Monoamine metabolites in cerebrospinal fluid of depressive subgroups

Lumbar punctures were performed on 69 patients who met Research Diagnostic Criteria (RDC) for major affective disorder, while they were drug-free and depressed. None of the patients met RDC for alcoholism. Cerebrospinal fluid 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) were measured by fluorometry and 3-methoxy-4-hydroxyphenylglycol (MHPG) by gas chromatography. Family histories were ascertained by systematic interviews of patients and their relatives, and diagnoses were made by family history diagnostic criteria (Andreasen et al., 1977). Depressed patients with alcoholism in a first degree relative had significantly lower levels of 5-HIAA and MHPG than patients without a family history of alcoholism (p < 0.05). No difference in HVA levels was found. The metabolite differences remained significant when the influence of sex ratio was considered. These results are in agreement with previous work linking alcoholism to abnormal serotonin metabolism. They provide further biochemical evidence of distinct genetic subtypes of affective disorder along lines suggested by Winokur (1979a, 1979b), and illustrate the usefulness of the family history method in defining patient subgroups.     

Monoamine metabolites in human cerebrospinal fluid. HPLC/ED method

Catecholamines and indolealkylamines are of clinical interest in neurological and psychiatric disorders. We measured 3-methoxy-DOPA, 3-methoxy-4-hydroxyphenylglycol, dihydroxyphenylacetic acid, tryptophan, 5-hydroxyindoleacetic acid and homovanillic acid in human cerebrospinal fluid with a simple, sensitive , inexpensive, rapid and accurate procedure using high performance liquid chromatography coupled to an electrochemical detector. Patients with Parkinson's disease have a decrement in homovanillic acid that is reversed by treatment with L-3,4-dihydroxyphenylalanine. After this medication, 3-methoxy-DOPA is measurable in cerebrospinal fluid. Patients with depression show a decrease in serotonin turnover expressed by diminished 5-hydroxyindoleacetic acid content in cerebrospinal fluid. Depressed patients also show low levels of tryptophan. Monoamine metabolites are augmented in patients with subarachnoid hemorrhage.     

Proteinase inhibitors in cerebrospinal fluid in multiple sclerosis.

Levels of the proteinase inhibitors alpha 2-macroglobulin (alpha 2-m) and alpha 1-antitrypsin (alpha 1-at), and total protein, IgG and transferrin were measured in cerebrospinal fluid (CSF) from patients with multiple sclerosis (MS) and other neurological diseases. All groups except that termed "meningitis" had similar alpha 2-m levels, but alpha 1-at and transferrin were significantly depressed in MS. Total protein levels were normal and IgG levels were elevated in MS. Serum levels of alpha 1-at were normal so the decreases observed in the CSF in MS were not due to impaired systemic production. In view of previous reports that proteinase activity is high in MS plaques and CSF, the inhibitory capacity of alpha 2-m and alpha 1-at in CSF was measured. As any decreases in inhibitory capacity noted in MS were slight, they could only be important in the local environment of a plaque where enzyme levels may be critically high.     

Nitric oxide metabolites and interleukin-6 in cerebrospinal fluid from multiple sclerosis patients

Interleukin-6 (IL-6) and nitric oxide (NO) are implicated in the pathology of multiple sclerosis (MS). We have investigated the levels of these mediators in the cerebrospinal fluid (CSF) from 50 patients with MS and 23 control subjects. Mean CSF IL-6 level was higher in the total MS group in comparison with controls, but not significantly, whilst the difference between patients with stable MS and controls reached the level of statistical significance. Mean CSF nitrite/nitrate level was significantly higher in the total MS group compared with the control group, as well as in active MS patients versus controls. There was significant difference neither in the mean CSF IL-6 nor in nitrite/nitrate levels between active and stable MS patients. Interestingly, we observed a significant negative correlation between IL-6 and nitrite/nitrate levels in the CSF in the total MS group. Such a trend existed in both subgroups with active and stable MS, but without reaching the level of statistical significance. Our data further support the involvement of IL-6 and NO in ongoing pathological processes in MS, suggesting their potential interplay within the central nervous system in this disease.     

Monoamine metabolites in cerebrospinal fluid during and after acute cerebral ischemia

In order to understand the role of monoamines in cerebral ischemia, 3-methyoxy-4-hydroxyphenylglycol(MHPG), 5-hydroxyindoleacetic acid (5-HIAA), and homovanillic acid(HVA), the three major unconjugated monoamine metabolites in cerebrospinal fluid (CSF), of 33 patients and 18 controls were measured with high performance liquid chromatography. Results showed all three metabolites were raised in patients with severe ischemia, but only MHPG and 5-HIAA were elevated significantly, MHPG changes more quickly and regularly as a consequence of cerebral ischemia than the two others. A positive correlation between any pair of metabolites was found in controls and in patients in the first week after stroke, but not at the end of the second week. Computer assisted multivariate analysis indicated 5-HIAA and MHPG correlated more closely with the state of illness in the acute stage, whereas HVA correlated the least. Possible explanations for the changes of CSF levels of amine metabolites are discussed.     

Increased cerebrospinal fluid tau protein in multiple sclerosis

Axonal damage is now being recognized as a common finding in multiple sclerosis (MS) lesions and a cause of irreversible neurological damage. Attempts to identify markers of early axonal damage are of great significance. This prompted us to examine the microtubule-associated protein tau in the cerebrospinal fluid (CSF) of patients with MS vs. controls. Tau was measured by double antibody sandwich ELISA. Increased CSF tau levels were found in MS as compared to controls (medians 249.6 and 135 pg/ml respectively, p<0.001). Half of the MS patients presented with levels above the upper limit of the controls. A significant increase vs. controls was found in both relapsing-remitting and progressive subtypes. These data may indicate axonal impairment in a subpopulation of MS patients and may provide a tool for the estimation of axonal damage during life.     

Proteomic analysis of multiple sclerosis cerebrospinal fluid

Two-dimensional gel electrophoresis and peptide mass fingerprinting were used to identify proteins in cerebrospinal fluid (CSF) pooled from three patients with multiple sclerosis (MS) and in CSF pooled from three patients with non-MS inflammatory central nervous system (CNS) disorders. Resolution of CSF proteins on three pH gradients (3-10, 4-7 and 6-11) enabled identification of a total of 430 spots in the MS CSF proteome that represented 61 distinct proteins. The gels containing MS CSF revealed 103 protein spots that were not seen on control gels. All but four of these 103 spots were proteins known to be present in normal human CSF. The four exceptions were: CRTAC-IB (cartilage acidic protein), tetranectin (a plasminogen-binding protein), SPARC-like protein (a calcium binding cell signalling glycoprotein), and autotaxin t (a phosphodiesterase). It remains unknown whether these four proteins are related to the cause and pathogenesis of MS.     

Cystatin C in cerebrospinal fluid and multiple sclerosis

OBJECTIVE: A recent study using surface-enhanced laser desorption/ionization time-of-flight analysis of cerebrospinal fluid identified a 12.5 kDa truncated isoform of cystatin C (CysC) as a specific biomarker for multiple sclerosis (MS). METHODS: Surface-enhanced laser desorption/ionization time-of-flight analysis of cerebrospinal fluid samples from 43 MS patients and 46 healthy control subjects. RESULTS: Full-length CysC (13.4 kDa) concentration was similar in MS and control samples. The 12.5 kDa CysC protein was produced from full-length CysC by N-terminal cleavage during storage at -20 degrees C. INTERPRETATION: The 12.5 kDa CysC isoform is a storage-related artifact and is not useful as a diagnostic marker for MS.     

Monoamine acid metabolites and cerebrospinal fluid dynamics in normal pressure hydrocephalus: preliminary results.

Lumbar and ventricular CSF concentration of homovanillic acid (HVA) and 5-hydroxy-indole-acetic acid (5-HIAA) have been determined in 13 patients admitted to hospital for suspected normal pressure hydrocephalus. Low values of HVA in lumbar CSF were found in all patients with reduced CSF absorption and CSF flow inversion. The HVA lumbar concentration remained low after shunt procedure; it increased if obstruction of the shunt occurred. The ventricular CSF concentration of HVA was normal before surgery; it became higher, in two cases, after surgery. No important variations were found in the lumbar and ventricular CSF concentration of 5-HIAA. The possible mechanisms and diagnostic value of these findings are discussed.     

Low somatostatin content in cerebrospinal fluid in multiple sclerosis

In 27 patients with multiple sclerosis (MS), and in 10 control subjects of comparable age, percent ideal body weight and sex ratio, the cerebrospinal fluid (CSF) content of somatostatin was measured by radioimmunoassay.
The results showed that the group of patients in relapse (n = 16) had significantly lower somatostatin content in CSF (95 ± 4.1 (SEM) pg/ml) than both the control group (142 ± 8.4 pg/ml) and the group of MS patients (n =11), who had been in a clinical stable phase for more than 6 months (131 ± 3.2 pg/ml). Duration of the disease and degree of neurological impairment were apparently without relation to the reduction of somatostatin content in the CSF. There was no relationship between CSF content of somatostatin and the content of total protein or IgG, neither of which showed any relationship to the activity of the disease.     

Cross-reactive idiotypy in cerebrospinal fluid immunoglobulins in multiple sclerosis

The presence of oligoclonal bands in cerebrospinal fluid (CSF) in multiple sclerosis (MS) indicates a restricted heterogeneity of immunoglobulin (Ig). The portion of myelin basic protein encompassing residues 80-96 contains epitopes frequently recognized by T and B cells of MS patients. To define further this restricted heterogeneity and to direct further efforts to identify an antigenic target of CSF oligoclonal bands, the presence of idiotope (Id)-bearing antibodies sharing an Id with a murine monoclonal antibody to myelin basic protein peptide 80-89 was examined in the CSF of MS patients. CSF samples from 57 patients with clinically definite MS and 45 patients with other neurological diseases were standardized for amount of IgG and analyzed by immunoblotting for detection of Id-bearing antibodies. Id-bearing Ig was detected in the CSF of 79% of MS patients and 16% of other neurological disease patients. Further statistical analysis revealed an 84% specificity, an 86% positive predictive value, and a 76% negative predictive value of the test. The probability that a positive screening result indicated MS was 81%. Thus, antibodies containing a cross-reactive Id are present preferentially in the CSF of patients with MS compared with those with other neurological diseases. An immune network that has limited V region gene usage likely exists in the CSF and central nervous system of patients with MS and may provide evidence about antigens relevant to the pathogenesis of MS.     

Screening of multiple sclerosis cerebrospinal fluid for autoantibodies

An enzyme-linked immunoadsorbent assay, using nitrocellulose discs as solid phase and small sample volumes (50 microliter), was developed for the measurement of antibodies. This was used to screen CSF samples for autoantibodies against tissue components. Extracts from a selection of tissues from both "normal" and MS patients and from 3 glial cell lines were made in phosphate-buffered saline; in the case of neural and lymphoid samples the remaining particulate materials were subsequently solubilised with octylglucoside. The saline-soluble components were screened against CSF samples from MS patients (18), patients with other neurological disorders (10), and matched orthopaedic patients but no differences were found among the 3 groups. However, when the detergent-soluble components were screened a significant (at the P less than or equal to 0.01 level) elevation of reactivity towards brain was found in 6/16 MS patients and 2/12 patients with other neurological diseases when compared to their controls.     

Primary progressive multiple sclerosis: cerebrospinal fluid considerations

Diagnosing the 'primary progressive' form of multiple sclerosis (PPMS) requires assurance that other conditions that might cause a chronic inflammatory neurodegenerative central nervous system (CNS) disease have been ruled out. Both imaging and pathological studies have shown that this form of MS tends to be less inflammatory compared with either the relapsing-remitting or secondary progressive types. There are therefore many conditions that cause a slowly progressive wasting of the CNS that might be confused with MS. The new MS diagnostic scheme has made the presence of 'typical' MS abnormalities in the cerebrospinal fluid (CSF) a mandatory first criterion, but there may well be individuals that still have PPMS even in the absence of a typical MS CSF. Here we explore what the CSF can tell about an individual's disease process and outline the current state of the art in terms of CSF analysis. Used properly, the CSF can be very helpful in clarifying a diagnosis of PPMS.     

Diagnostic value of cerebrospinal fluid study in multiple sclerosis

Multiple sclerosis ist a very frequent chronic inflammatory disease of the central nervous system. Since clinical and neuro-imaging findings often may be ambiguous, cerebrospinal fluid examination has received great importance for diagnosis. By that method it becomes possible to differentiate inflammatory from noninflammatory diseases. Furthermore, cerebrospinal fluid findings are discussed which seem to be characteristic for multiple sclerosis.     

Leukotrienes in the cerebrospinal fluid of multiple sclerosis patients

The concentration of the leukotrienes B4 (LTB4) and C4 (LTC4) was measured in the cerebrospinal fluid (CSF) of 38 multiple sclerosis (MS) patients and 51 with other neurological diseases. The LTB4 and LTC4 levels were significantly elevated in MS compared with the controls. The findings suggest that lipoxygenase products might play a pathogenetic role in the early, encephalitogenic phase of MS. The administration of lipoxygenase inhibitors or leukotriene antagonists might well open new perspectives for the treatment of MS.     

Plasma and cerebrospinal fluid tryptophan in multiple sclerosis and degenerative diseases.

Tryptophan and competing neutral amino acid levels were found to be diminished in the plasma of patients with multiple sclerosis and degenerative diseases, the greatest decrease being of tryptophan. Cerebrospinal fluid tryptophan was decreased in multiple sclerosis and motor neurone disease, while leucine and valine were increased. These changes might lead to decreased synthesis of brain serotonin and brain proteins. The ratio between neutral amino acids and tryptophan might be used as an ancillary test in the screening of degenerative diseases.     

Amine metabolites in the cerebrospinal fluid of patients with disseminated sclerosis

Mean homovanillic acid and 5-hydroxyindoleacetic acid concentrations were significantly low in the lumbar CSF of a group of patients with disseminated sclerosis (DS) who were severely disabled but not in the CSF of a less severely restricted group with DS. CSF concentrations were also low in a group of patients with superior cerebellar peduncular tremor due to DS and in a single patient with a similar tremor associated with a post-traumatic brain-stem lesion. The interpretation of abnormal CSF amine metabolite concentrations is discussed in the light of these findings.