaging markers, and cognitive decline, during the progression of autosomal dominant Alzheimer's disease. Methods We did a longitudinal analysis of data from the Dominantly Inherited Alzheimer Network (DIAN) observational study, which includes families with a history of autosomal dominant Alzheimer's disease. Participants aged over 18 years who were enrolled in DIAN between Jan 1, 2009, and July 31, 2019, were categorised as either carriers of pathogenic variants in PSEN1 , PSEN2 , and APP genes (n=155) or non-carriers (n=93). We measured amounts of cleaved soluble TREM2 using a novel immunoassay in CSF samples obtained every 2 years from participants who were asymptomatic (Clinical Dementia Rating [CDR]=0) and annually for those who were symptomatic (CDR > 0). CSF concentrations of A beta 40, A beta 42, total tau (t-tau), and tau phosphorylated on threonine 181 (p-tau) were measured by validated immunoassays. Predefined neuroimaging measurements were total cortical uptake of Pittsburgh compound B PET (PiB-PET), cortical thickness in the precuneus ascertained by MRI, and hippocampal volume determined by MRI. Cognition was measured using a validated cognitive composite (including DIAN word list test, logical memory delayed recall, digit symbol coding test [total score], and minimental status examination). We based our statistical analysis on univariate and bivariate linear mixed effects models. Findings In carriers of pathogenic variants, a high amyloid burden at baseline, represented by low CSF A beta 42 (beta=-4.28 x 10(-2) [SE 0.013], p=0.0012), but not high cortical uptake in PiB-PET (beta=-5.51 x 10(-3) [0.011], p=0.63), was the only predictor of an augmented annual rate of subsequent increase in soluble TREM2. Augmented annual rates of increase in soluble TREM2 were associated with a diminished rate of decrease in amyloid deposition, as measured by A beta 42 in CSF (r=0.56 [0.22], p=0.011), in presymptomatic carriers of pathogenic variants, and with diminished annual rate of increase in PiB-PET (r=-0.67 [0.25], p=0.0060) in symptomatic carriers of pathogenic variants. Presymptomatic carriers of pathogenic variants with annual rates of increase in soluble TREM2 lower than the median showed a correlation between enhanced annual rates of increase in p-tau in CSF and augmented annual rates of increase in PiB-PET signal (r=0.45 [0.21], p=0.035), that was not observed in those with rates of increase in soluble TREM2 higher than the median. Furthermore, presymptomatic carriers of pathogenic variants with rates of increase in soluble TREM2 above or below the median had opposite associations between A beta 42 in CSF and PiB-PET uptake when assessed longitudinally. Augmented annual rates of increase in soluble TREM2 in presymptomatic carriers of pathogenic variants correlated with decreased cortical shrinkage in the precuneus (r=0.46 [0.22]), p=0.040) and diminished cognitive decline (r=0.67 [0.22], p=0.0020). Interpretation Our findings in autosomal dominant Alzheimer's disease position the TREM2 response within the amyloid cascade immediately after the first pathological changes in A beta aggregation and further support the role of TREM2 on A beta plaque deposition and compaction. Furthermore, these findings underpin a beneficial effect of TREM2 on A beta deposition, A beta-dependent tau pathology, cortical shrinkage, and cognitive decline. Soluble TREM2 could, therefore, be a key marker for clinical trial design and interpretation. Efforts to develop TREM2-boosting therapies are ongoing. Funding German Research Foundation, US National Institutes of Health.Copyright (C) 2022 Elsevier Ltd. All rights reserved.
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36.
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37.
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38.
  • Nellgård, Bengt, et al. (författare)
  • Cerebral protection by AMPA- and NMDA-receptor antagonists administered after severe insulin-induced hypoglycemia
  • 1992
  • Ingår i: Experimental Brain Research. - 0014-4819. ; 92:2, s. 259-266
  • Tidskriftsartikel (refereegranskat)abstract
    • Excitatory amino acids are implicated in the development of neuronal cell damage following periods of reversible cerebral ischemia or insulin-induced hypoglycemic coma. To explore the importance of glutamate receptor activation in the posthypoglycemic phase, we exposed rats to 20 min of insulin-induced severe hypoglycemia. The rats were treated immediately after the hypoglycemic insult with four regimes of glutamate receptor antagonists: (1) the AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propriate)-receptor antagonist NBQX [2.3-dihydroxy-6-nitro-7-sulfamoyl-benzo (F) quinoxaline] given as a bolus dose of 30 mg · kg-1 i.p., followed by an i.v. infusion of 225 μg · kg-1 · min-1 for 6 h; (2) the non-competitive NMDA-receptor antagonist, dizocilpine (MK-801) 1 mg · kg-1 given i.v.; (3) a combined NBQX treatment, (a bolus dose of 10 mg · kg-1 i.p., followed by an i.v. infusion of 225 μg · kg-1 · min-1 for 6 h), with dizocilpine 0.33 mg · kg-1 given twice i.p. at 0 and 15 min after recovery and (4) the competitive NMDA-receptor blocker CGP 40116 [D-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid] 10 mg · kg-1 given i.p.. In the striatum, all glutamate receptor blockers significantly decreased neuronal damage by approximately 30%. An approximately 50% decrease in neuronal damage was demonstrated in neocortex and hippocampus following the combined treatment with NBQX and dizocilpine, while protection was variable following the treatment with a single glutamate-receptor antagonist. We conclude that neuronal damage continues to develop in the striatum and in cortical brain regions in the posthypoglycemic period and that both NMDA- and AMPA-receptors contribute to this process, possibly by a change in the cellular response to both AMPA- and NMDA-receptor stimulation.
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39.
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40.
  • Nilsson, Johanna, 1993, et al. (författare)
  • Cerebrospinal fluid biomarkers of synaptic dysfunction are altered in Parkinson's disease and related disorders
  • 2023
  • Ingår i: Movement Disorders. - : John Wiley & Sons. - 0885-3185 .- 1531-8257. ; 38:2, s. 267-277
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Synaptic dysfunction and degeneration are central contributors to the pathogenesis and progression of parkinsonian disorders. Therefore, identification and validation of biomarkers reflecting pathological synaptic alterations are greatly needed and could be used in prognostic assessment and to monitor treatment effects.Objective: To explore candidate biomarkers of synaptic dysfunction in Parkinson's disease (PD) and related disorders.Methods: Mass spectrometry was used to quantify 15 synaptic proteins in two clinical cerebrospinal fluid (CSF) cohorts, including PD (n1 = 51, n2 = 101), corticobasal degeneration (CBD) (n1 = 11, n2 = 3), progressive supranuclear palsy (PSP) (n1 = 22, n2 = 21), multiple system atrophy (MSA) (n1 = 31, n2 = 26), and healthy control (HC) (n1 = 48, n2 = 30) participants, as well as Alzheimer's disease (AD) (n2 = 23) patients in the second cohort.Results: Across both cohorts, lower levels of the neuronal pentraxins (NPTX; 1, 2, and receptor) were found in PD, MSA, and PSP, compared with HC. In MSA and PSP, lower neurogranin, AP2B1, and complexin-2 levels compared with HC were observed. In AD, levels of 14-3-3 zeta/delta, beta- and gamma-synuclein were higher compared with the parkinsonian disorders. Lower pentraxin levels in PD correlated with Mini-Mental State Exam scores and specific cognitive deficits (NPTX2; rho = 0.25–0.32, P < 0.05) and reduced dopaminergic pre-synaptic integrity as measured by DaTSCAN (NPTX2; rho = 0.29, P = 0.023). Additionally, lower levels were associated with the progression of postural imbalance and gait difficulty symptoms (All NPTX; β-estimate = −0.025 to −0.038, P < 0.05) and cognitive decline (NPTX2; β-estimate = 0.32, P = 0.021).Conclusions: These novel findings show different alterations of synaptic proteins in parkinsonian disorders compared with AD and HC. The neuronal pentraxins may serve as prognostic CSF biomarkers for both cognitive and motor symptom progression in PD. 
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41.
  • Nylén, Karin, 1961, et al. (författare)
  • CSF -neurofilament correlates with outcome after aneurysmal subarachnoid hemorrhage.
  • 2006
  • Ingår i: Neurosci Lett. - : Elsevier BV. - 0304-3940. ; 404:1-2, s. 132-6
  • Tidskriftsartikel (refereegranskat)abstract
    • Aneurysmal subarachnoid hemorrhage (aSAH) is a devastating event. Following the bleeding, a number of pathophysiological changes and clinical factors determine outcome. Not surprisingly, attempts to predict outcome based on a single factor have failed. The neurological status graded at admission to hospital and distributions of the blood on CT are the strongest predictors. There is evidence that cerebrospinal fluid (CSF) proteins may serve as markers of the extent of brain damage. The present study is focused on the light unit of neurofilament protein (NFL), previously not evaluated in aSAH. Lumbar puncture (LP), neurological grading according to World Federation of Neurological Surgeons (WFNS) and neurological examination according to the National Institute of Health Stroke Scale (NIHSS) were performed in 48 consecutive patients with aSAH 10-14 days after the hemorrhage. CSF-NFL concentrations were analyzed using an ELISA. Outcome was assessed after 1 year and categorised according to the extended Glasgow Outcome Scale (GOSE). A significant correlation between CSF-NFL and GOSE was detected at follow up after 1 year. CSF-NFL also correlated with WFNS and NIHSS on the day of the lumbar puncture. CSF-NFL is a biochemical marker of brain damage correlating to neurological status and long-term outcome after aneurysmal subarachnoid hemorrhage.
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42.
  • Nylen, K, et al. (författare)
  • Increased serum-GFAP in patients with severe traumatic brain injury is related to outcome
  • 2006
  • Ingår i: J Neurol Sci. - : Elsevier BV. - 0022-510X. ; 240:1-2, s. 85-91
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVES: Several studies have established the relevance of S-100 in blood as a marker of brain damage after traumatic brain injury. However, a more specific marker is required and glial fibrillary acidic protein (GFAP) is considered to be a good candidate. METHODS: In order to assess the increase of GFAP in serum (s-GFAP) after a severe traumatic brain injury (TBI) we collected daily serum samples from 59 patients with severe TBI starting on the day of the trauma. S-GFAP was measured using a sandwich ELISA. The Glasgow outcome scale (GOS) assessed outcome after 1 year. RESULTS: All but one patient had maximal s-GFAP values above the laboratory reference value (median increased 10-fold). The highest detected levels were seen during the first days after TBI and then decreased gradually. Patients with unfavourable outcome had significantly (p<0.001) higher maximal s-GFAP values in the acute phase compared with patients with favourable outcome. All patients (n=5) with s-GFAP>15.04 microg /L died (reference level<0.15 microg/L). We found no significant difference in the maximal s-GFAP levels of patients with isolated brain injury in comparison with patients with multiple traumas. CONCLUSION: Serum-GFAP is increased during the first days after a severe traumatic brain injury and related to clinical outcome.
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43.
  • Nylén, Karin, 1961, et al. (författare)
  • Serum glial fibrillary acidic protein is related to focal brain injury and outcome after aneurysmal subarachnoid hemorrhage.
  • 2007
  • Ingår i: Stroke. - 1524-4628. ; 38:5, s. 1489-94
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND AND PURPOSE: Aneurysmal subarachnoid hemorrhage (aSAH) stands out from other subtypes of stroke because of the high early mortality and the risk of complications. Serum glial fibrillary acidic protein (s-GFAP) concentrations are increased after stroke. The aim of this study was to investigate whether s-GFAP could be used as a marker of brain damage and outcome after aSAH. METHODS: Serum samples were obtained on a regular basis from 116 adults during a 2-week period after aSAH and analyzed using an enzyme-linked immunosorbent assay. The World Federation of Neurological Surgeons scale was used for neurological evaluation. Outcome was assessed after 1 year and categorized according to the Extended Glasgow Outcome Scale. RESULTS: Increased s-GFAP levels were seen in 81 of the 116 patients. Maximum s-GFAP correlated with World Federation of Neurological Surgeons scale on arrival and on days 10 to 15 (r=0.37, P<0.001 and r=0.47, P<0.001, respectively). Furthermore, maximum s-GFAP levels were increased in the patient group with radiological signs of focal lesions acute or at 1 year, compared with the group without focal lesions (P<0.001 in both comparisons). Patients with secondary events (re-bleeding or ischemia) reached maximum levels later in the series and both maximum and final s-GFAP levels increased compared with the levels in patients without secondary events (P<0.001 in all 3 comparisons). Finally, maximum s-GFAP correlated with outcome (r=-0.48, P<0.001) and s-GFAP was an independent predictor of dichotomized outcome. CONCLUSIONS: s-GFAP provides information about brain injury severity and outcome after aSAH, which can be useful as a complement to clinical data.
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44.
  • Nylén, Karin, 1961, et al. (författare)
  • Serum levels of S100B, S100A1B and S100BB are all related to outcome after severe traumatic brain injury.
  • 2008
  • Ingår i: Acta neurochirurgica. - : Springer Science and Business Media LLC. - 0942-0940 .- 0001-6268. ; 150:3
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVES: S100B is an established marker of brain damage. Used in the context as a biochemical marker, S100B denotes a measurement of all S100 proteins, including at least one S100B monomer, i.e. the sum of the two dimers S100A1B and S100BB. Almost all published studies are based on this "sum concentration". However, the brain specificity of S100B has been questioned and increased serum levels have also been reported after trauma without head injury. Since the S100B monomer dominates in the brain, we hypothesised that the S100BB dimer should be better related to outcome after severe traumatic brain injury than S100A1B or the "sum concentration". METHODS: Daily serum samples were collected from 59 patients with severe traumatic brain injury. Three different ELISA methods were used for measurements of S100B, S100A1B and S100BB respectively. Outcome was assessed after one year and categorised according to the Glasgow Outcome Scale. RESULTS: Serum levels of S100B, S100A1B and S100BB followed the same temporal course, with early maximum and rapidly decreasing values over the first days after the trauma. Maximum serum concentrations of each of the parameters were increased in the patient group with an unfavourable outcome compared with those with a favourable outcome (p = 0.01, 0.006 and 0.004, respectively). CONCLUSION: Both S100A1B and S100BB were related to outcome after severe traumatic brain injury. Even though this study is small, it seems unlikely that separate analyses of the dimers are of any advantage compared with measuring S100B alone.
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45.
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46.
  • Olofsson, Christina, et al. (författare)
  • A multicenter clinical study of the safety and activity of maleimide-polyethylene glycol-modified Hemoglobin (Hemospan) in patients undergoing major orthopedic surgery.
  • 2006
  • Ingår i: Anesthesiology. - : Ovid Technologies (Wolters Kluwer Health). - 0003-3022 .- 1528-1175. ; 105:6, s. 1153-63
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Hemospan (Sangart Inc., San Diego, CA), a polyethylene glycol-modified hemoglobin with unique oxygen transport properties, has successfully completed a phase I trial in healthy volunteers. Because adverse events are expected to increase with age, the authors conducted a phase II safety study of Hemospan in elderly patients undergoing elective hip arthroplasty during spinal anesthesia. METHODS: Ninety male and female patients, American Society of Anesthesiologists physical status I-III, aged 50-89 yr, in six Swedish academic hospitals were randomly assigned to receive either 250 or 500 ml Hemospan or Ringer's acetate (30 patients/group) before induction of spinal anesthesia. Safety assessment included vital signs and Holter monitoring from infusion to 24 h, evaluation of laboratory values, and fluid balance. The hypothesis to be tested was that the incidence of adverse events would be no more frequent in patients who received Hemospan compared with standard of care (Ringer's acetate). RESULTS: Three serious adverse events were noted, none of which was deemed related to study treatment. Liver enzymes, amylase, and lipase increased transiently in patients in all three groups. There were no significant differences in electrocardiogram or Holter parameters, but there was a suggestion of more bradycardic events in the treated groups. Hypotension was less frequent in the treated patients compared with controls. CONCLUSIONS: In comparison with Ringer's acetate, Hemospan mildly elevates hepatic enzymes and lipase and is associated with less hypotension and more bradycardic events. The absence of a high frequency of serious adverse events suggests that further clinical trials should be undertaken.
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47.
  • Olsen, Fredrik, 1973, et al. (författare)
  • Fractional spinal anesthesia and systemic hemodynamics in frail elderly hip fracture patients
  • 2023
  • Ingår i: F1000 Research. - : F1000 Research Ltd. - 2046-1402. ; 12
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Systemic haemodynamic effects of intrathecal anaesthesia in an aging and frail population has not been well investigated. We examined the systemic haemodynamics of fractional spinal anaesthesia following intermittent microdosing of a local anaesthetic and an opioid. Methods: We included 15 patients aged over 65 with significant comorbidities, planned for hip fracture repair. Patients received a spinal catheter and cardiac output monitoring using the LiDCOplus system. All measurements were performed prior to start of surgery. Invasive mean arterial pressure (MAP), cardiac index (CI), systemic vascular resistance index (SVRI), heart rate and stroke volume index (SVI) were registered. Two doses of bupivacaine 2.25 mg and fentanyl 15 µg were administered with 25-minute intervals. Hypotension was defined as a fall in MAP by >30% or a MAP <65 mmHg. Results: The incidence of hypotension was 30%. Hypotensive patients (n=5) were treated with low doses of norepinephrine (0.01-0.12 µg/kg/min). MAP showed a maximum reduction of 17% at 10 minutes following the first dose. CI, systemic vascular resistance index and stroke volume index decreased by 10%, 6%, and 7%, respectively, while heart rate was unchanged over time. After the second dose, none of the systemic haemodynamic variables were affected. Conclusions: Fractional spinal anaesthesia administered prior to surgery induced a minor to moderate fall in MAP, mainly caused by a reduction in cardiac output, induced by systemic venodilation, causing a fall in venous return. Our results are contrary to the widely held belief that hypotension is mainly the result of a reduction of systemic vascular resistance.
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48.
  • Olsen, Fredrik, 1973, et al. (författare)
  • The role of bone cement for the development of intraoperative hypotension and hypoxia and its impact on mortality in hemiarthroplasty for femoral neck fractures
  • 2020
  • Ingår i: Acta Orthopaedica. - : Medical Journals Sweden AB. - 1745-3674 .- 1745-3682. ; 91:3, s. 293-298
  • Tidskriftsartikel (refereegranskat)abstract
    • Background and purpose - The bone cement implantation syndrome characterized by hypotension and/or hypoxia is a well-known complication in cemented arthroplasty. We studied the incidence of hypotension and/or hypoxia in patients undergoing cemented or uncemented hemiarthroplasty for femoral neck fractures and evaluated whether bone cement was an independent risk factor for postoperative mortality. Patients and methods - In this retrospective cohort study, 1,095 patients from 2 hospitals undergoing hemiarthroplasty with (n = 986) and without (n = 109) bone cementation were included. Pre-, intra-, and postoperative data were obtained from electronic medical records. Each patient was classified for grade of hypotension and hypoxia during and after prosthesis insertion according to Donaldson's criteria (Grade 1, 2, 3). After adjustments for confounders, the hazard ratio (HR) for the use of bone cement on 1-year mortality was assessed. Results - The incidence of hypoxia and/or hypotension was higher in the cemented (28%) compared with the uncemented group (17%) (p = 0.003). The incidence of severe hypotension/hypoxia (grade 2 or 3) was 6.9% in the cemented, but not observed in the uncemented group. The use of bone cement was an independent risk factor for 1-year mortality (HR 1.9, 95% CI 1.3-2.7), when adjusted for confounders. Interpretation - The use of bone cement in hemiarthroplasty for femoral neck fractures increases the incidence of intraoperative hypoxia and/or hypotension and is an independent risk factor for postoperative 1-year mortality. Efforts should be made to identify patients at risk for BCIS and alternative strategies for the management of these patients should be considered.
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49.
  • Olsen, Fredrik, 1973, et al. (författare)
  • Validation of the Nottingham Hip Fracture Score (NHFS) for the prediction of 30-day mortality in a Swedish cohort of hip fractures.
  • 2021
  • Ingår i: Acta anaesthesiologica Scandinavica. - : Wiley. - 1399-6576 .- 0001-5172. ; 65:10, s. 1413-1420
  • Tidskriftsartikel (refereegranskat)abstract
    • Hip fracture is a common osteoporotic fracture with great morbidity and mortality. The utility of ASA classification is limited, as most patients are ≥ASA 3. A reliable predictor of mortality risk could support decision-making. We aimed to evaluate Nottingham hip fracture score (NHFS) for the prediction of 30-day mortality and then to recalibrate the formula converting NHFS to risk of 30-day mortality.All patients >60years with surgically treated hip fracture surgery during 2015-16 were assessed. Data was extracted manually from routinely collected clinical data in registry and medical records. Discriminative performance of NHFS and ASA was assessed with C-statistics. The conversion formula from NHFS to risk of 30-day mortality was recalibrated using logistic binominal regression. Observed vs expected ratios of 30-day mortality were compared with the 2012NHFS-formula and recalibration was performed in a split dataset.1864 patients were included, with 213 deaths within 30days. C-statistic were 0.64 for NHFS and 0.62 for ASA. Comparing expected values from the 2012-revision with our observed deaths gave a ratio of 1.37. Relating predicted levels of 30-day mortality based on 70% of our cohort vs. 30% test portion of our Swedish dataset gave a ratio of 0.97.NHFS underestimated mortality in our cohort and showed poor discrimination. Revision of the formula based on a split dataset improved calibration. We suggest NHFS to be routinely implemented to support clinical judgements, expand preoperative assessment and escalate intraoperative monitoring.
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50.
  • Olsson, Annika, et al. (författare)
  • Marked increase of beta-amyloid(1-42) and amyloid precursor protein in ventricular cerebrospinal fluid after severe traumatic brain injury.
  • 2004
  • Ingår i: Journal of neurology. - : Springer Science and Business Media LLC. - 0340-5354 .- 1432-1459. ; 251:7, s. 870-6
  • Tidskriftsartikel (refereegranskat)abstract
    • Severe traumatic brain injury (TBI) may result in widespread damage to axons, termed diffuse axonal injury. Alzheimer's disease (AD) is characterised by synaptic and axonal degeneration together with senile plaques (SP). SP are mainly composed of aggregated beta-amyloid (Abeta), which are peptides derived from the amyloid precursor protein (APP). Apart from TBI in itself being considered a risk factor for AD, severe head injury seems to initiate a cascade of molecular events that are also associated with AD. We have therefore analysed the 42 amino acid forms of Abeta (Abeta1-42) and two soluble forms of APP (alpha-sAPP and ss-sAPP) in ventricular cerebrospinal fluid (VCSF) and Abeta(1-42) in plasma from 28 patients in a serial samples 0-11 days after TBI. The levels of alpha-sAPP, ss-sAPP and Abeta(1-42) were determined using ELISA assays. After TBI, there was a significant stepwise increase in VCSF-Abeta(1-42) up to 1173 % from day 0-1 to day 5-6 and in VCSF-beta-sAPP up to 2033 % increase from day 0-1 to day 7-11. There was also a slight but significant increase of VCSF-beta-sAPP from day 0-1 to day 5-6 and day 7-11. By contrast, the plasma- Abeta(1-42) level is unchanged after injury. The marked increase in VCSFAbeta(1-42) implies that increased Abeta expression may occur as a secondary phenomenon after TBI with axonal damage. The unchanged level of plasma-Abeta(1-42) in contrast to the marked increase in VCSF-Abeta(1-42) after severe TBI, supports the suggestion that plasma Abeta(1-42) does not reflect Abeta metabolism in the central nervous system (CNS).
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