Postmortem Cerebrospinal Fluid Research Articles

Characterization of the AD7C-NTP cDNA expression in Alzheimer's disease and measurement of a 41-kD protein in cerebrospinal fluid.

We have isolated a novel Alu sequence-containing cDNA, designated AD7c-NTP, that is expressed in neurons, and overexpressed in brains with Alzheimer's disease (AD). The 1,442-nucleotide AD7c-NTP cDNA encodes an approximately 41-kD protein. Expression of AD7c-NTP was confirmed by nucleic acid sequencing of reverse transcriptase PCR products isolated from brain. AD7c-NTP cDNA probes hybridized with 1. 4 kB mRNA transcripts by Northern blot analysis, and monoclonal antibodies generated with the recombinant protein were immunoreactive with approximately 41-45-kD and approximately 18-21-kD molecules by Western blot analysis. In situ hybridization and immunostaining studies localized AD7c-NTP gene expression in neurons. Using a quantitative enzyme-linked sandwich immunoassay (Ghanbari, K., I. Beheshti, and H. Ghanbari, manuscript submitted for publication) constructed with antibodies to the recombinant protein, AD7c-NTP levels were measured under code in 323 clinical and postmortem cerebrospinal fluid (CSF) samples from AD, age-matched control, Parkinson's disease, and neurological disease control patients. The molecular mass of the AD7c-NTP detected in CSF was approximately 41 kD. In postmortem CSF, the mean concentration of AD7c-NTP in cases of definite AD (9.2+/-8.2 ng/ml) was higher than in the aged control group (1.6+/-0.9; P < 0.0001). In CSF samples from individuals with early possible or probable AD, the mean concentration of AD7c-NTP (4.6+/-3.4) was also elevated relative to the levels in CSF from age-matched (1.2+/-0.7) and neurological disease (1.0+/-0.9) controls, and ambulatory patients with Parkinson's disease (1.8+/-1.1) (all P < 0.001). CSF levels of AD7c-NTP were correlated with Blessed dementia scale scores (r = 0. 66; P = 0.0001) rather than age (r = -0.06; P > 0.1). In vitro studies demonstrated that overexpression of AD7c-NTP in transfected neuronal cells promotes neuritic sprouting and cell death, the two principal neuroanatomical lesions correlated with dementia in AD. The results suggest that abnormal AD7c-NTP expression is associated with AD neurodegeneration, and during the early stages of disease, CSF levels correlate with the severity of dementia.

Comparison of cerebrospinal fluid monoamine metabolite levels in dominant-aggressive and non-aggressive dogs

Aggression has been shown to be related to reduced serotonergic activity in humans and non-human primates, and in rodents. We now studied the relationship between cerebrospinal fluid (CSF) monoamine metabolites and canine aggression in 21 dominant-aggressive dogs ( Canis familiaris) and 19 controls. The diagnosis of dominance-related aggression was based upon a history of biting family members in contexts associated with dominance challenges. Post-mortem CSF 5-HIAA, MHPG and HVA were measured by high-performance liquid chromatography using electrochemical detection. Concentrations of CSF 5-HIAA ( P = 0.01) and HVA ( P < 0.001) were lower in the aggressive group (median values: 5-HIAA 202.0 pmol/ml; HVA 318.0 pmol/ml) than in controls (5-HIAA 298.0 pmol/ml; HVA 552.0 pmol/ml). No differences were noted in CSF MHPG levels. Differences in 5-HIAA were maintained after controlling for breed and age of dogs, but HVA differences may have been breed-dependent. Lower levels of 5-HIAA ( P = 0.02) and HVA ( P = 0.04) were found in the subgroup of aggressive dogs with a history of biting without warning (5-HIAA 196.0 pmol/ml; HVA 302.0 pmol/ml) compared to dogs that warned (5-HIAA 244.0 pmol/ml; HVA 400.0 pmol/ml). This study suggests that reduced serotonergic function is associated with aggressive behavior and impaired impulse control in dogs, a finding that is consistent with observations in primates, and suggests that serotonin modulates aggressive behavior throughout mammals.

Changes in a CSF antigen associated with dementia.

An 85-kDa antigen was detected in cerebrospinal fluid (CSF) using a monoclonal antibody, 11.57, raised against a fraction of paired helical filaments extracted from Alzheimer's disease (AD) brain tissues. The antigen is a thermostable protein that is unrelated either to tau or amyloid beta-protein precursor. Its level was measured in lumbar and post-mortem CSF samples and found to be decreased significantly in patients with dementia as compared with non-demented controls. There was no difference in its level between patients with AD and those with non-Alzheimer type dementia. In AD, however, there was a significant relationship between disease progression and the amount of the 85-kDa antigen.

Increased cortisol levels in aging and Alzheimer's disease in postmortem cerebrospinal fluid.

The hypothalamo-pituitary-adrenal (HPA) axis is activated during aging and even more so in dementia. Increased levels of corticosteroids may be neurotoxic. Therefore we have investigated cortisol levels in cerebrospinal fluid (CSF) of Alzheimer patients and controls. Ventricular postmortem CSF was collected from clinically and neuropathologically well-defined Alzheimer patients (n = 26) and control subjects (n = 21). In the group of Alzheimer patients the mean CSF total cortisol level was 83% higher than that in the controls. In presenile Alzheimer patients (< 65 years of age; n = 13) the CSF-cortisol level was 5 times higher than that of presenile controls (n = 7). In contrast, senile Alzheimer patients (n = 13) and controls of over 65 years of age (n = 14) did not show a significant difference in CSF-cortisol levels. The presence or absence of a difference in the cortisol-CSF levels in, respectively, presenile or senile Alzheimer patients as compared to controls was due to the 3.5-fold rise of CSF-cortisol in control subjects over 65 years of age as compared with controls under 65 years of age. The CSF-cortisol levels in presenile and senile Alzheimer patients were similar. No significant correlation was observed in the Alzheimer patients between age of onset of the dementia and CSF cortisol levels or duration of Alzheimer's disease and CSF cortisol levels. The finding that in senile Alzheimer patients cortisol levels were similar to those of unaffected age-matched controls does not seem to support the cortisol neurotoxicity hypothesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Organic acids in post-mortem cerebrospinal fluid

Organic acids of cerebrospinal fluid (CSF) have been determinated by gas chromatography-mass spectrometry in 29 post-mortem samples obtained from infants and 10 samples obtained from hospitalized children, as controls. Though the organic acids profile was similar in the two groups, eight organic acids not observed in CSF from live infants were inconstantly found in post-mortem CSF and for three of them, malic acid, lactyllactic acid and uracile, concentrations were correlated with the delay in sampling.

Postmortem cerebrospinal fluid pleocytosis.

We show that postmortem cerebrospinal fluid (CSF) pleocytosis is a common event. Postmortem cerebrospinal or ventricular fluid was obtained from children and adults. The cells were counted and morphologically characterized using several histochemical markers. Infants exhibit a brisk postmortem CSF pleocytosis. Sudden infant death cases have relatively high CSF counts. Typeable cells are mononuclear and consist of approximately 60%-70% lymphocytes and 20%-40% macrophages. When postmortem duration is greater than 12 h, the cells become vacuolated and cannot be identified. The etiology of these findings requires further study.

Elevated CSF CRF in suicide victims

Introduction It has been suggested that several indices of enhanced hypothalamic-pituitary-adrenal axis activity, including dexamethasone nonsuppression, may be indicators of suicidal tendencies. However, recent studies have failed to prove that the Dexamethasone Suppression Test (DST) could be a predictor of suicidal behavior (Dam et al. 1985; Ennis et al. 1985; Kocsis et al. 1986; Secunda et al. 1986; Arato et al. 1986a; Modestin and Ruef 1987). Encouraged by a recent study of Stanley et al. (1985), we resorted to postmortem cerebrospinal fluid postmortem (CSF) analyses as a new research tool in the investigation of completed suicides (Arato et al. 1986b). We found no differences in CSF cortisol and adrenocorticotrophic hormone (ACTH) in suicides and controls. We now report on an extension of that investigation, involving measurement of the concentration of immunoreactive corticotropinreleasing factor (CRF) in CSF. It is quite plausible that excessive, long-lasting and/or uncontrollable stress could lead to a breakdown of the psychological defensive mechanisms and to the suicidal act. In that case,

Correlations between aminergic metabolites simultaneously obtained from human CSF and brain

Brain and cerebrospinal fluid (CSF) levels of homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) were simultaneously measured in 48 individuals at autopsy. Concentrations of 5-HIAA and HVA in the cerebral cortex were positively correlated with their levels in the CSF for the same individual. Additionally a positive correlation was observed between postmortem CSF levels of 5-HIAA and HVA and a significant concentration gradient for both metabolites was observed in serial fractions of CSF. These findings suggest that determinations of 5-HIAA and HVA in CSF from living individuals may reflect brain metabolite levels as well as the functional activity of these specific neuronal systems.

A study of CSF idiotypes in multiple sclerosis.

Six anti-idiotypic antisera have been raised against isolated cerebrospinal fluid (CSF) bands from five patients with multiple sclerosis and against a serum band from an additional patient. Preparative isoelectric focusing in agarose was useful for isolating highly purified bands. Individual antigenic specificities defined by these antisera were not detected on other bands from the same patients or in IgG isolated from the CSF of other patients. The CSF to serum ratios of the idiotypic determinants ranged from 1:2 to 1:8, consistent with substantial local synthesis in the central nervous system; the higher concentration in serum suggests that initial clonal expansion of antibody-making cells may have occurred outside the nervous system. An anti-idiotypic antiserum raised against the dominant band from postmortem CSF was used to compare the levels of idiotypic IgG eluted from four plaque areas. Although the amount of IgG eluted from each differed, the concentration of idiotype was similar for all plaques tested. The interaction of anti-idiotype with idiotype could not be inhibited by saline extracts of normal or multiple sclerosis brain.

Postmortem Biochemical Changes in Canine Cerebrospinal Fluid

Time and temperature effects on postmortem cerebrospinal fluid samples from 60 adult mongrel dogs were studied. After death the dogs were held at 4, 20, or 37 degrees C for intervals of 3, 6, 12, 24, or 48 h. Antemortem and postmortem cerebrospinal fluid was evaluated for sodium, chloride, potassium, urea nitrogen, glucose, creatinine, calcium, phosphorus, and carbon dioxide. Sodium and urea nitrogen values remained stable. Chloride may be of forensic science value. Low levels of postmortem calcium might indicate antemortem hypocalcemia; high levels of postmortem glucose may indicate antemortem hyperglycemia. Calcium and creatinine levels increased slightly but continually after death; carbon dioxide values dropped.

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.

Glutamate, -hydroxybutyrate and succinate dehydrogenases in post mortem inner ear fluids.

Polyacrylamide and agarose gel electro-phoresis was used to study glutamate (GluDH), β-hy-droxybutyrate (HBDH) and succinate dehydrogenase (SDH) activity in normal human serum (NHS), normal cerebrospinal fluid (CSF) and perilymph from two cases of Meniere's disease, and in corresponding post-mortem fluids, brain tissue and liver homo-genates. In post-mortem serum and in liver homo-genate, one strong band of GluDH was found at the site between the mobility of LDH2 and LDH3 and this band did not appear in CSF or inner ear fluids. The slower bands present in serum were absent from postmortem CSF and cochlear fluids. Activity corresponding to the sites of LDH1_3 was found in all fluids and control stainings. This was attributed to nonspecific reduction of NAD by the electrophoretic media.

Mala e dehydrogenase in post mortem perilymph.

Factors affecting the determination of malate dehydrogenase (MDH) activity in post-mortem serum, cerebrospinal fluid (CSF) and perilymph were studied using reactions from malate ⇒ oxalacetate in both directions. The former reaction order gave stable data which were much lower than those obtained with the reverse order; this was thought to be mainly due to different enzyme kinetics. The activity in serum was about double that in CSF and perilymph in malate → oxalacetate reaction. In reverse reaction perilymph MDH values were generally much higher than those of serum or CSF. Since these fluids contain several enzymes utilizing the same coenzymes only data obtained in exactly same experimental conditions can be compared with each other.

Cerebrospinal fluid electrolytes after death.

(1) Cations and anions of postmortem cerebrospinal fluid have been studied in 131 cases, and pH determinations performed in an additional 26 cases. (2) Postmortem changes observed include marked increases of potassium and inorganic phosphorus, moderate increases of magnesium, slight to moderate decreases of sodium, chlorides and HCO3 and a relative stability of calcium ions, the concentration of which approached closely antemortem values. (3) The acid-base equilibrium in postmortem cerebrospinal fluid was found shifted to the alkaline side by a deficit of anions in contrast to the actual acidity as determined by pH measurements, presumably due to liberation of organic acid radicals. (4) Postmortem electrolyte changes may be interpreted by greater permeability of cell membranes due to autolysis, while the increased inorganic phosphorus may result from postmortem esterase activity.

Urobilinogen in Cerebrospinal Fluid

Six cases of urobilinogen-orachia have been presented in which the postmortem cerebrospinal fluid urobilinogen ranged from traces to 9 mg %.