Non-neurological surgery and cerebrospinal fluid biomarkers for neuronal and astroglial integrity.

Non-neurological surgery has both acute and long-term effects on the brain. Markers for Alzheimer pathology may be used to study surgically induced neurological changes relevant for postoperative confusion, asthenia or cognitive decline. Inflammatory biomarkers, total tau (T-tau) and phosphorylated tau (P-tau) were recently shown to increase progressively in the cerebrospinal fluid (CSF) during surgery for nasal CSF leak, suggesting a neuroinflammatory response with signs of neuronal damage. We used a study group of 35 patients, undergoing knee arthroplasty with a spinal blockade and propofol sedation, to replicate this finding. Five CSF biomarkers were analyzed before, 3 h after and on the morning after the interventions: T-tau and P-tau for cortical axonal integrity and tangle pathology, respectively, the 42 amino acids form of amyloid ß (Aß42) for plaque formation, neurofilament light (NFL) for the integrity of large-caliber myelinated axons and glial fibrillary acidic protein (GFAp) for astroglial cell integrity. CSF T-tau concentrations increased significantly during and after surgery (p = 0.028) and were significantly correlated with the administered doses of bupivacaine. P-tau, Aß42 and NFL remained unchanged, while the mean GFAp concentration increased with a large standard deviation. CSF T-tau and P-tau correlated significantly with the CSF/serum albumin ratios as an indicator of blood-brain barrier permeability. Findings from earlier studies showing a significant increase in biomarkers for Alzheimer's pathology during surgery were partly replicated, as neurochemical signs of impaired cortical axonal integrity during non-neurological surgery were detected. Bupivacaine may be involved in these reactions.

Changes in serum and cerebrospinal fluid cytokines in response to non-neurological surgery: an observational study.

BACKGROUND: Surgery launches an inflammatory reaction in the body, as seen through increased peripheral levels of cytokines and cortisol. However, less is known about perioperative inflammatory changes in the central nervous system (CNS).Our aim was to compare inflammatory markers in serum and cerebrospinal fluid (CSF) before and after surgery and evaluate their association with measures of blood-brain barrier (BBB) integrity. METHODS: Thirty-five patients undergoing knee arthroplastic surgery with spinal anesthesia had CSF and serum samples drawn before, after and on the morning following surgery. Cytokines and albumin in serum and CSF and cortisol in CSF were assessed at all three points. RESULTS: Cytokines and cortisol were significantly increased in serum and CSF after surgery (Ps <0.01) and CSF increases were greater than in serum. Ten individuals had an increased cytokine response and significantly higher CSF/serum albumin ratios (Ps <0.01), five of whom had albumin ratios in the pathological range (>11.8). Serum and CSF levels of cytokines were unrelated, but there were strong correlations between CSF IL-2, IL-10 and IL-13, and albumin ratios (Ps <0.05) following surgery. CONCLUSION: Cytokine increases in the CNS were substantially greater than in serum, indicating that the CNS inflammatory system is activated during peripheral surgery and may be regulated separately from that in the peripheral body. CSF cytokine increase may indicate sensitivity to trauma and is linked to BBB macromolecular permeability.

The N-terminal domain of α-dystroglycan, released as a 38 kDa protein, is increased in cerebrospinal fluid in patients with Lyme neuroborreliosis.

α-Dystroglycan is an extracellular adhesion protein that is known to interact with different ligands. The interaction is thought to stabilize the integrity of the plasma membrane. The N-terminal part of α-dystroglycan may be proteolytically processed to generate a small 38 kDa protein (α-DG-N). The physiological significance of α-DG-N is unclear but has been suggested to be involved in nerve regeneration and myelination and to function as a potential biomarker for neurodegenerative and neuromuscular diseases. In this report we show that α-DG-N is released into different body fluids, such as lachrimal fluid, cerebrospinal fluid (CSF), urine and plasma. To investigate the significance of α-DG-N in CSF we examined the levels of α-DG-N and known neurodegenerative markers in CSF from patients diagnosed with Lyme neuroborreliosis (LNB) and healthy controls. In untreated acute phase LNB patients, 67% showed a significant increase of CSF α-DG-N compared to healthy controls. After treatment with antibiotics the CSF α-DG-N levels were normalized in the LNB patients.

Cerebrospinal fluid insulin during non-neurological surgery.

Insulin plays an important metabolic and transmitter role in the central nervous system, but few studies have investigated the relationship between central and peripheral insulin concentrations. 35 patients undergoing knee surgery had cerebrospinal fluid (CSF) samples drawn before, 3 h after, and in the morning following surgery. Serum insulin concentrations increased after surgery and CSF insulin concentrations changed in the same direction with far smaller amplitude. These results indicate that the blood-brain barrier protects the brain from stress-induced peripheral hormonal fluctuations.

Neuroinflammation in Lyme neuroborreliosis affects amyloid metabolism.

BACKGROUND: The metabolism of amyloid precursor protein (APP) and beta-amyloid (Abeta) is widely studied in Alzheimer's disease, where Abeta deposition and plaque development are essential components of the pathogenesis. However, the physiological role of amyloid in the adult nervous system remains largely unknown. We have previously found altered cerebral amyloid metabolism in other neuroinflammatory conditions. To further elucidate this, we investigated amyloid metabolism in patients with Lyme neuroborreliosis (LNB). METHODS: The first part of the study was a cross-sectional cohort study in 61 patients with acute facial palsy (19 with LNB and 42 with idiopathic facial paresis, Bell's palsy) and 22 healthy controls. CSF was analysed for the beta-amyloid peptides Abeta38, Abeta40 and Abeta42, and the amyloid precursor protein (APP) isoforms alpha-sAPP and beta-sAPP. CSF total-tau (T-tau), phosphorylated tau (P-tau) and neurofilament protein (NFL) were measured to monitor neural cell damage. The second part of the study was a prospective cohort-study in 26 LNB patients undergoing consecutive lumbar punctures before and after antibiotic treatment to study time-dependent dynamics of the biomarkers. RESULTS: In the cross-sectional study, LNB patients had lower levels of CSF alpha-sAPP, beta-sAPP and P-tau, and higher levels of CSF NFL than healthy controls and patients with Bell's palsy. In the prospective study, LNB patients had low levels of CSF alpha-sAPP, beta-sAPP and P-tau at baseline, which all increased towards normal at follow-up. CONCLUSIONS: Amyloid metabolism is altered in LNB. CSF levels of alpha-sAPP, beta-sAPP and P-tau are decreased in acute infection and increase after treatment. In combination with earlier findings in multiple sclerosis, cerebral SLE and HIV with cerebral engagement, this points to an influence of neuroinflammation on amyloid metabolism.

Neurochemical measures co-vary with personality traits: forensic psychiatric findings replicated in a general population sample.

Neurobiological markers in cerebrospinal fluid (CSF) and in serum, previously found to co-vary with destructive personality traits in violent offenders, were explored in a general population sample of 21 patients undergoing knee surgery. Results on the Karolinska Scales of Personality (KSP) and the Temperament and Character Inventory (TCI) were compared with CSF/serum albumin ratios and serum concentrations of beta-trace protein (betaTP) (as markers for blood-brain barrier (BBB) permeability), to CSF/serum albumin ratios between the dopamine and serotonin metabolites homovanillic acid (HVA)/5-hydroxyindoleacetic acid (HIAA) and to CSF and serum ratios between activated thyroid hormone (T3) and its precursor T4. Serum betaTP concentrations correlated with CSF/serum albumin ratios (P=0.018), but not with preoperative serum creatinine concentrations. Serum betaTP correlated significantly with Monotony Avoidance and Impulsiveness; CSF HVA/5-HIAA ratios with Irritability and low Cooperativeness. The betaTP is a potential serum marker for the integrity of the BBB that does not necessitate lumbar puncture. Thyroid hormones did not correlate with personality traits. As reported in forensic psychiatric patients, aggressive, unempathic personality traits were thus associated with increased dopaminergic activity in relation to the serotonergic activity and impulsivity to increased BBB permeability also in a general population group.

Association between thyroid hormone levels and monoaminergic neurotransmission during surgery.

BACKGROUND: Human studies assessing thyroid hormone metabolism in relation to brain monoaminergic activity in vivo are scarce. The few studies that do exist suggest significant associations between thyroid function and monoaminergic activity, but the cause-and-effect relationships are far from elucidated. METHODS: We simultaneously collected cerebrospinal fluid (CSF) and serum samples from 35 patients undergoing orthopaedic surgery before, 3h after and the morning after interventions and performed analyses for thyroid hormones and monoamine metabolites. RESULTS: At baseline, the CSF 3-methoxy-4-hydroxyphenylglycol concentrations were significantly correlated to the serum T(3)/T(4) ratio (rho=0.41, p=0.017). During surgery, serum thyroid hormones and the T(3)/T(4) ratio decreased (p<0.0001), while the CSF T(3)/T(4) ratio increased (p=0.0009). There were no correlations between serum and CSF levels of T(3) and T(4) at any of the samplings. Strong correlations were noted between baseline CSF thyroid hormone concentrations and subsequent increases in CSF 5-hydroxyindoleacetic acid (5-HIAA), and homovanillinic acid (HVA), but not vice versa. CONCLUSIONS: Thyroid hormone levels in serum and CSF during stress seem to be distinctly regulated. Baseline thyroid hormone activity may facilitate changes in brain monoaminergic neurotransmission in response to stress.

Confounding factors influencing amyloid Beta concentration in cerebrospinal fluid.

Background. Patients afflicted with Alzheimer's disease (AD) exhibit a decrease in the cerebrospinal fluid (CSF) concentration of the 42 amino acid form of beta-amyloid (Abeta(42)). However, a high discrepancy between different centers in measured Abeta(42) levels reduces the utility of this biomarker as a diagnostic tool and in monitoring the effect of disease modifying drugs. Preanalytical and analytical confounding factors were examined with respect to their effect on the measured Abeta(42) level. Methods. Aliquots of CSF samples were either treated differently prior to Abeta(42) measurement or analyzed using different commercially available xMAP or ELISA assays. Results. Confounding factors affecting CSF Abeta(42) levels were storage in different types of test tubes, dilution with detergent-containing buffer, plasma contamination, heat treatment, and the origin of the immunoassays used for quantification. Conclusion. In order to conduct multicenter studies, a standardized protocol to minimize preanalytical and analytical confounding factors is warranted.

Proteomic profiling of cerebrospinal fluid in parkinsonian disorders.

Parkinson's disease (PD) and atypical parkinsonian disorders (APD), including multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD), are a group of neurodegenerative diseases sharing many similar signs and symptoms but distinguished by their particular clinical features, treatment response, prognosis and mortality. The differential diagnosis may be challenging, especially in early disease stages. Considering the importance of an accurate diagnosis both for clinical management and for research, new diagnostic tools are needed. In this study, we investigated 56 PD, 42 MSA, 39 PSP, 9 CBD patients, and 24 healthy controls. After screening the cerebrospinal fluid (CSF) proteome using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS), we identified 4 proteins (ubiquitin [mass-to-charge ratio (m/z) 8590], beta2-microglobulin [m/z 11730], and 2 secretogranin 1 [chromogranin B] fragments [m/z 7260 and m/z 6250]) that differentiated healthy controls and PD patients from patients with APD. However, they could not differentiate PD patients from controls. As none of these changes were APD subgroup-specific, they most likely reflect the intensity and/or extent of the neurodegenerative process in general.