Cerebrospinal Fluid Spermidine, Glutamine and Putrescine Predict Postoperative Delirium Following Elective Orthopaedic Surgery.

Delirium is a marker of brain vulnerability, associated with increasing age, pre-existing cognitive impairment and, recently, cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease. This nested case-control study used a targeted quantitative metabolomic methodology to profile the preoperative CSF of patients (n = 54) who developed delirium following arthroplasty (n = 28) and those who did not (n = 26). The aim was to identify novel preoperative markers of delirium, and to assess potential correlations with clinical data. Participants without a diagnosis of dementia (≥65 years) undergoing elective primary hip or knee arthroplasty were postoperatively assessed for delirium once-daily for three days. Groups were compared using multivariate, univariate and receiving operator characteristic (ROC) methods. Multivariate modelling using Orthogonal Partial Least Squares-Discriminant Analysis (OPLS-DA) of metabolomic data readily distinguished between delirium and control groups (R2 ≤ 0.56; Q2 ≤ 0.10). Three metabolites (spermidine, putrescine and glutamine) significantly differed between groups (P < 0.05; FDR < 0.07), and performed well as CSF biomarkers (ROC > 0.75). The biomarker performance of the two polyamines (spermidine/putrescine) was enhanced by ratio with CSF Aß42 (ROC > 0.8), and spermidine significantly correlated with Aß42 (pearson r = -0.32; P = 0.018). These findings suggest that spermidine and putrescine levels could be useful markers of postoperative delirium risk, particularly when combined with Aß42, and this requires further investigation.

'Smelling' the cerebrospinal fluid: olfactory signaling molecules are expressed in and mediate chemosensory signaling from the choroid plexus.

The olfactory-type signaling machinery has been known to be involved not only in odorant detection but also in other tissues with unsuspected sensory roles. As a barrier, the choroid plexus (CP) is an active participant in the monitoring of the cerebrospinal fluid (CSF), promptly responding to alterations in its composition. We hypothesized that olfactory signaling could be active in CP, contributing to the surveillance of the CSF composition. We determined the mRNA and protein expression of the major components of the olfactory transduction pathway in the rat CP, including odorant receptors, the olfactory G-protein (Gαolf), adenylate cyclase 3 and cyclic nucleotide-gated channel 2. The functionality of the transduction pathway and the intracellular mechanisms involved were analyzed by DC field potential recording electrophysiological analysis, in an ex vivo CP-brain setup, using polyamines as stimuli and blockers of the downstream signaling pathways. Concentration-dependent responses were obtained for the polyamines studied (cadaverine, putrescine, spermine and spermidine), all known to be present in the CSF. Transfection of a CP epithelial cell line with siRNA against Gαolf effectively knocked down protein expression and reduced the CP cells' response to spermine. Thus, the key components of the olfactory chemosensory apparatus are present and are functional in murine CP, and polyamines seem to trigger both the cAMP and the phospholipase C-inositol 1,4,5-trisphosphate pathways. Olfactory-like chemosensory signaling may be an essential component of the CP chemical surveillance apparatus to detect alterations in the CSF composition, and to elicit responses to modulate and maintain brain homeostasis.

Radiation brain injury is reduced by the polyamine inhibitor alpha-difluoromethylornithine.

Alpha-difluoromethylornithine (DFMO) was used to reduce 125I-induced brain injury in normal beagle dogs. Different DFMO doses and administration schedules were used to determine if the reduction in brain injury was dependent on dose and/or dependent upon when the drug was administered relative to the radiation treatment. Doses of DFMO of 75 mg/kg/day and 37.5 mg/kg/day given 2 days before, during and for 14 days after irradiation reduced levels of putrescine (PU) in the cerebrospinal fluid relative to controls. Volume of edema was significantly reduced by 75 mg/kg/day of DFMO before, during and after irradiation and by the same dose when the drug was started immediately after irradiation. A reduction in edema volume after 37.5 mg/kg/day before, during and after irradiation was very near significance. Ultrafast CT studies performed on dogs that received a DFMO dose of 75 mg/kg/day before, during and after irradiation suggested that the reduced edema volume was associated with reduced vascular permeability. Volume of necrosis and volume of contrast enhancement (breakdown of the blood-brain barrier) were significantly lower than controls only after a DFMO dose of 75 mg/kg/day before, during and after irradiation. These latter data, coupled with the findings relative to edema, suggest that different mechanisms may be involved with respect to the effects of DFMO on brain injury, or that the extents of edema, necrosis and breakdown of the blood-brain barrier may depend upon different levels of polyamine depletion. The precise mechanisms by which DFMO exerts the effects observed here need to be determined.

Cerebrospinal fluid polyamines: biochemical markers of malignant childhood brain tumors.

The clinical value of cerebrospinal fluid (CSF) polyamine determinations in childhood medulloblastoma has been suggested. We performed 72 CSF polyamine determinations in 35 children with primary brain tumors. Spermine values were normal and spermidine values were inconsistently elevated. CSF putrescine values, however, were consistently elevated in patients with histologically malignant brain tumors: medulloblastoma, ependymoma, pineal germ cell tumors, primitive neuroectodermal tumors, and brainstem gliomas. Children with supratentorial astrocytomas had normal CSF polyamine values. CSF putrescine values were closely correlated with clinical state, with the highest concentrations identified in patients with widely disseminated recurrent disease. We found CSF putrescine to be a sensitive indicator of active disease in childhood malignant brain tumors. Further investigation is warranted into the predictive value of CSF polyamines in determining tumor relapse before clinical or other diagnostic studies reveal recurrent disease.

Evaluation of polyamine levels in cerebrospinal fluid of children with brain tumors.

Cerebrospinal fluid (CSF) polyamine levels were analyzed retrospectively in 21 pediatric patients with different types of intracranial malignant tumors to determine the benefit of following these markers during the clinical management of brain tumors. The tumors included 16 medulloblastomas and 1 each of germinoma, ependymoma, primitive neuroectodermal tumor, astrocytoma, and malignant teratoma. The clinical course of each patient was followed by neurologic examination, cranial computed tomography, CSF cell count, and cytology after cytocentrifugation. The correlation of CSF putrescine and spermidine levels with the clinical course of the brain tumors was analyzed. The following results were obtained: (1) A significant increase in CSF putrescine levels was observed in children with medulloblastoma when there was recurrent or metastatic disease in the sites close to the CSF pathway compared with the children whose disease status was stable after successful treatment (P less than 0.005). (2) The increase of CSF putrescine levels was the earliest predictor of recurrence or metastasis near the CSF pathway. (3) In tumors other than medulloblastoma, the levels of polyamines were not predictive of disease activity with the possible exception of germinoma. (4) Spermidine levels in the CSF were of limited clinical importance for patients with brain tumors. CSF putrescine levels may be the earliest and most sensitive quantitative marker of the progression of medulloblastoma, and their evaluation should be included in the diagnostic work-up and follow-up examination of children with medulloblastoma.

Free and total putrescine in cerebrospinal fluid quantified by reversed-phase liquid chromatography.

This is a simple, rapid, sensitive method for routine quantification of the polyamine putrescine (1,4-diaminobutane) in cerebrospinal fluid. Sample preparation involves protein precipitation, acid hydrolysis for 18 h (if total putrescine is to be measured), pre-column derivatization with o-phthalaldehyde, and extraction into acetonitrile. The derivative is separated and quantified by "high-performance" liquid chromatography on a reversed-phase C18 radial-compression column. A single chromatographic run takes less than 18 min. Putrescine concentrations as low as 50 nmol/L in cerebrospinal fluid can be detected.

Cerebrospinal fluid polyamines in childhood leukemia.

Cerebrospinal fluid (CSF) polyamines were measured in children with acute lymphocytic leukemia or non-Hodgkin's lymphoma in various stages of the disease ranging from complete remission to active central nervous system (CNS) involvement. Polyamines were analyzed by ion exchange chromatography with o- pthalaldehyde fluorimetric detection. Putrescine concentrations in random CSF samples obtained from leukemic patients with and without CNS involvement were not significantly different. Spermidine levels were generally higher in patients without CNS leukemia than in patients with the disease. In serial CSF specimens from an individual patient, spermidine levels correlated well with clinical status, being high in the active stages of the disease and low in remission. Thus, CSF polyamines appear to be of limited value as a screening test for early detection of CNS leukemia; however, they may offer an additional means of evaluating CNS leukemia and its response to therapy.

CSF polyamines in childhood.

Specimens of CSF from 76 children without neurologic disease and from 191 children with neurosurgical conditions were assayed for polyamine content. Putrescine and spermidine concentrations decreased with age. In children with intracranial tumors, polyamine concentrations in lumbar CSF were comparable with those in ventricular CSF. Putrescine level was significantly increased in children with medulloblastomas. Spermidine level was increased in children with medulloblastomas, glioblastomas, and astrocytomas. Concentrations of putrescine and spermidine were significantly increased in infants with myelomeningocele and hydrocephalus. Spermidine concentrations were significantly increased in older children with myelomeningocele, encephalocele, and hydrocephalus. Polyamines thus seem to be increased by rapid cell proliferation and by disorders affecting myelination. Since putrescine and spermidine concentrations may be of use in monitoring tumor progression, the effects of childhood growth and of hydrocephalus must be considered for children whose brain tumors are associated with hydrocephalus.

Polyamines: current review and their perspectives in neurosurgery.

A short review of polyamines and their possible clinical interest and applications in the field of brain neoplasms is presented. Dosage of CSF polyamines was proved to be useful in monitoring patients with medulloblastomas and others malignancies with meningeal involvement. Polyamines and their enzymes in neoplastic tissue may correlate to tumor growth. Inhibition of polyamines synthesis by drugs may be a possible way of slowing down tumor growth.

Polyamine levels in CSF from patients with pituitary tumors or nonneoplastic pituitary disease.

Cerebrospinal fluid polyamine determinations were performed in 21 patients harboring pituitary tumors and six patients with nonneoplastic pituitary disease. Although CSF putrescine levels were significantly elevated in some patients harboring tumors, other patients showed no elevation. Polyamine levels did not correlate with tumor size, as assessed by the presence or absence of suprasellar extension. Data on patients harboring nonneoplastic pituitary disease were variable. Compared with other findings from this laboratory on the use of polyamine levels for the diagnosis and management of other brain tumors, these findings suggest that CSF polyamine levels will not have a significant diagnostic role in the treatment of patients suspected to have pituitary disease.

CSF putrescine levels. The enzymatic-isotopic method vs liquid chromatography.

Twenty-six samples of CSF were assayed for their putrescine content by three analytical techniques: total and free putrescine levels were assayed by fluorometry after separation by column chromatography and compared with putrescine levels as assayed by the enzymatic-isotopic method. Putrescine levels obtained by the enzymatic-isotopic method correlated relatively well with free putrescine levels, but grossly underestimated the results obtained for total putrescine values. The difference between total and free putrescine values is mostly due to metabolites of putrescine, such as monoacetylputrescine, which account for about 40% of the total putrescine value. The importance of the free putrescine level as a marker of CNS malignant neoplasms in comparison to that of the total putrescine level deserves investigation.

CSF polyamines. Potential as brain tumor markers.

The use of CSF polyamine levels for the detection of brain tumors is discussed, with special emphasis on the use of CSF polyamine levels for the diagnosis and care of patients with medulloblastoma.

Predictive value of cerebrospinal fluid polyamines in medulloblastoma.

Seventy-five cerebrospinal fluid polyamine determinations were evaluated in 16 patients with medulloblastoma. Parameters utilized in evaluating patient status for correlation with the polyamine concentrations were neurological examination, computerized tomography, radionuclide scan, myelography, and cerebrospinal fluid cytology. Fifteen of the 16 patients showed absolute correlation with the eventual clinical picture. One determination on one patient resulted in a false negative. No false positives have been observed to date.

Polyamines and brain tumors.

Although their precise functions are unknown, the polyamines have been linked to cellular proliferation and division. The demonstration of a definite correlation between growth rate and the synthesis of the polyamines in tissues has led to the hope that such correlations might extend to polyamine concentrations in physiologic fluids. Polyamine determinations may then offer a simple index of tumor burden and growth rate. Studies of the relationship of cerebrospinal fluid polyamine levels to the presence of brain tumors indicated that thes determinations may assist in the early diagnosis of brain tumors, in the longterm evaluation of tumor therapy, and in the short-term evaluation of the efficacy of specific therapies.