KLOTHO KL-VS heterozygosity is associated with diminished age-related neuroinflammation, neurodegeneration, and synaptic dysfunction in older cognitively unimpaired adults.

INTRODUCTION: We examined whether the aging suppressor KLOTHO gene's functionally advantageous KL-VS variant (KL-VS heterozygosity [KL-VSHET]) confers resilience against deleterious effects of aging indexed by cerebrospinal fluid (CSF) biomarkers of neuroinflammation (interleukin-6 [IL-6], S100 calcium-binding protein B [S100B], triggering receptor expressed on myeloid cells [sTREM2], chitinase-3-like protein 1 [YKL-40], glial fibrillary acidic protein [GFAP]), neurodegeneration (total α-synuclein [α-Syn], neurofilament light chain protein), and synaptic dysfunction (neurogranin [Ng]). METHODS: This Alzheimer disease risk-enriched cohort consisted of 454 cognitively unimpaired adults (Mage = 61.5 ± 7.75). Covariate-adjusted multivariate regression examined relationships between age (mean-split[age ≥ 62]) and CSF biomarkers (Roche/NeuroToolKit), and whether they differed between KL-VSHET (N = 122) and non-carriers (KL-VSNC; N = 332). RESULTS: Older age was associated with a poorer biomarker profile across all analytes (Ps ≤ 0.03). In age-stratified analyses, KL-VSNC exhibited this same pattern (Ps ≤ 0.05) which was not significant for IL-6, S100B, Ng, and α-Syn (Ps ≥ 0.13) in KL-VSHET. Although age-related differences in GFAP, sTREM2, and YKL-40 were evident for both groups (Ps ≤ 0.01), the effect magnitude was markedly stronger for KL-VSNC. DISCUSSION: Higher levels of neuroinflammation, neurodegeneration, and synaptic dysfunction in older adults were attenuated in KL-VSHET. HIGHLIGHTS: Older age was associated with poorer profiles across all cerebrospinal fluid biomarkers of neuroinflammation, neurodegeneration, and synaptic dysfunction. KLOTHO KL-VS non-carriers exhibit this same pattern, which is does not significantly differ between younger and older KL-VS heterozygotes for interleukin-6, S100 calcium-binding protein B, neurogranin, and total α-synuclein. Although age-related differences in glial fibrillary acidic protein, triggering receptor expressed on myeloid cells, and chitinase-3-like protein 1 are evident for both KL-VS groups, the magnitude of the effect is markedly stronger for KL-VS non-carriers. Higher levels of neuroinflammation, neurodegeneration, and synaptic dysfunction in older adults are attenuated in KL-VS heterozygotes.

Effect of Lipopolysaccharide-Induced Inflammatory Challenge on ß-Glucuronidase Activity and the Concentration of Quercetin and Its Metabolites in the Choroid Plexus, Blood Plasma and Cerebrospinal Fluid.

Quercetin-3-glucuronide (Q3GA), the main phase II metabolite of quercetin (Q) in human plasma, is considered to be a more stable form of Q for transport with the bloodstream to tissues, where it can be potentially deconjugated by ß-glucuronidase (ß-Gluc) to Q aglycone, which easily enters the brain. This study evaluates the effect of lipopolysaccharide (LPS)-induced acute inflammation on ß-Gluc gene expression in the choroid plexus (ChP) and its activity in blood plasma, ChP and cerebrospinal fluid (CSF), and the concentration of Q and its phase II metabolites in blood plasma and CSF. Studies were performed on saline- and LPS-treated adult ewes (n = 40) receiving Q3GA intravenously (n = 16) and on primary rat ChP epithelial cells and human ChP epithelial papilloma cells. We observed that acute inflammation stimulated ß-Gluc activity in the ChP and blood plasma, but not in ChP epithelial cells and CSF, and did not affect Q and its phase II metabolite concentrations in plasma and CSF, except Q3GA, for which the plasma concentration was higher 30 min after administration (p < 0.05) in LPS- compared to saline-treated ewes. The lack of Q3GA deconjugation in the ChP observed under physiological and acute inflammatory conditions, however, does not exclude its possible role in the course of neurodegenerative diseases.

Klotho: a humeral mediator in CSF and plasma that influences longevity and susceptibility to multiple complex disorders, including depression.

Klotho is a hormone secreted into human cerebrospinal fluid (CSF), plasma and urine that promotes longevity and influences the onset of several premature senescent phenotypes in mice and humans, including atherosclerosis, cardiovascular disease, stroke and osteoporosis. Preliminary studies also suggest that Klotho possesses tumor suppressor properties. Klotho's roles in these phenomena were first suggested by studies demonstrating that a defect in the Klotho gene in mice results in a significant decrease in lifespan. The Klotho-deficient mouse dies prematurely at 8-9 weeks of age. At 4-5 weeks of age, a syndrome resembling human ageing emerges consisting of atherosclerosis, osteoporosis, cognitive disturbances and alterations of hippocampal architecture. Several deficits in Klotho-deficient mice are likely to contribute to these phenomena. These include an inability to defend against oxidative stress in the central nervous system and periphery, decreased capacity to generate nitric oxide to sustain normal endothelial reactivity, defective Klotho-related mediation of glycosylation and ion channel regulation, increased insulin/insulin-like growth factor signaling and a disturbed calcium and phosphate homeostasis accompanied by altered vitamin D levels and ectopic calcification. Identifying the mechanisms by which Klotho influences multiple important pathways is an emerging field in human biology that will contribute significantly to understanding basic physiologic processes and targets for the treatment of complex diseases. Because many of the phenomena seen in Klotho-deficient mice occur in depressive illness, major depression and bipolar disorder represent illnesses potentially associated with Klotho dysregulation. Klotho's presence in CSF, blood and urine should facilitate its study in clinical populations.

Evaluation of AAV-mediated Gene Therapy for Central Nervous System Disease in Canine Mucopolysaccharidosis VII.

Mucopolysaccharidosis VII (MPS VII) is a lysosomal storage disease arising from mutations in ß-d-glucuronidase (GUSB), which results in glycosaminoglycan (GAG) accumulation and a variety of clinical manifestations including neurological disease. Herein, MPS VII dogs were injected intravenously (i.v.) and/or intrathecally (i.t.) via the cisterna magna with AAV9 or AAVrh10 vectors carrying the canine GUSB cDNA. Although i.v. injection alone at 3 days of age resulted in normal cerebrospinal fluid (CSF) GUSB activity, brain tissue homogenates had only ~1 to 6% normal GUSB activity and continued to have elevated GAG storage. In contrast, i.t. injection at 3 weeks of age resulted in CSF GUSB activity 44-fold normal while brain tissue homogenates had >100% normal GUSB activity and reduced GAGs compared with untreated dogs. Markers for secondary storage and inflammation were eliminated in i.t.-treated dogs and reduced in i.v.-treated dogs compared with untreated dogs. Given that i.t.-treated dogs expressed higher levels of GUSB in the CNS tissues compared to those treated i.v., we conclude that i.t. injection of AAV9 or AAVrh10 vectors is more effective than i.v. injection alone in the large animal model of MPS VII.

Altered KLOTHO and NF-κB-TNF-α Signaling Are Correlated with Nephrectomy-Induced Cognitive Impairment in Rats.

Renal insufficiency can have a negative impact on cognitive function. Neuroinflammation and changes in klotho levels associate with chronic kidney disease (CKD) and may play a role in the development of cognitive impairment (CI). The present study evaluates the correlation of cognitive deficits with neuroinflammation and soluble KLOTHO in the cerebral spinal fluid (CSF) and brain tissue of nephrectomized rats (Nx), with 5/6 renal mass ablation. Nx and sham Munich Wistar rats were tested over 4 months for locomotor activity, as well as inhibitory avoidance or novel object recognition, which started 30 days after the surgery. EMSA for Nuclear factor-κB and MILLIPLEXMAP or ELISA kit were used to evaluate cytokines, glucocorticoid and KLOTHO levels. Nx animals that showed a loss in aversive-related memory and attention were included in the CI group (Nx-CI) (n=14) and compared to animals with intact learning (Nx-M n=12 and Sham n=20 groups). CSF and tissue samples were collected 24 hours after the last behavioral test. The results show that the Nx-groups have increased NF-κB binding activity and tumor necrosis factor-alpha (TNF-α) levels in the hippocampus and frontal cortex, with these changes more pronounced in the Nx-CI group frontal cortex. In addition, the Nx-CI group showed significantly increased CSF glucocorticoid levels and TNF-α /IL-10 ratio compared to the Sham group. Klotho levels were decreased in Nx-CI frontal cortex but not in hippocampus, when compared to Nx-M and Sham groups. Overall, these results suggest that neuroinflammation mediated by frontal cortex NF-κB, TNF-α and KLOTHO signaling may contribute to Nx-induced CI in rats.

Functional correction of CNS phenotypes in a lysosomal storage disease model using adeno-associated virus type 4 vectors.

Lysosomal storage diseases (LSDs) represent a significant portion of inborn metabolic disorders. More than 60% of LSDs have CNS involvement. LSD therapies for systemic diseases have been developed, but efficacy does not extend to the CNS. In this study, we tested whether adeno-associated virus type 4 (AAV4) vectors could mediate global functional and pathological improvements in a murine model of mucopolysaccharidosis type VII (MPS VII) caused by beta-glucuronidase deficiency. Recombinant AAV4 vectors encoding beta-glucuronidase were injected unilaterally into the lateral ventricle of MPS VII mice with established disease. Transduced ependyma expressed high levels of recombinant enzyme, with secreted enzyme penetrating cerebral and cerebellar structures, as well as the brainstem. Immunohistochemical studies revealed close association of recombinant enzyme and brain microvasculature, indicating that beta-glucuronidase reached brain parenchyma via the perivascular spaces lining blood vessels. Aversive associative learning was tested by context fear conditioning. Compared with age-matched heterozygous controls, affected mice showed impaired conditioned fear response and context discrimination. This behavioral deficit was reversed 6 weeks after gene transfer in AAV4 beta-glucuronidase-treated MPS VII mice. Our data show that ependymal cells can serve as a source of enzyme secretion into the surrounding brain parenchyma and CSF. Secreted enzymes subsequently spread via various routes to reach structures throughout the brain and mediated pathological and functional disease correction. Together, our proof-of-principal experiments suggest a unique and efficient manner for treating the global CNS deficits in LSD patients.

Correlation of cerebrospinal fluid beta-glucuronidase activity with plasma methotrexate concentrations in leukemic children receiving high-dose methotrexate.

BACKGROUND: The activity of lysosomal enzymes is increased in body fluids during inflammation, in which cellular malfunction and cellular death occurs. Because chemotherapy also causes cell malfunction and death, for identifying a neurologic effect, we studied the activity of beta-glucuronidase in the cerebrospinal fluid (CSF) of leukemic children during treatment. PROCEDURE: The beta-glucuronidase activity in CSF was determined in 13 patients with B-precursor acute lymphoblastic leukemia (ALL) treated with the medium risk arm of ALL Berlin-Frankfurt-Munster (BFM) 95 protocol. Plasma methotrexate (MTX) levels were determined at 24 and 48 hr after the infusion of high-dose (5 g/m(2)/24 hr) MTX (MCA phase). RESULTS: The mean (SD) beta-glucuronidase activity prior to the onset of chemotherapy was 19.9 (5.6) nmoles/4-methylumbelliferone/ml/hr. No significant changes in activity were noted during the phases of the protocol except of the MCA3. The activity was 24.4 (6.8) on MCA2, 28.4 (9.3) on MCA3, and 24.1 (9.5) on MCA4. The beta-glucuronidase activity was positively correlated with the plasma MTX levels at both 24 hr (r = 0.483, P = 0.006) and 48 hr (r = 0.676, P < 0.0001). No progressive changes were noted during the different phases of the protocol. The greatest beta-glucuronidase activity was measured in two patients with neurotoxicity. CONCLUSIONS: The beta-glucuronidase activity is increased in the CSF of leukemic children receiving high-dose MTX and particularly in neurotoxicity. It is positively correlated with plasma MTX levels. No cumulative effect of the chemotherapy was observed. The increased beta-glucuronidase activity is most likely due to enzyme leakage through the cell membranes caused mainly by a toxic effect of MTX on the cells of the central nervous system (CNS).

Ventriculolumbar perfusion chemotherapy with methotrexate and cytosine arabinoside for meningeal carcinomatosis: a pilot study in 13 patients.

Thirteen patients with meningeal carcinomatosis were treated by ventriculolumbar perfusion using methotrexate (MTX) and cytosine arabinoside (Ara-C). MTX (10-30 mg) and Ara-C (40 mg) were infused at 8- to 12-hour intervals on six or nine occasions via an Ommaya reservoir placed in the lateral ventricle. Nine of thirteen patients had evaluable response (69% response rate with a mean survival of 8.8 months among responders) and ventriculolumbar perfusion therapy was effective in improving cerebral, cranial nerve, and spinal root signs and symptoms, especially sensorimotor disturbance in the lower limbs. Three of the six bedridden patients became ambulatory without assistance and two of the four patients who were walking with assistance became ambulatory without assistance. Urinary incontinence also markedly improved, except in one nonresponder. Lumbar cerebrospinal fluid parameters (cytological findings and tumor markers) also improved in association with the clinical improvement. Our pilot results were encouraging, especially the improvement of sensorimotor function in the lower limbs. However, the toxicity was unacceptable when compared with that of standard intrathecal chemotherapy. Thus, this therapy needs to be investigated further to establish the most appropriate drug doses and perfusate volume to reduce toxicity as well as determine its true efficacy in the treatment of meningeal carcinomatosis.

Measurements of CSF biochemical tumor markers in patients with meningeal carcinomatosis and brain tumors.

CSF beta-glucuronidase, polyamines and carcinoembryonic antigen (CEA) were analyzed in 16 patients with meningeal carcinomatosis from solid tumor in systemic organs, 27 with benign brain lesions, 18 with primary brain tumors, 14 with metastatic brain tumors and 5 with leptomeningeal dissemination of other malignant diseases. Beta-glucuronidase levels in all cases of meningeal carcinomatosis, meningeal gliomatosis and meningeal lymphoma were higher than 100 micrograms/dl/hr; on the other hand, levels in all cases of benign brain lesions were below 100 micrograms/dl/hr. Levels of beta-glucuronidase and polyamines were not high in the cases with positive cytology after tumor resection. Polyamine levels were below 0.05 nmol/ml in all cases after resection of the metastatic brain tumor. Cystic fluid of malignant tumors showed high levels of beta-glucuronidase and polyamines. On the other hand, the levels of polyamines in the cystic fluid of benign tumor were low, although the levels of beta-glucuronidase were high. Some cases of meningeal carcinomatosis with high levels of serum CEA did not show high levels of CSF CEA. For metastatic brain tumors, the cases with intraparenchymal tumors, especially with dural attachment showed high levels of beta-glucuronidase and CEA preoperatively, but they returned to normal after surgery. In cases of meningeal carcinomatosis treated by intrathecal chemotherapy with methotrexate (MTX) and cytosine arabinoside (Ara-C), CSF beta-glucuronidase reflected the neurological status better than the cell count decreased rapidly following chemotherapy and beta-glucuronidase was considered as a useful CSF marker in cases of meningeal carcinomatosis to monitor the course of the disease. The same situation was observed in CSF CEA and CEA was also considered as a useful marker when CEA levels in CSF are higher than those in serum.

[Measurements of CSF biochemical tumor markers in patients with meningeal carcinomatosis].

CSF beta--glucuronidase, polyamines and carcinoembryonic antigen (CEA) were analyzed in 16 patients with meningeal carcinomatosis from solid tumors in systemic organs, 27 with benign brain lesions, 11 with primary brain tumors, 14 with metastatic brain tumors and 5 with leptomeningeal dissemination of other malignant diseases. beta--glucuronidase levels in all cases of meningeal carcinomatosis, meningeal gliomatosis and meningeal lymphoma were higher than 100 micrograms/dl/hr. On the other hand, levels in all cases of benign brain lesions were below 100 micrograms/dl/hr. Levels of beta--glucuronidase in the cases of metastatic brain tumors returned to normal levels after tumor resection. Levels of beta--glucuronidase and polyamines were not high in the cases with positive cytology in CSF after tumor resection. The polyamine level seemed to be dependent on the growth rate of the disease and was shown to below 0.05 nmol/ml in all cases after resection of the metastatic brain tumors. Cystic fluid of both benign and malignant tumor showed high levels of beta--glucuronidase and polyamines except for spermidine and spermine levels in a suprasellar cyst. Some cases of meningeal carcinomatosis with high levels of serum CEA did not always show high levels of CSF CEA. In the surgical cases with a metastatic brain tumor, the cases with leptomeningeal, especially dural attachment showed high levels of beta--glucuronidase and CEA preoperatively, but they returned to normal after surgery. In 2 cases of meningeal carcinomatosis treated by intrathecal chemotherapy with MTX and Ara-C, CSF beta--glucuronidase and CEA showed clinical condition better than the cell count in CSF decreased rapidly following chemotherapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Cerebrospinal fluid tumour markers in patients treated for meningeal malignancy.

The results of cerebrospinal fluid (CSF) biochemical markers were compared with conventional CSF cytology in patients treated for leptomeningeal metastases from extra cranial malignancies. For lumbar CSF, before treatment, no statistically significant difference of the probabilities of being positive was found between CSF cytology and a classification by linear discriminant analysis, based on patient's age, of beta-glucuronidase and beta 2-microglobulin. During treatment, classification by linear discriminant analysis was found more often positive than cytology. Possible mechanisms for this difference are discussed. For ventricular CSF a correlation was found between CSF cytology and beta-glucuronidase for solid tumours, and between CSF cytology and beta 2-microglobulin for haematological malignancies. Reference values for ventricular protein, CEA beta-glucuronidase and beta 2-microglobulin were obtained for cytological negative samples.

Serial lumbar and ventricular cerebrospinal fluid biochemical marker measurements in patients with leptomeningeal metastases from solid and hematological tumors.

This study presents results of investigations of lumbar and ventricular cerebrospinal fluid (CSF) biochemical markers (Beta-glucuronidase (B-gluc), Beta-2-microglobulin (B2-m), and carcinoembrionic antigen (CEA] in 28 patients with five different tumor types with leptomeningeal metastasis diagnosed by CSF cytology and/or autopsy. All received methotrexate and radiotherapy at some stage. Decadron or other symptomatic treatments were not used. Measurements of the concentrations of B-gluc, B2-m and CEA were evaluated with the aim of correlating the results of these measurements to site of disease, of monitoring response and early relapse of leptomeningeal disease, and of establishing the duration of survival. In almost all our patients the results of ventricular CSF B-gluc, B2-m and CEA measurements were lower than those obtained from lumbar CSF. The markers did not correlate with site of disease or CSF cytology. A clear relationship was found between pretreatment lumbar CSF B2-m and CEA levels, response to therapy and survival. The markers are also useful for monitoring response. The findings of this study indicate that B2-m and CEA levels have a prognostic value with regard to response to therapy and time of survival.

Lysosomal hydrolases in cerebrospinal fluid of multiple sclerosis patients. A follow-up study.

The change in activity of lysosomal hydrolases in the brain tissue of patients with demyelinating disease has been suggested to reflect the demyelination process. In this study we measured neutral proteinase (NP), acid proteinase (AP), and beta-glucuronidase (BG) activities in CSF of 32 patients with multiple sclerosis (MS) (remitting, remitting and relapsing, or chronic progressive course of the disease), 62 controls, and 4 patients with chronic inflammatory disease of central nervous system (ID). Samples from MS patients were taken at different clinical conditions of the disease during the 22-month follow-up. Elevated NP activity was found in patients with relapsing course of MS and also in patients with ID (P less than 0.05). NP activity correlated with the number of leucocytes in CSF of both MS (P less than 0.005, r = 0.50) and control (P less than 0.05, r = 0.21) patients. AP activity decreased in the MS group, especially in patients with remitting or remitting and relapsing courses of the disease (P less than 0.05), but even more in patients with ID (P less than 0.01). During the follow-up the increase in NP activity seemed to be associated with the clinical relapses of MS patients. Other enzymes did not fluctuate with the disease. This study suggests that the change in activity of lysosomal hydrolases is not specific for MS. The increase in NP activity in CSF is associated with clinical relapse of individual MS patients during the follow-up and may indicate immunological activation of the demyelination process in the brain. The large intra- and interindividual variation in enzyme activities in the CSF, however, makes the use of these enzymes difficult for diagnosis of MS and follow-up of MS activity.

Sensitivity and specificity of single and combined tumour markers in the diagnosis of leptomeningeal metastasis from breast cancer.

The clinical efficacy of four laboratory tests in detecting leptomeningeal metastases in 57 patients with breast carcinoma was assessed. The sensitivity and specificity of beta-glucuronidase, beta 2-microglobulin, carcinoembryonic antigen and lactate dehydrogenase in cerebrospinal fluid were determined. As a single test beta-glucuronidase was the most sensitive (93%) and specific (93%) for discriminating between leptomeningeal metastases and other CNS metastases from breast cancer. Lactate dehydrogenase was the next most useful marker. Both beta 2-microglobulin and carcinoembryonic antigen had a sensitivity of 60%. More specific results were achieved by combining beta-glucuronidase and lactate dehydrogenase. CSF beta-glucuronidase may be useful by itself and in combination with lactate dehydrogenase in the detection of leptomeningeal metastases from breast carcinoma.

Assessment of tumor markers in cerebrospinal fluid.

In clinical practice, the examination of cerebrospinal fluid from patients with primary or metastatic brain tumors is commonly limited to cytomorphologic and routine chemistry analysis. The relative lack of sensitivity and specificity of these tests has led to a search for markers that can detect nervous system involvement by neoplasms at an earlier stage and even predict the site of origin of the neoplasms. This article summarizes recent investigators of biochemical tumor markers and cytoplasmic and cell surface markers in cerebrospinal fluid from patients with nervous system tumors.

Assay for beta-glucuronidase in cerebrospinal fluid: usefulness for the detection of neoplastic meningitis.

The specificity and sensitivity of the assay for beta-glucuronidase in cerebrospinal fluid were evaluated to determine the usefulness of this test for the detection of neoplastic meningitis. The enzyme activity was first measured in cerebrospinal fluid from 131 patients with various disorders and was then prospectively measured in cerebrospinal fluid from 30 patients with cytologic results that were positive for or suggestive of malignant disease. Within the first group, elevated levels of beta-glucuronidase were found only among patients with neoplastic processes in the central nervous system, including neoplastic meningitis. Among 26 patients with neoplastic processes in the central nervous system, including neoplastic meningitis. Among 26 patients with positive cytologic results, 13 had elevated beta-glucuronidase activities. Elevated values were more frequent among patients with adenocarcinoma (75%) and myelogenous leukemia (60%). The patients with these two disorders also had the highest enzyme activities. The correlation of th beta-glucuronidase level with other cerebrospinal fluid values, including total protein, glucose content, and cell count, was not significant. The findings of this study indicate that measurement of beta-glucuronidase in cerebrospinal fluid can be used as an adjunctive diagnostic test for neoplastic meningitis. The results should be interpreted with caution, however, because of the possibility that the elevated enzyme levels may be due to acute or subacute bacterial or fungal meningitis.

Cerebrospinal fluid beta-glucuronidase activities in patients with central nervous system metastases.

beta-Glucuronidase activities were determined in cerebrospinal fluid from 249 patients suffering from various neurological diseases. Reference values were established as 9-27 mU/l. Marked elevations of cerebrospinal beta-glucuronidase activities were observed in patients with bacterial and carcinomatous meningitis. Slight elevations of cerebrospinal beta-glucuronidase activities were observed in epidural and parenchymal metastases from solid tumours. Comparison was made with the determination of total protein, glucose and lactate dehydrogenase in cerebrospinal fluid. Cerebrospinal beta-glucuronidase activity appeared the most useful test in monitoring patients at risk in developing meningeal metastases from solid primary tumours.

[The cerebrospinal fluid concentrations of beta-glucuronidase and beta 2-microglobulin in neurological disorders].

beta-Glucuronidase (beta-GL) and beta 2-microglobulin (beta 2-m) of the cerebrospinal fluid (CSF) were assayed from the patients with various neurological diseases, in order to evaluate the difference of mean value of these enzyme activities in several groups of neurological diseases, diagnostic usefulness for one of the central nervous system tumor markers, and the usefulness to differentiate carcinomatous meningitis from infectious meningitides. The subjects were 99 patients with various neurological diseases, and these were classified in the following eight diagnostic groups, central nervous system degenerative diseases (6 cases), cervical spondylotic radiculomyelopathy (15 cases), Guillain-Barre syndrome (8 cases), subarachnoid hemorrhage secondary to ruptured aneurysm (6 cases), infectious meningitides (21 cases), carcinomatous meningitis (9 cases), metastatic extradural spinal cord tumors (10 cases) and brain tumors (24 cases). CSF was also obtained from 13 subjects without any known neurological diseases for beta-GL and beta 2-m as the normal control values. beta-GL and beta 2-m were measured by Tsukamoto's method and the radioimmunoassay method (Phadebas, beta 2-m test) respectively. The statistical analyse were done by using the student t-test and expressed as p values. In the normal control group of 13 individuals without any obvious neurological diseases, the mean values +/- standard error of means (SEM) of beta-GL and beta 2-m were 122.5 +/- 10.8 micrograms/dl/hr, and 0.99 +/- 0.15 mg/l respectively.(ABSTRACT TRUNCATED AT 250 WORDS)