Cerebrospinal fluid biomarkers showing neurodegeneration in dogs with GM1 gangliosidosis: possible use for assessment of a therapeutic regimen.

The present study investigated cerebrospinal fluid (CSF) biomarkers for estimating degeneration of the central nervous system (CNS) in experimental dogs with GM1 gangliosidosis and preliminarily evaluated the efficacy of long-term glucocorticoid therapy for GM1 gangliosidosis using the biomarkers identified here. GM1 gangliosidosis, a lysosomal storage disease that affects the brain and multiple systemic organs, is due to an autosomal recessively inherited deficiency of acid beta-galactosidase activity. Pathogenesis of GM1 gangliosidosis may include neuronal apoptosis and abnormal axoplasmic transport and inflammatory response, which are perhaps consequent to massive neuronal storage of GM1 ganglioside. In the present study, we assessed some possible CSF biomarkers, such as GM1 ganglioside, aspartate aminotransferase (AST), lactate dehydrogenase (LDH), neuron-specific enolase (NSE) and myelin basic protein (MBP). Periodic studies demonstrated that GM1 ganglioside concentration, activities of AST and LDH, and concentrations of NSE and MBP in CSF were significantly higher in dogs with GM1 gangliosidosis than those in control dogs, and their changes were well related with the months of age and clinical course. In conclusion, GM1 ganglioside, AST, LDH, NSE and MBP could be utilized as CSF biomarkers showing CNS degeneration in dogs with GM1 gangliosidosis to evaluate the efficacy of novel therapies proposed for this disease. In addition, we preliminarily treated an affected dog with long-term oral administration of prednisolone and evaluated the efficacy of this therapeutic trial using CSF biomarkers determined in the present study. However, this treatment did not change either the clinical course or the CSF biomarkers of the affected dog, suggesting that glucocorticoid therapy would not be effective for treating GM1 gangliosidosis.

Biochemical markers of central nervous system tumors measured in cerebrospinal fluid and their potential use in diagnosis and patient management: a review.

The concept of tumor markers was reviewed, and the potential uses of markers of central nervous system (CNS) tumors and methods for their evaluation were discussed. Markers examined included lactate dehydrogenase, aspartate aminotransferase, fructose-bisphosphate aldolase, the polyamines, desmosterol, and several other enzymatic, nonenzymatic, and immunologic markers. Data collated from the clinical studies surveyed showed isocitrate dehydrogenase, desmosterol, and the polyamines to have the greatest potential utility in the diagnosis of CNS tumors.

Amino acids and transaminases activity in ventricular CSF and in brain of normal and Alzheimer patients.

The present study was conducted to determine the concentration of amino acids in the cerebrospinal spinal fluid (CSF) and the activities of two tramsaminases: glutamic oxaloacetate transaminase (GOT) and glutamic pyruvate transaminase (GPT) in human Alzheimer disease (AD) and normal brain. L-glutamic acid, L-glutamine and L-alanine are the most abundant amino acids in the CSF (50-55% of total amino acids). L-glutamine occurs at much higher levels in Alzheimer CSF compared to the normal CSF (229+/-91.8 nmol/ml in AD versus 107+/-47.2 nmol/ml in normal; P=0.0041). In contrast, L-aspartate occurs at significantly lower concentrations in Alzheimer CSF than normal CSF (46.1+/-25.7 nmol/ml in Alzheimer versus 95.2+/-52.6 nmol/ml in normal; P=0.020). In Alzheimer brain (frontal, parietal and occipital cortices) GOT is present at significantly higher activities than in normal brain cortices (about 1.5 times higher; P<0.01). No significant differences for GPT activity occurred between normal and AD brain. Since CSF receives amino acids from brain tissues, and since GOT catalyzes the conversion of L-aspartate to L-glutamate, the higher concentrations of L-glutamine (which is derived from L-glutamate), and the lower concentrations of L-aspartate found in Alzheimer CSF could be considered as a consequence of the higher activity of GOT that occurs in Alzheimer brain.

Enzyme level changes in the cerebrospinal fluid of patients with acute stroke.

Creatine kinase (CK), brain CK (CKBB), lactate dehydrogenase (LD), and aspartate aminotransferase (ASAT) levels were determined in cerebrospinal fluid (CSF) obtained from 35 patients with acute stroke. In patients with transient, minor neurological disturbances, only LD levels increased; in those who remained comatose and died, the levels of all the enzymes, except ASAT, increased. Patients who remained with focal motor defects had increased CK and LD levels, while CKBB and ASAT levels were variable. In most of the CSF samples, muscle CK activity was also detectable, suggestive of a leakage from blood to CSF. The pattern of the enzyme increase could be related to the causative mechanisms for the strokes. The study suggests that CSF enzyme determinations may provide supplementary information as to the extent and severity of brain damage and the recovery potentials of selected patient groups with strokes.

Systematic review of prediction of poor outcome in anoxic-ischaemic coma with biochemical markers of brain damage.

OBJECTIVE: To investigate whether accurate prognostic rules can be derived from the combined results of studies concerning prediction of poor prognosis in anoxic-ischaemic coma with biochemical markers of brain damage in cerebrospinal fluid (CSF) or serum. DESIGN: A meta-analysis of prognostic studies in anoxic-ischaemic coma, selected from Medline and EMBASE databases, according to predefined criteria. SUBJECTS: Twenty-eight studies, with a total of 802 unselected, consecutive patients, in which tests, sampling time and outcome measures were described unequivocally and results were described using clear cut-off values or raw data. MAIN OUTCOME MEASURES: Poor outcome, defined as death or vegetative state, versus good outcome, defined as any other outcome state. ANALYSES: The overall prognostic accuracy of these variables was expressed as the 95% CIs of the pooled false-positive test rate and the pooled positive-likelihood ratios. RESULTS: Only markers in CSF (creatine kinase isoenzyme (CKBB) >204 U/l, neuron specific enolase (NSE) >33 ng/ml, lactate dehydrogenase (LDH) >82 U/l and glutamate oxaloacetate (GOT) >62 U/l) reached a 0% false-positive rate. However, due to small sample sizes, the confidence limits were wide. The accuracy of prediction of poor outcome seemed acceptably high for CSF-CKBB (pooled false-positive rate 0% [95% CI 0-2.3%]; pooled positive-likelihood ratio 33.2 [95% CI 4.8-230.2]), but this result was based on two retrospective studies without blinding of the treating physicians for the test result. CONCLUSIONS: Because of small numbers of patients studied and methodological limitations the combined results are not sufficiently accurate to provide a solid basis for non-treatment decisions.

Enzymes in the cerebrospinal fluid in diagnosis of brain death.

The increase of enzymes in the cerebrospinal fluid is shown to indicate an adverse prognosis, with the implication of irreversibility. The massive increase of glutamate-oxaloacetate transaminase and lactate dehydrogenase and the appearance of alkaline phosphatases in a sample of cerebrospinal fluid in which the cytology is normal constitute an easy and reliable test for brain death. The increase in lactate dehydrogenase fraction V and lysozyme in cerebrospinal fluid supports the macrophagic origin of these enzymes.

The effects of acute cerebrovascular disease on serum and cerebrospinal fluid parameters.

In order to evaluate the effects due to acute cerebrovascular disease on serum and cerebrospinal fluid (CSF) parameters, biochemical data from 312 patients were studied. In serum, CK, LD and alpha 1 protein fraction showed a moderately close relationship to the severity of stroke. In CSF there could not be observed any relation between enzymatic activities (LD, ASAT, CK) and the severity of the disease. The same result was found for CSF protein and the ratio CSF albumin/serum albumin, parameters which are indicative for Blood Brain Barrier (BBB) disturbances. Substances from the intermediate metabolism in the Central Nervous System (CNS) (lactate and pyruvate) were evidently raised in CSF and there was a clear relation between the CSF concentration and the severity of stroke. No indication for IgG immunoglobulin abnormalities in CSF was found. The concentration of neurotransmitter metabolite 5HIAA in CSF was significantly higher in (in)completed stroke than in Transient Ischaemic Attack.

Measurement and diagnostic value of cerebrospinal fluid enzymes.

The diagnostic value of cerebrospinal fluid (CSF) enzyme activities in neurological disorders has been evaluated most extensively with the enzymes aspartate aminotransferase (ASAT), lactate dehydrogenase (LDH), creatine kinase (CK) and lysozyme. Methods use for performing the assays have been similar to those employed for serum analysis. Reference intervals for these enzymes in the CSF are given from several sources and demonstrate much lower activities than in serum. Studies of these CSF enzymes in cerebral infarction, brain tumors, central nervous system (CNS) infections and acute brain injury and reviewed.

Efficacy of cerebro-spinal fluid biochemistry in the diagnosis of brain insult.

Postmortem biochemical indices may provide a useful adjunct to morphological studies in the identification of antemortem brain insult. We studied 34 routine medico-legal cases categorising them into one of four diagnostic groups. There were 11 cases of head trauma, 7 of 'hypoxia' (3 hangings and 4 carbon monoxide or drug poisonings), 7 sudden cardiac deaths and 9 miscellaneous cases. Survival time and postmortem interval was known for each case. The degree of cranio-cerebral trauma was graded. Cerebro-spinal fluid (CSF) and vitreous humour were analysed for calcium, glucose, total proteins, aldolase, aspartate transaminase (AST), alanine transaminase (ALT), gamma glutamyltransferase (GGT), lactate dehydrogenase (LDH), creatine kinase (CK) and creatine kinase BB isoenzyme (CK-BB). CK-BB was also measured in superior vena cava serum. In CSF there was a significant correlation between the severity of cranio-cerebral trauma and levels of aldolase, CK-BB, AST, ALT and total proteins. CSF CK-BB, median units/l (range), for the groupings of head trauma, hypoxia, sudden cardiac death and miscellaneous were respectively 823 (2-3431); 96 (2-187); 4 (2-25); 5 (1-69). Corresponding serum CK-BB levels were 240 (28-322); 390 (26-411); 180 (20-482); 79 (18-530).

Evaluation of enzymes in serum and cerebrospinal fluid in cases of cerebrovascular accidents.

Gamma glutamyl transpeptidase (GGTP), glutamic oxaloacetic transaminase (GOT), and glutamic pyruvic transaminase (GPT) were measured serially in the serum and cerebrospinal fluid (CSF) of 22 patients with fresh stroke and an equal number of age- and sex-matched healthy control subjects. It was observed that levels of these enzymes in the CSF of control subjects were very low but were significantly elevated (p less than 0.001) in both serum and CSF in patients with stroke. The elevation was greater in the CSF than in the serum and was maximum during the first four days of stroke. Thereafter, the enzymatic activity declined. Of all these enzymes, GGTP in CSF correlated best with the clinical picture. It was possible to differentiate between the ischemic and hemorrhagic type of stroke on the basis of CSF levels of GGTP (greater than 60.0 units in hemorrhagic stroke). There was no correlation between GGTP levels in CSF and serum or among GOT, GPT, and GGTP in CSF. It can be concluded, therefore, that estimation of GGTP in CSF is helpful not only in predicting the degree of cerebral damage and functional outcome of the patient following stroke but also in differentiating the type of stroke.

Biochemical constituents of cerebrospinal fluid in premature and full term foals.

Total protein content and a variety of enzyme activities and electrolyte values were determined in 73 cerebrospinal fluid (CSF) samples from 66 horses and ponies. The foals (48) were divided into 3 categories-spontaneously delivered normal foals (Group A), full term induced normal foals (Group B) and premature induced non-surviving foals (Group C). CSF samples from a group of 18 normal adults (Group D) were included for comparison. Paired serum and CSF samples were collected on 32 occasions and subjected to similar analyses. CSF sodium and chloride were always higher than serum sodium and chloride; the reverse occurred with potassium. The CSF protein and enzyme levels were always lower than corresponding serum values. The foals had higher total protein and creatine kinase in CSF than the adults, except for Group C (non-survivors) which had significantly lower creatine kinase than either of the other 2 foal groups. Creatine kinase values tended to fall towards adult levels over 40 h post partum. It was also noted that foals with both high total protein and creatine kinase in CSF, compared with adult values, had a better chance of survival than those with high total protein but low creatine kinase.

Aminotransferases in post-mortem cochlear fluids.

Aspartate and alanine aminotransferase (ASAT, ALAT) activities were measured in human post-mortem sera, cerebrospinal fluid (CSF), perilymph and endolymph. Due to heart and/or liver morbidity during a terminal illness, the ASAT and ALAT serum activities were considerably increased as compared with normal and both were 20--30 times higher (p less than 0.001) than in CSF or inner ear fluids. CSF and inner ear fluids showed mutually similar values.

[The activity of aminotransferases in serum and cerebrospinal fluid in neurological diseases (author's transl)]. / Uber die Aktivität der Aminotransferasen in Serum und Liquor cerebrospinalis bei neurologischen Erkrankungen

The activities of the aminotransferases, GOT and GPT, were determined in the serum and cerebrospinal fluid of patients with Parkinson's disease, Huntington's chorea, Wilson's disease, amyotrophic lateral sclerosis (ALS), Friedreich's ataxia, phenylketonuria, and head injuries. 1. In patients with Huntington's chorea the activity of SGOT was lower than in controls (P = 0.02); in Friedreich's ataxia LGPT activity was decreased (P less than 0.001); in patients suffering from ALS SGOT (P = 0.005), SGPT (P less than 0.001) and LGOT (P less than 0.001) activities were increased. 2. Long-term treatment of Parkinson's disease and Wilson's disease with L-dopa resulted in an increase in SGOT, LGOT, and SGPT activity over approximately 2 months, with subsequent normalization of these enzyme activities in spite of continued therapy. Guanidine treatment led to an increase in aminotransferase activities in patients with ALS. Penicillamine caused a decrease in SGOT and SGPT activities in Wilson's disease. These results illustrate the necessity of taking therapeutic measures into account in the interpretation of data on aminotransferase activities.

Cerebrospinal fluid enzyme estimation in the diagnosis of central nervous system damage in the dog.

Cerebrospinal fluid was obtained from dogs with and without neurological conditions. Enzyme levels were raised in six out of 14 affected dogs but there was a lack of specificity to a particular disease entity.

Clinical, cerebrospinal fluid, and histological data from thirty-four cats with primary noninflammatory disease of the central nervous system.

The purpose of this study was to report the clinical, cerebrospinal fluid (CSF), and histological data derived from a study of 34 cats with noninflammatory central nervous system (CNS) disease, and to report the activities of the enzymes lactate-dehydrogenase (LDH), aspartate transferase (AST), and creatine kinase (CK) in the CSF from 15 cats with a variety of CNS diseases. The cats were part of a study of 61 cats that were admitted to two university clinics because of signs of CNS disease. The most frequent noninflammatory diseases were neoplasia (n = 12) and ischemic encephalopathy (n = 4). The majority of cats with CNS neoplasia had a mild increase in CSF protein concentration (less than 1 g/L [100 mg/dL]), an increased percentage of neutrophils or lymphocytes, and a normal total white cell count. Cats with ischemic encephalopathy (IE) had a mild to moderate increase in CSF protein concentration (< or = 2 g/L [200 mg/dL]) and a mild increase in white cell count (< or = 10 cells/microL) with an increased percentage of lymphocytes. The enzymes LDH, AST, and CK in the CSF were not sensitive indicators of chronic CNS disease. The CSF differential cell count was frequently abnormal when the total white cell count was normal, and blood contamination in the CSF samples was a frequent problem that had to be considered in the interpretation of the results. The history, signalment, and clinical signs, when combined with the CSF findings, were valuable in the diagnosis of noninflammatory CNS disease.

[CSF enzyme activities in patients with head injury--especially on GOT, GPT, LDH, and CPK (AUTHOR'S TRANSL)].

In our studies on patients with head injury, it was noted that there are some correlations between their clinical courses and the urinary excretion of creatine (cr), creatinine (Crn), 17-ketosteroid and 17-hydroxycorticosteroid. We observed the high urinary excretion of Cr in patients with severe head injury while almost negative in a mild case. We reported those facts in 1974. Also noted in patients with head injury is the relationship between the enzyme-activities (GOT, GPT, LDH and CPK) in the cerebrospinal fluid and their clinical courses. In this paper, we reported 34 cases of head injured patients (simple type: 2, concussion: 9, contusion: 8, acute intracranial hematoma: 7 and chronic intra-cranial hematoma: 8). The control values of CSF enzyme-activities were determined in these 14 cases (simple head injury, whip-lash injury and osteoma of the skull) as GOT less that 15, GPT less than 7, LDH less than 12 and CPK less than 8 units. In the moderate cases, a slight increase in activities of 4 enzymes in CSF were observed, while in severe or comatose cases, the enzyme-activities (especially LDH and CPK) were greater than in the controls. In the dead cases these values were five times as high as the normal case. In the patients recovering from a serious stage, these activities decreased to normal. High CSF enzyme-levels tend to indicate a poor prognosis and low levels a favorable progrosis. In the patients with a significant elevation of CSF enzymes, a high urinary excretion of Cr [normal range: 0-150 (ca. 50)mg/day] was often observed. There was no apparent correlation between the enzyme level in CSF and that in serum and the increase or decrease of these 4 enzymes are not always proprotionate with each other. As reported by Green (1958) and Lending (1961), cerebral cell necrosis and increased permeability of BLB, BBB or cerebral cell membrane can be related to the increase of enzymeactivities. With these observations, it can be considered that severe head injury gives influence on metabolic function in the hypothalamus and may cause in the levels of CSF enzymes and/or the urinary excretions of Cr, Crn and corticosteroids. And the examinations of enzyme activities in the patients with head injury may become a useful aid to make an outlook of their clinical coure and prognosis.

[Etiology and pathogenesis of epilepsy in children]. / K voprosu ob étiologii i patogeneze épilepsii u detei.

Under examination there were 420 children suffering from epilepsy. In 230 of them the convulsive seizures appeared during the first year of the life: in most of these children (71%) this was in the presence of perinatal pathology. A genealogical analysis of 112 families, from which 135 epileptic children descended, is presented. Various types of hereditary epilepsy were revealed. An examination of some enzymes contained in the cerebrospinal fluid of the epileptic patients revealed shifts in their metabolism in cases of both hereditary and sporadic epilepsy. This reflects common features of the pathogenesis of those forms.

[Clinical picture and changes in the activity of several cerebrospinal fluid enzymes in stroke]. / Klinicheskaia kartina i izmeneniie aktivnosti nekotorykh fermentov spinnomozgovoi zhidkosti pri mozgovykh insul'takh.

Having studied the clinical picture and changes in the activity of various enzymes in the cerebrospinal fluid (CSF) in 140 patients with cerebral strokes, the authors showed a diagnostic and prognostic value of determining the activity of LDH and GGTP in the CSF. The activity of these enzymes increased in hemorrhagic stroke and in cases of unfavourable outcome. Their activity was lower in ischemic stroke and in cases of a favourable course of the disease.

[Acid-base equilibrium and spinal fluid enzyme activity in newborn infants with pathology of the nervous system]. / Kislotno-shchelochnoe ravnovesie i aktivnost' fermentov spinnomozgovoi zhidkosti u novorozhdennykh s patologiei nervnoi sistemy.

The acid-base balance of the blood and cerebrospinal fluid was studied in 90 babies born in asphyxia in order to use these data in assessing the damage to the nervous system. Analysis revealed the hypoxic nature of the cerebral affection which was manifested by anaerobic glycolysis of the cerebral tissue and arterial hypoxemia. The degree of acidosis detected in the cerebrospinal fluid correlated with the severity of the nervous system damage. Children with the lethal outcome presented deeompensated respiratory acidosis, in the cerebrospinal fluid whereas children with severe neurological pathology had alkalosis. It is concluded that alkolosis is induced by an intensified catabolism of the nervous system proteins which leads to the accumulation of ammoniac compounds. The same children showed pulmonary hyperventilation leading to respiratory acidocis which was not related to pulmonary pathology. The latter points to the hypoxic impairment of the respiratory centre. At the same time, a considerable increase in the activity of the glycolytic enzymes was observed; the activity of glutamate oxalacetate transaminase increased 5-fold, the activity of lactate dehydrogenase rose two-fold.

[Possible pathways of changes in the activity of a number of enzymes in spinal fluid in stroke]. / O vozmozhnykh putiakh izmeneniia aktivnosti riada fermentov v likvore pri mozgovykh insul'takh.

Examination of 234 cases with cerebral stroke showed that the activity of enzymes in the cerebrospinal fluid (CSF) of these patients increased as compared to the control group. In hemorrhagic strokes their activity was considerably higher than in ischemic ones. In 92 cases the results of examination were compared to sectional findings. The activity of enzymes was affected by numerous factors including the speed of stroke development, its nature, the size of the focus, the distance of the latter from the CSF pathways, and the severity of brain oedema.