Effect of intraventricularly administered low-dose recombinant tissue plasminogen activator on interleukin 1-beta and transforming growth factor beta concentrations in cerebrospinal fluid of patients with primary intracerebral hemorrhage associated with intraventricular hemorrhage: A retrospective study.

It is increasingly recognized that modulation of brain inflammation may uncover new potential therapeutic strategies for stroke. Recent studies have shifted focus from immunological implications in ischemic stroke to a more devastating form; the hemorrhagic stroke.The aim of this study was to investigate the neuroinflammatory response in cerebrospinal fluid in patients with primary intracerebral hemorrhage (ICH) associated with intraventricular hemorrhage (IVH) in the presence of low-dose recombinant tissue plasminogen activator (rt-PA).This retrospective study included 88 adults with primary ICH associated with IVH. Patients were divided into 2 groups: rt-PA group and non-rt-PA group, which received normal standard of care for this diagnosis. The rt-PA group was treated via catheter-based clot lysis using low-dose rt-PA injected through the external ventricular drain (EVD) system, and the non-rt-PA group was treated with saline applied to EVD system in equivalent volume. Cerebrospinal fluid samples from rt-PA were obtained from the EVD system at 4 time points: once before the drug administration, and then on day 1, 3, and 7. No attempt at randomization was made. The decision to inject rt-PA was based on the preference of the primary attending neurologist and the ability to obtain consent. Temporal interleukin-1 beta and transforming growth factor beta concentration changes were analyzed and compared between the 2 groups.The concentration of interleukin-1 beta was significantly lower in the rt-PA group than in the non-rt-PA group on day 7. In addition, the concentration of transforming growth factor beta was significantly higher in the rt-PA group than in the non-rt-PA group on day 1. There was a significant difference in interleukin-1 beta concentration between days 0 and 1 in comparison to day 3 in the rt-PA group, and between day 0 in comparison to day 3 and 7 in the non-rt-PA group. We also observed a significant difference in transforming growth factor beta concentration between days 0 and 1 and between days 3 and 7.The different pattern of pro- and anti-inflammatory cytokines in patients with ICH associated with IVH suggest distinct characteristics of secondary brain injury depending on the treatment modality.

Effect of Transforming Growth Factor-ß upon Taenia solium and Taenia crassiceps Cysticerci.

Taeniids exhibit a great adaptive plasticity, which facilitates their establishment, growth, and reproduction in a hostile inflammatory microenvironment. Transforming Growth Factor-ß (TGFß), a highly pleiotropic cytokine, plays a critical role in vertebrate morphogenesis, cell differentiation, reproduction, and immune suppression. TGFß is secreted by host cells in sites lodging parasites. The role of TGFß in the outcome of T. solium and T. crassiceps cysticercosis is herein explored. Homologues of the TGFß family receptors (TsRI and TsRII) and several members of the TGFß downstream signal transduction pathway were found in T. solium genome, and the expression of Type-I and -II TGFß receptors was confirmed by RT-PCR. Antibodies against TGFß family receptors recognized cysticercal proteins of the expected molecular weight as determined by Western blot, and different structures in the parasite external tegument. In vitro, TGFß promoted the growth and reproduction of T. crassiceps cysticerci and the survival of T. solium cysticerci. High TGFß levels were found in cerebrospinal fluid from untreated neurocysticercotic patients who eventually failed to respond to the treatment (P = 0.03) pointing to the involvement of TGFß in parasite survival. These results indicate the relevance of TGFß in the infection outcome by promoting cysticercus growth and treatment resistance.

Possible role of transforming growth factor ß in tuberculous meningitis.

BACKGROUND: Transforming growth factor ß (TGF-ß) is an anti-inflammatory cytokine and its role in hydrocephalus and stoke has been suggested. Tuberculous meningitis (TBM) is associated with exudates, stroke, hydrocephalus and tuberculoma, but the role of TGF-ß has not been evaluated in relation to these changes. AIM: To evaluate the cerebrospinal fluid (CSF) TGF-ß level in the patients with TBM, and correlate these with clinical findings, MRI changes, paradoxical response and outcome at 6months. METHODS: TBM patients diagnosed on the basis of clinical, CSF and MRI criteria were prospectively included. The clinical details including duration of illness, seizures, focal motor deficit, Glasgow Coma Scale (GCS) score and stage of TBM were noted. Presence of exudate, hydrocephalus, tuberculoma and infarction in MRI was also noted. MRI was repeated at 3months and presence of paradoxical response was noted. Cerebrospinal fluid TGF-ß was measured using ELISA on admission and repeated at 3months and these were compared with 20 controls. RESULTS: TGF-ß level was significantly higher in TBM compared to the controls (385.76±249.98Vs 177.85±29.03pg/ml, P<0.0001). TGF-ß correlated with motor deficit, infarction and tuberculoma on admission but did not correlate with CSF abnormalities, drug induced hepatitis, paradoxical response and outcome. TGF-ß level at 3months was significantly lower than the baseline but remained higher than the controls. CONCLUSION: CSF TGF-ß levels are elevated in TBM and correlate with infarction and tuberculoma.

Altered cerebrospinal fluid concentrations of TGFß1 in patients with drug-resistant epilepsy.

Transforming growth factor beta (TGFß) signaling participates in pathogenesis of epilepsy. TGFß1, as a transmitter of TGFß signaling, might be a useful marker for predicting the prognosis of patients with epilepsy. The present study aimed to measure TGFß1 level in the cerebrospinal fluid (CSF) of patients with drug-resistant epilepsy and non-resistant epilepsy. A total of 43 patients with epilepsy were recruited, 28 were non-resistant epilepsy subgroup, 15 drug-resistant epilepsy subgroup. 11 patients with intracranial infection and 11 individuals with primary headache were used as controls. The concentration of CSF and serum TGFß1 was measured by enzyme-linked immunosorbent assay. The concentration of CSF-TGFß1 was 209.26 ± 81.07 pg/ml in the drug-resistant epilepsy subgroup, 121.80 ± 40.32 pg/ml in the non-resistant epilepsy subgroup, 552.17 ± 456.20 pg/ml in intracranial infection control, 133.80 ± 68.55 pg/ml in headache control, respectively. TGFß1 level was significantly increased in the drug-resistant epilepsy subgroup compared to the non-resistant epilepsy subgroup. TGFß1 level in intracranial infection control was higher than that in the non-resistant epilepsy subgroup. There was no statistically difference of CSF-TGFß1 between the non-resistant epilepsy subgroup and headache controls, between the resistant epilepsy subgroup and intracranial infection controls. TGFß levels are increased in the CSF of patients with drug-resistant epilepsy. High CSF-TGFß1 levels may be a potential screening biomarker of antiepileptic drug resistance in patients with epilepsy.

Blood lactate functions as a signal for enhancing fatty acid metabolism during exercise via TGF-ß in the brain.

Moderate-intensity running (treadmill velocity of 21 m/min) increased blood lactate and actived transforming growth factor-ß (TGF-ß) concentration in rat cerebrospinal fluid (CSF). On the other hand, low-intensity running (15 m/min) did not increase blood lactate and caused no change in CSF TGF-ß. Intraperitoneal (i.p.) administration of lactate to anesthetized rats caused an increase in blood lactate similar to that observed after a 21 m/min running exercise and increased the level of active TGF-ß in CSF. Intraperitoneal administration of lactate at the same dose to awake and unrestricted rats caused a decrease in the respiratory exchange ratio, that is, enhancement of fatty acid oxidation and depression of spontaneous motor activity (SMA). Given that intracisternal administration of TGF-ß to rats has been reported to enhance fatty acid metabolism and to depress SMA, we surmise that the observed changes caused by i.p. lactate administration in this study were mediated, at least in part, by TGF-ß in the brain.

Increased leakage of brain antigens after traumatic brain injury and effect of immune tolerance induced by cells on traumatic brain injury.

BACKGROUND: Although traumatic brain injury can lead to opening the blood-brain barrier and leaking of blood substances (including water) into brain tissue, few studies of brain antigens leaking into the blood and the pathways have been reported. Brain antigens result in damage to brain tissues by stimulating the immune system to produce anti-brain antibodies, but no treatment has been reported to reduce the production of anti-brain antibodies and protect the brain tissue. The aim of the study is to confirm the relationship between immune injury and arachnoid granulations following traumatic brain injury, and provide some new methods to inhibit the immune injury. METHODS: In part one, methylene blue was injected into the rabbits' cisterna magna after traumatic brain injury, and concentrations of methylene blue and tumor necrosis factor (TNF)-α in blood were detected to determine the permeability of arachnoid granulations. In part two, umbilical cord mesenchymal stem cells and immature dendritic cells were injected into veins, and concentrations of interleukin 1 (IL-1), IL-10, interferon (IFN)-γ, transforming growth factor (TGF)-ß, anti-brain antibodies (ABAb), and IL-12 were measured by ELISA on days 1, 3, 7, 14 and 21 after injury, and the numbers of leukocytes in the blood were counted. Twenty-one days after injury, expression of glutamate in brain tissue was determined by immunohistochemical staining, and neuronal degeneration was detected by H&E staining. RESULTS: In part one, blood concentrations of methylene blue and TNF-α in the traumatic brain injury group were higher than in the control group (P < 0.05). Concentrations of methylene blue and TNF-α in the trauma cerebrospinal fluid (CSF) injected group were higher than in the control cerebrospinal fluid injected group (P < 0.05). In part two, concentrations of IL-1, IFN-γ, ABAb, IL-12, expression of glutamate (Glu), neuronal degeneration and number of peripheral blood leukocytes were lower in the group with cell treatment compared to the control group. IL-10 and TGF-ß were elevated compared to the control group. CONCLUSIONS: Traumatic brain injury can lead to stronger arachnoid granulations (AGs) permeability; umbilical cord mesenchymal stem cells and immature dendritic cells can induce immune tolerance and reduce inflammation and anti-brain antibodies to protect the brain tissue.

Central inflammation versus peripheral regulation in multiple sclerosis.

Th17 cells are a highly pro-inflammatory T-helper cell subset characterised by the expression of IL17. They have been implicated in a variety of allergic and autoimmune conditions. T-regulatory (Treg) cells, a subset of CD4 cells which express Foxp3, CD25, IL10 and TGFß, can suppress the activity of Th17 cells. In this study, we show that the circulating levels of Th17 and Treg cells in peripheral blood are correlated; furthermore, the expression of the pro-inflammatory cytokine IL17 and the anti-inflammatory cytokine IL10 by CD4 cells are also correlated. However, we found no clear correlation between cerebrospinal fluid (CSF) IL10 and IL17 cytokine levels in MS, approaching a negative correlation at the time of relapse, and an overall negative correlation between CSF IL17 and TGFß levels, suggesting a lack of central regulation of pro:anti-inflammatory balance in this demyelinating condition.

Inhibition of fatty acid oxidation activates transforming growth factor-beta in cerebrospinal fluid and decreases spontaneous motor activity.

We have previously reported that transforming growth factor (TGF)-beta in the cerebrospinal fluid (CSF) is involved in the mechanism underlying the regulation of spontaneous motor activity (SMA) by the central nervous system after exercise. However, it remained unclear what physiological condition triggers the activation of TGF-beta. We hypothesized that the shortage of energy derived from fatty acid (FA) oxidation observed in the early phase of exercise activated TGF-beta in the CSF. To test this hypothesis, we investigated whether mercaptoacetate (MA), an inhibitor of FA oxidation, could induce an activation of TGF-beta in the CSF and a decrease in SMA. Intraperitoneal (i.p.) administration of MA activated TGF-beta in CSF in rats and depressed SMA; 2-deoxyglucose, an inhibitor of carbohydrate oxidation, on the other hand, depressed SMA but failed to activate CSF TGF-beta. Intracisternal administration of anti-TGF-beta antibody abolished the depressive effect of MA on SMA. We also found that the depression of SMA and the activation of TGF-beta in the CSF by i.p. MA administration were eliminated by vagotomy. Our data suggest that TGF-beta in the CSF is activated by the inhibition of FA oxidation via the vagus nerve and that this subsequently induces depression of SMA.

Different apolipoprotein E, apolipoprotein A1 and prostaglandin-H2 D-isomerase levels in cerebrospinal fluid of schizophrenia patients and healthy controls.

OBJECTIVES: To identify proteins differentially expressed in schizophrenia patients, we collected 50 microl cerebrospinal fluid from 17 first-episode schizophrenia patients and 10 healthy controls. METHODS: Their proteins were separated by two-dimensional gel electrophoresis without using any depletion method and identified by mass spectrometry. RESULTS: Approximately 550 spots were detected, six of which had significantly different intensities in schizophrenia compared to control specimens. We were able to validate in individual samples the upregulation of apolipoprotein E, apolipoprotein A1 and prostaglandin-H2 D-isomerase by Western blot analyses and detect the downregulation of transthyretin, TGF-beta receptor type-1 and coiled-coil domain-containing protein 3 precursor. CONCLUSIONS: These findings may help to elucidate the disease mechanisms and confirm the hypothesis of disturbed cholesterol and phospholipid metabolism in schizophrenia, and thus reveal the final role players. Moreover, a grouped protein expression analysis of apolipoprotein E, apolipoprotein A-I, and prostaglandin-H2 D-isomerase in cerebrospinal fluid from patients might be a potential diagnostic tool for schizophrenia.

High CSF transforming growth factor beta levels after subarachnoid haemorrhage: association with chronic communicating hydrocephalus.

BACKGROUND: Chronic communicating hydrocephalus is a common sequela of subarachnoid haemorrhage and develops when the flow and drainage of CSF are impaired after fibrosis in the subarachnoid space. Released by platelets into the CSF after subarachnoid haemorrhage, transforming growth factor (TGF)beta1/beta2 are potent fibrogenic agents that may promote post-haemorrhagic fibrosis and chronic communicating hydrocephalus. METHODS: Temporal changes in total (latent plus active) TGFbeta1/beta2 CSF levels of post-haemorrhage patients developing acute hydrocephalus were measured using ELISA to discover if titres were higher in patients that subsequently developed chronic communicating hydrocephalus, compared with those that did not. RESULTS: Mean (SD) CSF levels of total TGFbeta1 were 97 (42) pg/ml and total TGFbeta2 were 395 (39) pg/ml in control patients with (non-haemorrhagic) hydrocephalus. For days 1-5 post-subarachnoid haemorrhage (dph), levels of 1427 (242) pg/ml and 976 (191) pg/ml were seen for total TGFbeta1 and TGFbeta2, respectively. Beyond 5 dph, total TGFbeta1/beta2 levels declined but remained significantly elevated (p<0.01) above control patient values for at least 19 dph. Haemorrhagic patients that went on to develop chronic communicating hydrocephalus had significantly higher levels of total TGFbeta1 (p<0.01) and TGFbeta2 (p<0.05) between 1 and 9 dph, compared with those of haemorrhagic patients that did not. CONCLUSIONS: Acutely measured levels of TGFbeta1/beta2 in the CSF of patients with subarachnoid haemorrhage are thus potential prognostic biomarkers for the subsequent development of chronic communicating hydrocephalus, indicating likely dependency on CSF shunting.

Osteoinductive effect of cerebrospinal fluid from brain-injured patients.

Patients with traumatic brain injury (TBI) are predisposed to heterotopic ossification, which is believed to be due to osteoinductive factors released at the site of the brain injury. To date, little is known about the presence of such factors in human cerebrospinal fluid (CSF). This study investigated whether CSF of TBI patients is osteoinductive. In addition, known osteoinductive factors--such as bone morphogenetic protein (BMP)-2, BMP-4, and BMP-7, and S100B--were measured in CSF. Eighty-four consecutive patients were classified according to brain pathology: TBI (n = 11), non-traumatic brain pathology (NTBP) (n = 26), and no brain pathology (control group) (n = 47). The osteoinductive effect of CSF was measured repeatedly in proliferation assays using a fetal human osteoblast cell line. The mean proliferation rate (normalized to the internal negative control) of the TBI, NTBP, and control groups was 138.2% (SD 13.1), 110.0% (SD 22.1), and 118.8% (SD 16.9), respectively. The potentially confounding effect of age was investigated further by restricting the selection of patients for analysis to that of the oldest patient in the TBI group and use of multiple regression analysis. After implementation of both, it was shown that age is highly unlikely to account for the higher rates of proliferation observed among the TBI patients in this study. Of note, the TBI group had a significantly higher mean proliferation rate than the NTBP (p = 0.001) and the control group (p = 0.006). S100B and BMP-2, -4, or -7 concentrations were measured using enzyme-linked immunosorbent assay (ELISA). There was no correlation between proliferation rates and S100B (r = 0.023). Only three of 36 CSF samples had measurable levels of BMP-2 and -7, and none had detectable concentrations of BMP-4. Consequently, it is unlikely that S100B or BMP-2, -4, or -7 are the putative osteoinductive factors. The results indicate that CSF from TBI patients has an osteoinductive effect in vitro. However, the osteoinductive factor has still to be characterized.

Increase in transforming growth factor-beta in the brain during infection is related to fever, not depression of spontaneous motor activity.

When viral infection occurs, this information is transmitted to the brain, and symptoms such as fever and tiredness are induced. One of the causes of these symptoms is the secretion of proinflammatory cytokines in blood and the brain. In this study, the i.p. administration of polyinosinic:polycytidylic acid (poly I:C), a synthetic double-stranded RNA, to rats was used as an infection model. Poly I:C decreased spontaneous motor activity (SMA) 2 h after i.p. administration, and this decrease was maintained thereafter. The concentration of active transforming growth factor-beta (TGF-beta) in cerebrospinal fluid (CSF) increased 1 h after the administration. This increase occurred earlier than those in the concentrations of other proinflammatory cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha), in serum. The intracisternal administration of an anti-TGF-beta antibody partially inhibited fever induced by poly I:C administration; however, this treatment did not affect the decrease in SMA. Furthermore, intracisternal administration of TGF-beta raised the body temperature. These results indicate that TGF-beta in the brain, which was increased by poly I:C administration, is associated with fever but not with a decrease in SMA.

Increased intrathecal TGF-beta1, but not IL-12, IFN-gamma and IL-10 levels in Alzheimer's disease patients.

An inflammatory response has been hypothesised to be involved in the pathogenesis of primary dementias, above all Alzheimer's disease (AD). This study was aimed at evaluating interleukin (IL)-12 and a panel of related cytokine levels in paired CSF and sera of demented patients. IL-12 (p70 heterodimer and total IL-12 p40 chain), interferon (IFN)-gamma, IL-10 and transforming growth factor (TGF)-beta1 levels were measured in 30 patients with probable Alzheimer's disease (PrAD), 57 patients with other dementing disorders, including probable vascular dementia (PrVD), Parkinson's disease (PD) and normal pressure hydrocephalus (NPH), and 25 cognitively normal control subjects. In the presence of unchanged concentrations of IL-12, IFN-gamma and IL-10, the mean CSF level of TGF-beta1 and the correspondent TGF-beta1 index, but not the serum level, were significantly increased in PrAD compared to controls and PrVD, whereas no difference was found vs. NPH and PD. Our results support the pathophysiological role of TGF-beta1 system in AD.

Pro- and anti-inflammatory cytokines in the CSF of patients with Creutzfeldt-Jakob disease.

We investigated cerebrospinal fluid (CSF) samples from patients with Creutzfeldt-Jakob disease (CJD) and other neurological diseases. Concentrations of pro- and anti-inflammatory cytokines IL-1beta, IL-6, IL-8, IL-12, TNF-alpha and TGF-beta 2 were determined in CSF using ELISA. Significant changes were found for IL-8 and TGF-beta 2. IL-8 levels were elevated in the CSF of CJD patients. Of interest, the increase was significant to other dementia and to controls. In contrast, TGF-beta 2 was significantly decreased in CSF of CJD compared to all groups. IL-1beta, IL-12 and TNF-alpha could not be detected in CSF or in case of IL-6 in only low concentrations without significant difference.

Cytokines involved in CNS manifestations caused by Mycoplasma pneumoniae.

Mycoplasma pneumoniae sometimes causes central nervous system manifestations, which may involve the host immune response, as the organism does not directly damage neural cells, or release toxins. Therefore we measured the levels of interleukin-6, interleukin-8, interleukin-18, interferon-gamma, tumor necrosis factor-alpha, and transforming growth factor-beta1 in serum and cerebrospinal fluid samples from patients who manifested central nervous system manifestations during acute M. pneumoniae infection. The subjects were nine patients with early-onset encephalitis (central nervous system disease onset within 7 days from the onset of fever), four with late-onset encephalitis (onset at 8 days or later), three with encephalitis but without fever, and three with aseptic meningitis. Intrathecal elevations of interleukin-6 and interleukin-8 in all four types of central nervous system manifestations, and of interleukin-18 in late-onset encephalitis were observed. None of the cerebrospinal fluid samples contained detectable levels of interferon-gamma, tumor necrosis factor-alpha, or transforming growth factor-beta1. In conclusion, interleukin-6, interleukin-8, and interleukin-18 might be involved in the inflammatory process leading to the central nervous system manifestations caused by M. pneumoniae.

Accumulation of transforming growth factor-beta2 and nitrated chondroitin sulfate proteoglycans in cerebrospinal fluid correlates with poor neurologic outcome in preterm hydrocephalus.

BACKGROUND: Progressive post-hemorrhagic hydrocephalus in preterm infants strongly predicts abnormal neurologic development, and often accompanies cystic periventricular leukomalacia (cPVL). Transforming growth factor-beta1 (TGF-beta1), associated with hydrocephalus, can upregulate the chondroitin sulfate proteoglycan (CSPG) synthesis. To date, CSPG and their nitrated metabolites (NT-CSPG) have not been evaluated in hydrocephalus. OBJECTIVES: We hypothesized that TGF-beta1, TGF-beta2, CSPG, and NT-CSPG would accumulate in cerebrospinal fluid (CSF) in preterm hydrocephalus, and their concentrations would correlate with poor long-term outcomes. METHODS: TGF-beta1, TGF-beta2, CSPG, and NT-CSPG concentrations in CSF were measured prospectively by ELISA in 29 preterm newborns with (n=22) or without (n=34) progressive post-hemorrhagic hydrocephalus, and correlated with progressive neonatal hydrocephalus and neurologic outcome. Only concentrations from each patient's initial CSF sample were used for statistical analysis. RESULTS: Compared to neonates without hydrocephalus, CSF [TGF-beta1], [TGF-beta2], [CSPG] and [NT-CSPG] were significantly greater by >3-, >35-, >8-, and >3-fold, respectively. Unlike CSF [TGF-beta2] and [CSPG], [TGF-beta1] correlated with CSF [total protein]. Only CSF [NT-CSPG] correlated with cPVL. Unlike [TGF-beta2] or [CSPG], [NT-CSPG] correlation with preterm progressive post-hemorrhagic hydrocephalus (PPHH) was explained entirely by the presence of cPVL among these patients. [TGF-beta2] was >20-fold greater in preterm survivors who required a ventriculoperitoneal shunt for PPHH (n=9), as compared to survivors who did not require a shunt (n=2), or those without hydrocephalus (n=12). [TGF-beta2] and [NT-CSPG] correlated inversely with Bayley Index Scores (15.0 months median adjusted age). CONCLUSIONS: This is the first report that [TGF-beta2], [CSPG], and [NT-CSPG], measured well before term, accumulate abnormally in preterm progressive post-hemorrhagic hydrocephalus CSF, and correlate with adverse neurologic outcome.

Vascular endothelial growth factor and transforming growth factor-beta1 are highly expressed in the cerebrospinal fluid of premature infants with posthemorrhagic hydrocephalus.

The expression of specific growth factors such as vascular endothelial growth factor (VEGF) and transforming growth factor-beta1 (TGF-beta1) is of importance during brain development and in the pathogenesis of neurodegenerative disorders. VEGF and TGF-beta1 was studied in the cerebrospinal fluid (CSF) of neonates with posthemorrhagic hydrocephalus (PHHC) and nonhemorrhagic hydrocephalus. For determining the interference of inflammatory cytokine interaction with the expression of VEGF and TGF-beta1, IL-6 and IL-10 CSF concentrations were measured. Eighteen neonates who had PHHC and underwent serial reservoir puncture and nine neonates who had congenital nonhemorrhagic hydrocephalus (CHC) and underwent first shunt surgery were included in the study. CSF samples of 11 neonates with lumbar puncture for the exclusion of meningitis served as control subjects. VEGF, TGF-beta1, IL-6, and IL-10 concentrations in the CSF were measured by ELISA technique. VEGF concentrations in the CSF of patients with PHHC were significantly higher (median: 377 pg/mL; range: 101-1301 pg/mL) when compared with patients with CHC (median: 66 pg/mL; range: 3-1991; p < 0.001) and control subjects (median: 2 pg/mL; range: 0-12 pg/mL; p < 0.0001). TGF-beta1 CSF concentrations did not differ from control infants in all groups. Median IL-6 and IL-10 concentrations in the CSF were found to be low in all patient groups. Increased release of VEGF in the CSF of neonates with PHHC and nonhemorrhagic hydrocephalus may serve as an indicator of brain injury from progressive ventricular dilation. TGF-beta1 CSF concentrations are not elevated in the phase of acute fibroproliferative reactions in patients with PHHC.

Increased cerebrospinal fluid levels of transforming growth factor-beta1 in Alzheimer's disease.

Accumulation of beta-amyloid (Abeta) in senile plaques in specific brain regions is a key event in the development of Alzheimer's disease (AD). Expression of transforming growth factor-beta1 (TGF-beta1), a regulator of brain responses to inflammation and injury, has been correlated with Abeta accumulation, aggregation and clearance in transgenic mice and increased production of amyloid precursor protein (APP) followed by Abeta generation in murine and human astrocyte cultures. Here, we compared TGF-beta1 levels in cerebrospinal fluid (CSF) from 20 AD patients and 20 healthy controls and correlated TGF-beta1 to intrathecal levels of the amyloidogenic 42-amino acid fragment of Abeta (Abeta42). AD patients had higher concentration of TGF-beta1 than controls (P = 0.002). Moreover, TGF-beta1 levels were negatively correlated to Abeta42 levels in the whole material (cases and controls, r = -0.35; P = 0.020), although this correlation failed to reach significance in the AD group alone (r = -0.38; P = 0.099). Taken together, the data indicate that TGF-beta1 plays a role in the processes that affect amyloid metabolism in AD.

Increased intrathecal inflammatory activity in frontotemporal dementia: pathophysiological implications.

OBJECTIVE: Immunological mechanisms may be part of the pathophysiological mechanisms in frontotemporal dementia (FTD), but hitherto only vague evidence of such mechanisms has been presented. The aim of this study was to compare the cerebrospinal fluid (CSF) levels of the pro-inflammatory cytokines interleukin (IL)-1beta and tumour necrosis factor (TNF)-alpha, and the anti-inflammatory cytokine transforming growth factor (TGF)-beta in patients with FTD and normal controls. Furthermore, serum levels of TNF-alpha, TGF-beta, and IL-1beta were measured in FTD patients. METHODS: The CSF levels of IL-1beta, TNFalpha, and TGF-beta were measured using ELISA in 19 patients with FTD and 24 sex and age matched healthy controls. RESULTS: The CSF levels of TNF-alpha (FTD 0.6 pg/mL (median: lower, upper quartile 0.3, 0.7); controls: 0.0 pg/mL (0.0, 0.0); p = 0.008) and TGF-beta (FTD 266 pg/mL (157, 371), controls: 147 pg/mL (119, 156); p = 0.0001) were significantly increased in FTD patients compared with controls. No correlations were found between CSF and serum levels of the cytokines. In the controls, but not in the FTD patients, a positive correlation was found between the CSF levels of TGF-beta and age (r = 0.42, p < 0.05). No correlation was found between any of the cytokines and degree of brain atrophy or white matter changes. No differences between the groups were found for age, gender, or CSF/serum albumin ratio. CONCLUSIONS: The results suggest an increased intrathecal production of both pro- and anti-inflammatory cytokines in FTD. As no correlations were found with the albumin ratio, and no correlations between CSF and serum levels of the cytokines were found, these changes in the CSF cannot be explained by a systemic overproduction of cytokines.

Posthaemorrhagic ventricular dilatation: new mechanisms and new treatment.

Post haemorrhagic ventricular dilatation is associated with a high rate of disability, multiple impairments and adverse effects of shunt surgery for hydrocephalus. Post haemorrhagic ventricular dilatation results initially from multiple small blood clots throughout the cerebrospinal fluid channels impeding circulation and re-absorption. Transforming growth factor beta is released into the cerebrospinal fluid and there is evidence that this cytokine stimulates the laying down of extracellular matrix proteins which produce permanent obstruction to the cerebrospinal fluid pathways. Prolonged raised pressure, pro-inflammatory cytokines and free radical damage from iron may contribute to periventricular white matter damage and subsequent disability. Interventions such as early lumbar punctures, diuretic drugs to reduce cerebrospinal fluid production and intraventricular fibrinolytic therapy have been tested and, not only fail to prevent shunt dependence, death or disability, but have significant adverse effects. Surgical interventions such as subcutaneous reservoir, external drain, choroid plexus coagulation and third ventriculostomy have not been subject to controlled trial. Ventriculoperitoneal shunt is not feasible in the early phase after intraventricular haemorrhage but, despite the problems with blockages and infections, remains the only option for infants with excessive head expansion over periods of weeks. We have piloted drainage, irrigation and fibrinolytic therapy as a way of removing blood early enough to stop the progressive deposition of matrix proteins, permanent hydrocephalus and shunt dependence.