Variants in ACPP are associated with cerebrospinal fluid Prostatic Acid Phosphatase levels.

BACKGROUND: Prostatic Acid Phosphatase (PAP) is an enzyme that is produced primarily in the prostate and functions as a cell growth regulator and potential tumor suppressor. Understanding the genetic regulation of this enzyme is important because PAP plays an important role in prostate cancer and is expressed in other tissues such as the brain. METHODS: We tested association between 5.8 M SNPs and PAP levels in cerebrospinal fluid across 543 individuals in two datasets using linear regression. We then performed meta-analyses using METAL =with a significance threshold of p < 5 × 10(-8) and removed SNPs where the direction of the effect was different between the two datasets, identifying 289 candidate SNPs that affect PAP cerebrospinal fluid levels. We analyzed each of these SNPs individually and prioritized SNPs that had biologically meaningful functional annotations in wANNOVAR (e.g. non-synonymous, stop gain, 3' UTR, etc.) or had a RegulomeDB score less than 3. RESULTS: Thirteen SNPs met our criteria, suggesting they are candidate causal alleles that underlie ACPP regulation and expression. CONCLUSIONS: Given PAP's expression in the brain and its role as a cell-growth regulator and tumor suppressor, our results have important implications in brain health such as cancer and other brain diseases including neurodegenerative diseases (e.g., Alzheimer's disease and Parkinson's disease) and mental health (e.g., anxiety, depression, and schizophrenia).

Acid phosphatase activity in senile plaques and cerebrospinal fluid of patients with Alzheimer's disease.

The origin of the various components of senile plaques in Alzheimer's disease (AD) continues to be a focus of intense research scrutiny. Lysosomal enzyme activity within the plaques is of particular interest because of its possible relevance to a presumed abnormal processing of precursor molecules that may lead to the formation of plaque amyloid. Histochemical evidence of acid phosphatase (ACP), a lysosomal hydrolase, activity in senile plaques has been documented long before many of the current biochemical data regarding plaque pathogenesis became available. Recent evidence suggests the presence of neuronal membrane abnormalities that may allow "leakage" of some intracellular molecules, including enzymes, into the perineuronal environment and from there, possibly, to the cerebrospinal fluid (CSF). In the course of investigating this hypothesis, we decided to readdress the issue of ACP activity in AD by assaying the enzyme both in brain tissue sections as well as in CSF samples from neuropathologically confirmed cases of AD and from normal control subjects. Brain frozen sections from five cases with AD and five control subjects were histochemically stained for ACP using the alpha-naphthylphosphate hydrolysis method. Frozen CSF samples from 15 cases with AD and 19 control subjects were assayed for ACP activity using the thymolphthalein monophosphate hydrolysis method. In all cases studied, CSFs were cytologically unremarkable. Neurons in normal and AD brains were strongly positive for ACP. In AD, numerous senile plaques showed strong ACP activity with both granular and diffuse patterns. The CSFs from six of 15 AD cases (40%) showed ACP activity with values ranging from 0.04 to 0.4 U/L. No ACP activity was detected in any of the 19 control CSFs analyzed. The exact source of ACP in senile plaques and CSF of patients with AD cannot be established based on these data alone but the ACP may have originated from neurons with oxidative stress or oxygen free radical-mediated membrane damage. The data encourage further investigation of this hypothesis.

[Changes in the biochemical composition of the cerebrospinal fluid in acute carbophos poisoning]. / Izmeneniia biokhimicheskogo sostava tserebrospinal'noi zhidkosti pri ostrom otravlenii karbofosom.

As far as the pathogenesis of poisonings with organophosphorus pesticides is concerned, in addition to irreversible inhibition of acetylcholinesterase (AGE) in tissues, of importance are changes in the other systems which essentially determine the outcome of intoxication. The purpose of the present study was to examine the nature of changes occurring in total protein and protein fractions, free amino acids (aspartic and glutamic acids, glycine, isoleucine, leucine) and in certain enzymes (AST, ALT, CP, GGTP, GDH) in the cerebrospinal fluid (CSF) of patients with acute Malathion insecticide poisoning. 137 patients aged 20 to 50 years were placed under observation. There were 77 men and 60 women. 40 persons had poisoning of medium gravity and 97 were severely poisoned. The intake of the CSF was performed on days 1, 3, 10, 14 and 21 since the disease onset. It has been established that in acute Malathion insecticide poisoning, the CSF content of the stimulating mediator amino acids, aspartic and glutamic, rises within the early periods, whereas the concentration of the inhibitory mediator glycine decreases. The changes in protein fractions of the CSF are characterized by a fall of the content of globulins and a rise of albumins, thus attesting to the predominance of pathological processes in the brain, especially in the initial period of intoxication, and to the impairment of the blood-brain barrier. The development of intoxication is associated with activation in the CSF of LDN, CP, GGTP and GDH as well as by activation of LDH isozymes which is viewed as the result of the membranotoxic effect of a Malathion insecticide.

Acid phosphatase activity of cerebrospinal fluid cells in bacterial and abacterial meningitis.

Acid phosphatase staining is performed on cerebrospinal fluid cells of 365 samples from 105 patients with various types of meningitis. This enzyme activity is strongly positive in the early samples of bacterial meningitis, as far as the patients had not received a pretreatment with antibiotics for more than 24 h. It allows monitoring the response to therapy in subsequent samples. Acid phosphatase activity is positive in 2 cases of cryptococcus meningitis. It is negative in all cases of aseptic and Mycoplasma pneumoniae meningitis. The results in herpes encephalitis are variable, depending on the clinical state and the degree of brain destruction. Acid phosphatase staining is a useful and rapid cytological technique for determination of the nature of the meningitis and for monitoring the therapeutical response.

Acid phosphatase activity of cerebrospinal fluid cells in leptomeningeal haemorrhage.

One hundred and twenty samples of haemorrhagic spinal fluid were examined by acid phosphatase staining. This enzyme activity starts to appear in mono-histiocytic cells 2 days after bleeding and increases up to the 5th day. After 1 week the activity decreases rapidly. Similar results are found in mixtures of incubated clear spinal fluid, to which blood is added. Acid phosphatase staining is a useful additional method for determination of the age of a leptomeningeal bleed.

CSF lysosomal hydrolase activity as an aid in the diagnosis of bacterial meningitis.

The activity of the lysosomal enzymes acid phosphatase, beta-glucuronidase, alpha-mannosidase and hexosaminidase were determined in CSF obtained from patients with proven bacterial meningitis and from patients with various other diagnoses. The mean value for CSF beta-glucuronidase from bacterial meningitis was elevated 73-fold when compared to the aggregate mean of all control groups. Acid phosphatase and alpha-mannosidase means were 26-fold and 33-fold elevated respectively while hexosaminidase was threefold elevated. Measurement of CSF acid phosphatase and beta-glucuronidase should prove a rapid useful test in establishing the diagnosis of bacterial meningitis. Chromatography of CSF samples on DEAE Sephadex allowed the resolution of hexosaminidase and beta-glucuronidase into individual isozymes. The ratio of hexosaminidase A to hexosaminidase B was generally higher in CSF from patients with bacterial meningitis but was very variable. The isozyme distribution for beta-glucuronidase was identical to that found in serum and no differences in pattern were found between patients and control subjects.

The use of leukocyte acid phosphatase in the diagnosis of malignant disease. Case report and review of literature.

Tartrate resistant acid phosphatase (TRAP) has been demonstrated during relapse in the cells in the cerebral spinal fluid (CSF) in a patient with the clinical features of acute T cell lymphocytic leukemia which suggests this isozyme may be a marker for malignant transformation of some types of lymphocytes. The presence of TRAP may be helpful in establishing the diagnosis of a lymphocytic malignancy since normal lymphocytes appear to have tartrate sensitive acid phosphatase. The presence of TRAP can no longer be considered specific for hairy cell leukemia, since children with acute lymphocytic leukemia are being found with this isozyme in their malignant blasts. The presence of TRAP does not appear to be specific for T or B cell lines of malignant lymphocytes since it has been described in cells with either type of cell markers. The presence of TRAP seems most useful in differentiating lymphocytic malignancies from monocytic and histiocytic malignancies and from benign lymphocytoses when the cells of the peripheral blood and marrow may have similar morphologic features with routine staining.

Lysosomal hydrolases in CSF of patients with multiple sclerosis.

The activities of acid phosphatase and N-acetyl-beta-glucosaminidase have been measured in 171 samples of cerebrospinal fluid from 104 patients suffering from multiple sclerosis. The mean level of activity of these enzymes was lower than of controls. Patients who had the first or second bouts had somewhat higher activity of these enzymes compared to controls. The lowest values of these enzymes were found in patients with severe disability. Patients with late onset of the disease had higher levels of the enzymes compared to patients with an earlier debut of the illness, whereas patients with a short history had higher values than patients with a longer duration.

Diagnostic value of determinations of lysosomal hydrolases in CSF of patients with neurological diseases.

The activities of four lysosomal acid hydrolases, beta-galactosidase, alpha-mannosidase at pH 4.5 and 5.5, N-acetyl-beta-glucosaminidase, and acid phosphatase, have been measured in serum and cerebrospinal fluid from 179 patients with different neurological diseases and from 20 healthy controls. In patients with tumours, decreased activity of beta-galactosidase was found in both serum and cerebrospinal fluid, and in patients with multiple sclerosis and collagen diseases, decreased activities of beta-galactosidase and N-acetyl-beta-glucosaminidase were found in cerebrospinal fluid. The variations of enzyme activities were great between the individual patients even with these groups and analysis of lysosomal enzymes seems to have a very poor clinical value.

Lysosomal enzymes in cerebral atrophy.

In seven patients with cerebral atrophy due to pre-senile dementia and/or cerebrovascular disease, the activity of acid phosphatase in lumbar cerebrospinal fluid (CSF) was higher (p less than 0.05) than in six controls. The activity of arylsulphatase and beta-galactosidase in CSF was the same in the two groups. In the serum, the activities of acid phosphatase and arylsulphatase were the same in the two groups but the activity of beta-galactosidase was lower (p less than 0.02) in patients with cerebral atrophy.

Cyclic adenosine-3',5-monophosphate concentration and enzyme activities of cerebrospinal fluid in meningitis of children.

The concentration of cyclic adenosine-3',5'-monophosphate (cAMP) and the activities of some enzymes of 29 children were measured from cerebrospinal fluid (CSF) and plasma at various stages of meningitis. The CSF cAMP values in acute untreated phase of aseptic and purulent meningitis were equal, but significantly higher than those of convalescent children with no pathological clinical or laboratory findings. During the whole course (up to 2 weeks) of antimicrobial treatment of the purulent meningitis CSF cAMP concentration was higher than in the convalescent phase. Of the CSF enzymes studied, the lactic dehydrogenase activity seemed to be the best indicator of changing stages of meningitis. It was clearly elevated in the acute, untreated phase of purulent meningitis then decreasing during the course of treatment. In aseptic meningitis this activity was at the normal level and the activities of creatine kinase and acid phosphatase behaved similarly. The plasma cAMP concentrations in the acute phase of purulent meningitis were in the same range as in the CSF. During the treatment no significant changes were seen. The enzyme activities in the plasma were normal. The CSF cAMP level seems to be a sensitive indicator of metabolic disturbances in meningitis and may serve as a diagnostic aid.

Monocytes and histiocytes in cell cultures of cerebrospinal fluid. Morphology of cultured CSF cells.

A method of CSF cell culturing, based on observations of cultured cells isolated from 700 CSF specimens obtained for routine diagnostic procedures by lumbar puncture from patients who had no proven or suspected neoplastic disease, is described which enables the demonstration of proliferating mononuclear elements even when they are present in specimens with low cell count. Spread on surfaces of plastic and glass material, monocytes and histiocytes in CSF cell cultures can appear as polygonal or crescent shaped epitheloid cells, may assume spindle shapes, or transform into multinucleated giant cells. Some cells given rise to clones with different rates of proliferation, up to the formation of a monolayer. After short term culturing the cytochemical characteristics of the cells are comparable to those of the native cells. Phagocytosis in culture is possible. Cells with a high rate of proliferation can be isolated from CSF specimens in subacute non-bacterial inflammatory processes, in chronic meningitis, in the state of repair of bacterial meningitis and subarachnoid hemorrhage, after repeated lumbar punctures and other unspecific irritations such as myelography and pneumencephalography, and in the course of intrathecal cytostatic therapy.