GABA content and glutamic acid decarboxylase activity in brain of Huntington's chorea patients and control subjects.

—GABA contents are significantly decreased in the caudate nucleus, putamen-globus pallidus, substantia nigra, and occipital cortex in autopsied brain from Huntington's chorea patients, as compared to values in the same regions from control subjects who have died without neurological disease. Homocarnosine levels are lower in choreic than in control brain, but only in the putamen-globus pallidus and the cerebellar cortex are the differences significant. Activity of the enzyme which synthesizes GABA, glutamic acid decarboxylase, is reduced in the brains of some choreic patients, but may be equally low in brain of control subjects, even though the latter exhibit normal brain GABA content. Low glutamic acid decarboxylase activity in autopsied human brain is not uniquely characteristic of Huntington's chorea. No evidence was found in this study for an inhibitor of glutamic acid decarboxylase in choreic brain, nor for the presence of an isoenzyme with decreased affinity for glutamate. GABA aminotransferase, the enzyme which degrades GABA, was equally active in control and choreic brain; therefore, increased activity of this enzyme cannot account for the low brain GABA levels in Huntington's chorea.     

Homocarnosinosis: Hypercarnosinuria

Abstract: Homocarnosine (γ-aminobutyrylhistidine) is a brain-specific dipeptide. Homocarnosinosis is a familial metabolic disorder in which spastic paraplegia, progressive mental deficiency, and retinal pigmentation coexist with increased CSF homocarnosine levels, i.e. approximately 20 times higher than the mean control level. In the present study, the urinary excretion of carnosine ( β -alanylhistidine) and anserine ( β -alanyl-1-methylhistidine) was determined in patients with homocarnosinosis and in their close relatives. Both the patients and their relatives were also loaded with chicken meat, which is rich in anserine and carnosine. The results were compared with those obtained in childhood hypercarnosinuria with serum carnosinase deficiency. Somewhat surprisingly, patients with homocarnosinosis were also shown to have hypercarnosinuria. Chicken meat loading in healthy individuals results in increased excretion of carnosine and anserine and, in addition, 1-methylhistidine in the urine. Homocarnosinosis patients and patients with serum carnosinase deficiency also showed an increased excretion of carnosine and anserine, but 1-methylhistidine was not detected in serum carnosinase deficiency, and it was present only in very small amounts in homocarnosinosis. This defect seems to be due to lack of the hydrolyzing enzyme activity. The biochemical and clinical similarities between adult homocarnosinosis and infantile serum carnosinase deficiency are intriguing. A complete insight into the relationship between them must await further investigation.     

REGIONAL DISTRIBUTION OF HOMOCARNOSINE, HOMOCARNOSINE-CARNOSINE SYNTHETASE AND HOMOCARNOSINASE IN HUMAN BRAIN

Homocarnosine (HCarn) content varied over a 6-fold range in different regions of autopsied human brain, being highest in the dentate nucleus and the inferior olive, and lowest in the caudate nucleus and mesolimbic system. HCarn content was similar in biopsied and autopsied frontal cortex. Very little if any carnosine (Carn) was present in human brain, except for the olfactory bulb, where Carn may have comprised 20% of the imidazole dipeptides present. Only HCarn was present in human CSF. HCarn-Carn synthetase enzyme activity in biopsy specimens of human frontal and temporal cortex was approx 10 times greater than has been reported for rat cerebral cortex. The enzyme synthesized Carn 3–5 times as rapidly as HCarn, when β-alanine (β-Ala) or GABA substrate concentrations were 10 MM. The synthetase was found to have an apparent K_m of 1.8 mM for β-Ala, and 8.8 mM for GABA. HCarn-Carn synthetase activity decreases rapidly after brain death, and was not detectable in autopsied brain specimens frozen more than 6 h after patients’deaths. Homocarnosinase activity was determined in brain, using L-[γaminobutyryl-1-¹⁴C]HCarn as substrate, and measuring radioactive GABA produced by hydrolysis of HCarn at pH 7.2 in the presence of Co²⁺ ions. Homocarnosinase activity was similar in biopsied and autopsied human cerebral cortex, and appeared to be stable for at least 10 h after death in unfrozen brain. Differences in the regional distribution of HCarn-Carn synthetase and homocarnosinase activities, as well as regional differences in GABA content in human brain, do not readily account for regional differences in HCarn content, nor do they suggest a physiological role for HCarn.     

Homocarnosinosis: Influence of dietary restriction of histidine

Homocarnosinosis, an inherited disorder, is characterized by an elevated level of the dipeptide homocarnosine (Hca) in the CSF and the brain and, in addition, by carnosinuria and serum carnosinase deficiency. In three children with homocarnosinosis the biochemical abberation co-exists with paraplegia, retinitis pigmentosa, and a progressive mental deficiency. In the mother, however, only the biochemical abberation was present without clinical symptoms. In order to study whether this elevated level of Hca and increased excretion of carnosine (Car) could be reduced towards normal, a dietary regimen with restriction of histidine (His) was maintained for nearly 2 1/2 years for two of the patients, 33 and 39 years old, with homocarnosinosis associated with neurological symptoms. His was reduced by about 90% in the CSF, in the plasma and in the urine. Within 5–6 months CSF Hca was reduced by about 70%, and urinary Car by 22 and 42%. The clinical neurological symptoms, however, did not alter significantly together with these biochemical changes.     

A novel, quantitative assay for homocarnosine in cerebrospinal fluid using stable-isotope dilution liquid chromatography-tandem mass spectrometry

We describe a rapid and sensitive method for the quantification of homocarnosine in physiological fluids, with particular emphasis on cerebrospinal fluid (CSF). Homocarnosine was quantified as the butyl derivative, with (2)H(2)-l-homocarnosine as internal standard. Following deproteinization of CSF samples, supernatants were evaporated to dryness and derivatized with 10% 6M HCl in butanol. Samples were chromatographed on a C(18) column and detected by liquid chromatography-tandem mass spectrometry (LC-MS/MS) operating in the multiple reaction monitoring mode. The intra- and inter-assay variations were 4.6 and 10.9%, respectively. Mean recovery of homocarnosine at two concentrations was 105%. The limit of detection in CSF approximated 20 nmol/L. CSF homocarnosine is age dependent and ranges from <0.02 to 10 micromol/L. Our method is applicable to the analysis of CSF derived from patients with heritable defects in the GABA pathway, patients with homocarnosinosis or serum carnosinase deficiency, and should be applicable to other model systems in order to further explore the biological role and significance of homocarnosine in mammalian systems.     

Homocarnosine in human cerebrospinal fluid: an age-dependent phenomenon

—Homocarnosine, rather than carnosine, is the major imidazole dipeptide present in human CSF. This compound can be readily detected in the CSF of normal infants and young children, while it is either not detectable or is present only in very small concentrations in the CSF of normal adult subjects. Slightly greater amounts of homocarnosine can be found in the CSF of some adults with neurological disorders.     

The basics of preclinical drug development for neurodegenerative disease indications

Background

Because of the emerging intersections of HIV infection and Alzheimer's disease, we examined cerebrospinal fluid (CSF) biomarkers related of amyloid and tau metabolism in HIV-infected patients.

Methods

In this cross-sectional study we measured soluble amyloid precursor proteins alpha and beta (sAPPα and sAPPβ), amyloid beta fragment 1-42 (Aβ_1-42), and total and hyperphosphorylated tau (t-tau and p-tau) in CSF of 86 HIV-infected (HIV+) subjects, including 21 with AIDS dementia complex (ADC), 25 with central nervous system (CNS) opportunistic infections and 40 without neurological symptoms and signs. We also measured these CSF biomarkers in 64 uninfected (HIV-) subjects, including 21 with Alzheimer's disease, and both younger and older controls without neurological disease.

Results

CSF sAPPα and sAPPβ concentrations were highly correlated and reduced in patients with ADC and opportunistic infections compared to the other groups. The opportunistic infection group but not the ADC patients had lower CSF Aβ_1-42 in comparison to the other HIV+ subjects. CSF t-tau levels were high in some ADC patients, but did not differ significantly from the HIV+ neuroasymptomatic group, while CSF p-tau was not increased in any of the HIV+ groups. Together, CSF amyloid and tau markers segregated the ADC patients from both HIV+ and HIV- neuroasymptomatics and from Alzheimer's disease patients, but not from those with opportunistic infections.

Conclusions

Parallel reductions of CSF sAPPα and sAPPβ in ADC and CNS opportunistic infections suggest an effect of CNS immune activation or inflammation on neuronal amyloid synthesis or processing. Elevation of CSF t-tau in some ADC and CNS infection patients without concomitant increase in p-tau indicates neural injury without preferential accumulation of hyperphosphorylated tau as found in Alzheimer's disease. These biomarker changes define pathogenetic pathways to brain injury in ADC that differ from those of Alzheimer's disease.     

Evidence of Glutamatergic Denervation and Possible Abnormal Metabolism in Alzheimer''s Disease

Excitatory dicarboxylic amino acids previously have been ascribed several functions in the brain. Here their total concentration and proposed neurochemical markers of neurotransmitter function have been measured in brain from patients with Alzheimer's disease (AD) and controls. Specimens were obtained antemortem (biopsy) approximately 3 years after emergence of symptoms and promptly (less than 3 h) postmortem some 10 years after onset. Early in the disease a slight elevation in aspartic acid concentration of cerebral cortex was observed in the patients with AD. A reduction in glutamic acid concentration of a similar magnitude was found. It is argued that this, together with a decrease in CSF glutamine content and lack of change in the phosphate-activated brain glutaminase activity of tissue, reflects an early metabolic abnormality. Later in the disease evidence of glutamatergic neurone loss is provided by the finding that in many regions of the cerebral cortex the Na+-dependent uptake of D-[3H]aspartic acid was almost always lowest in AD subjects compared with control when assessed by a method designed to minimise artifacts and epiphenomena. Release of endogenous neurotransmitters from human brain tissue postmortem did not appear to have the characteristics of that from human tissue antemortem and rat brain.     

Human CSF GABA Concentrations: Revised Dowd for Controls, but Not Decreased in Huntington''s Chorea

gamma-Aminobutyric acid (GABA) concentrations were measured in CSF specimens from two large groups of control subjects, one without neurological or psychiatric disease, and one with a variety of neurological disorders not known to involve altered GABAergic function in brain. CSF GABA was also measured in patients with Huntington's chorea and in patients with other choreiform disorders. GABA was measured in CSF by a modification of the ion exchange-fluorometric method that featured use of a relatively large cation exchange column, and a markedly decreased quantity of sulfosalicylic acid for deproteinization of CSF. Mean BABA concentrations in CSF were 87 and 77 nmol/liter for neurologically normal and abnormal control subjects, 82 nmol/liter for the Huntington's chorea patients, and 105 nmol/liter for patients with other forms of chorea. The mean concentration of homocarnosine was not reduced in CSF of Huntington's chorea patients as compared with controls. Mean CSF GABA concentrations found in control subjects were less than half the lowest control means previously reported. These low values are attributable in part to a reduction in on-column hydrolysis of conjugated forms of GABA in CSF, which can be produced by excessive sulfosalicylic acid, and in part to improved chromatographic resolution of GABA from other unknown o-phthalaldehyde-reactive compounds in CSF. Analysis of free GABA in CSF does not appear useful for diagnosis of suspected Huntington's chorea, nor as a possible predictive test for persons genetically at risk for Huntington's chorea.     

Cerebrospinal fluid S-100 protein levels in neurological pathologies

The aim of this paper was to evaluate S-100 concentration in cerebrospinal fluid (CSF) from patients with different neurological disorders, and in subjects with no proven neurological pathology, in order to study possible differences in their protein concentrations. The total number of patient-samples examined was 119 (58 males and 61 females; mean age 35 yrs, 1-79 yrs). Based on the final diagnoses, nine patient groups were studied: a control group, meningitis, acute lymphatic leukemia (ALL), dementia, hydrocephalia, polyneuropathy-motor neuron disease, acute cerebral infarction (ACI), and patients diagnosed with multiple sclerosis. S-100 protein concentrations were measured by the Sangtec 100 two-site immunoradiometric assay. The highest S-100 levels in CSF were found in the dementia group, ACI group, bacterial-fungal and lymphocytic meningitis groups (Kruskal-Wallis test). The S-100 concentrations in these groups were significantly higher compared with the control group (Mann-Whitney U test, p<0.05, p<0.01) and the multiple sclerosis group (p<0.05, p<0.01). No other significant differences were found between groups. Our results suggest that the high protein levels in CSF found in these pathologies may reflect the presence of brain damage. However, the levels need to be considered individually, as they depend on several factors, such as age, severity of brain damage or interval between the onset of brain damage and the taking of the sample.     

Region-Selective Decreases in Densities of [3H]Tryptamine Binding Sites in Autopsied Brain Tissue from Cirrhotic Patients with Hepatic Encephalopathy

Abstract: The distribution of [³H]tryptamine binding sites, in autopsied brain tissue from cirrhotic patients with hepatic encephalopathy (HE) and an equal number of age-matched control subjects free from hepatic, neurological, or psychiatric disorder, was investigated. Scatchard analysis demonstrated a heterogeneous distribution for this binding site, with the highest density being observed in hippocampus ≫ frontal cortex = caudate nucleus > temporal cortex = cerebellum. When comparing [³H]-tryptamine binding site densities in control brain tissue with that in brain tissue from patients with HE, significant decreases in densities were observed in the frontal cortex (by 56%, p < 0.001), hippocampus (by 43%, p < 0.001), and caudate nucleus (by 41%, p < 0.01) of the HE group. Binding site affinities were within normal limits. The findings of decreased densities of [³H]tryptamine binding sites taken in conjunction with previous reports of increased CSF and brain tryptamine concentrations in HE suggest a pathogenic role for this neuroactive amine in HE resulting from chronic liver failure.     

FREE AMINO ACIDS AND RELATED COMPOUNDS IN FIVE REGIONS OF BIOPSIED CAT BRAIN

Abstract— Contents (μmol/g wet wt.) of 34 free amino acids and related compounds were measured in grey matter from three areas of cerebral cortex, from the cerebellum, and from the caudate nucleus in unanaesthetized cats with classical cerveau isolé preparations. Brain specimens were frozen in liquid nitrogen within 10 s of removal; thus, the values found were expected to approximate those which occur in living cat brain. Levels of most of the compounds measured were lower than those previously reported for the cat. In the case of GABA, alanine, and ethanolamine, the lower values found seemed attributable to the rapid freezing of brain tissue, and may more closely approximate levels occurring in living cat brain. On the other hand, the relatively low levels of aspartic and glutamic acids found may have resulted from use of the cerveau isolé preparation. Little difference in levels of amino compounds was found among the three cerebral cortical areas examined. However, there were significant differences in the contents of a number of amino acids between cerebral cortex and the cerebellum or caudate nucleus. These differences resembled those previously observed in autopsied human brain. The content of GABA was two-fold higher in biopsied cat cortex than in biopsied human cortex, whereas the content of cystathionine was only 10 per cent of that in human cortex. Homocarnosine and α-(γ-aminobutyryl)-lysine, two GABA-containing dipeptides found in relatively large amounts in human brain, were not detectable in cat brain. Living cat brain contained two amino acids not previously reported for this species:putreanine and ɛ- N -methyllysine.     

Dementia of the Alzheimer Type: An Oral and Biochemical Study1

Alzheimer's disease, or pre-senile dementia, may occur as early as 40 years. Pathologically, there is, besides a loss of brain weight, a conical atrophy with ventricular dilatation and typical microscopic lesions in the cortex and the hippocampus. Previously, the authors [Sanchez & Gonzalez, 1986] have studied the modifications of the amino acids (AA) composition in the cerebrospinal fluid (CSF), Even if some were increased without specificity, three of them were decreased significantly in this type of dementia (Serine, Glutamate and Aspartate). Twenty subjects were studied (15 with Alzheimer's disease and 5 non-patients) having a mean age of 72 years. For each subject, two samples were tested (one blood and one saliva sample). In this study we tried to determine if our results would be similar to those previously obtained in the CSF, but in a different biological fluid, the saliva. Of the 13 AA of the saliva, tested by gas-liquid chromatology (Spectra Physics 7100), 3 were increased significantly, and curiously, these were similar to those found to be decreased in CSF. We attempted to find the possible biological and oral repercussions of this dementia, which is the most frequent type in elderly patients.     

REGIONAL AND SUBCELLULAR DISTRIBUTION OF HOMOCARNOSINE–CARNOSINE SYNTHETASE IN THE CENTRAL NERVOUS SYSTEM OF RATS

Homocarnosine–carnosine synthetase and carnosinase were assayed in homogenates, 100,000 g supernatants, and ammonium sulfate fractions of the supernatants from nine regions of the central nervous system (CNS), as well as subcellular fractions of whole brains. The enzymes were detected in all CNS regions tested, with olfactory bulbs having the highest activities of both enzymes. In the subcellular fractions, the synthetase was found mainly in the cell-sap; carnosinase was detected in all fractions, the highest activity being in the mitochondria. The synthetases from olfactory bulbs, cerebellum and spinal cord have similar K_m's for β-alanine and GABA.     

Neurochemical abnormality in I-cell disease: chemical analysis and a possible importance of beta-galactosidase deficiency.

Sphingolipid composition in both gray and white matter of a patient with I-cell disease was normal except for the higher proportion.of G_MI-ganglioside in gray and white matter. In the patient's liver and kidney there was a significant accumulation of ceramide dihexoside and ceramide trihexoside and of sulphatide in kidney. Non-lipid hexosamine and sialic acid concentration in brain was increased 1.2-1.5 times above normal. Recovery of myelin from I-cell's white matter was 80-100%, suggesting that demyelination, if present, is minimal. Myelin lipid and myelin specific glycoprotein patterns were normal. Except for β-galactosidase activity the activity of other brain lysosomal enzymes were within the normal range. This finding was similar to that of Hurler's syndrome. Only β-galactosidase activity was reduced to less than 10% of normal in the patient's brain. To examine the possible metabolic significance of β-galactosidase deficiency in I-cell disease the physical characteristics of this enzyme, isolated from tissues from I-cell, Hurler and control patients, were compared using isoelectric focusing, Con A-Sepharose and Sephadex G-150 chromatography. The isoelectric point and the binding affinity of I-cell β-galactosidase with Con A-Sepharose was comparable to normal. However, the isoenzyme patterns of brain and liver I-cell β-galactosidase with Sephadex G-150 gel filtration revealed decreased acid β-galactosidase. Effects of the addition of sodium chloride on each fraction of β-galactosidase isoenzymes isolated from I-cell tissues were markedly different from controls, whereas the pH optimum of these enzymes were similar to normal. These enzyme characteristics in I-cell tissues were different from normal and Hurler's syndrome. These findings suggest that β-galactosidase deficiency in I-cell disease is a more specific phenomenon rather than secondary inhibition as found in the mucopolysaccharidoses and thus may have an important role for the pathogenesis of brain damage and disease occurrence.     

Real-time fMRI Biofeedback Targeting the Orbitofrontal Cortex for Contamination Anxiety

We present a method for training subjects to control activity in a region of their orbitofrontal cortex associated with contamination anxiety using biofeedback of real-time functional magnetic resonance imaging (rt-fMRI) data. Increased activity of this region is seen in relationship with contamination anxiety both in control subjects¹ and in individuals with obsessive-compulsive disorder (OCD),² a relatively common and often debilitating psychiatric disorder involving contamination anxiety. Although many brain regions have been implicated in OCD, abnormality in the orbitofrontal cortex (OFC) is one of the most consistent findings.^{3, 4} Furthermore, hyperactivity in the OFC has been found to correlate with OCD symptom severity⁵ and decreases in hyperactivity in this region have been reported to correlate with decreased symptom severity.⁶ Therefore, the ability to control this brain area may translate into clinical improvements in obsessive-compulsive symptoms including contamination anxiety. Biofeedback of rt-fMRI data is a new technique in which the temporal pattern of activity in a specific region (or associated with a specific distributed pattern of brain activity) in a subject''s brain is provided as a feedback signal to the subject. Recent reports indicate that people are able to develop control over the activity of specific brain areas when provided with rt-fMRI biofeedback.^7-12 In particular, several studies using this technique to target brain areas involved in emotion processing have reported success in training subjects to control these regions.^13-18 In several cases, rt-fMRI biofeedback training has been reported to induce cognitive, emotional, or clinical changes in subjects.^{8, 9, 13, 19} Here we illustrate this technique as applied to the treatment of contamination anxiety in healthy subjects. This biofeedback intervention will be a valuable basic research tool: it allows researchers to perturb brain function, measure the resulting changes in brain dynamics and relate those to changes in contamination anxiety or other behavioral measures. In addition, the establishment of this method serves as a first step towards the investigation of fMRI-based biofeedback as a therapeutic intervention for OCD. Given that approximately a quarter of patients with OCD receive little benefit from the currently available forms of treatment,^20-22 and that those who do benefit rarely recover completely, new approaches for treating this population are urgently needed.     

Cerebrospinal fluid: A unique source of circulating tumor DNA with broad clinical applications

Malignancies involving the central nervous system present unique challenges for diagnosis and monitoring due to the difficulties and risks of direct biopsies and the low specificity and/or sensitivity of other techniques for assessment. In recent years, liquid biopsy of the cerebrospinal fluid (CSF) has emerged as a convenient alternative that combines minimal invasiveness with the ability to detect disease-defining or therapeutically actionable genetic alterations from circulating tumor DNA (ctDNA). Since CSF can be obtained by lumbar puncture, or an established ventricular access device at multiple time points, ctDNA analysis enables initial molecular characterization and longitudinal monitoring throughout a patient's disease course, promoting optimization of treatment regimens.This review outlines some of the key aspects of ctDNA from CSF as a highly suitable approach for clinical assessment, the benefits and drawbacks, testing methods, as well as potential future advancements in this field. We anticipate wider adoption of this practice as technologies and pipelines improve and envisage significant improvements for cancer care.     

REGIONAL BRAIN LEVELS OF γ-HYDROXYBUTYRATE IN HUNTINGTON''S DISEASE

A highly sensitive electron capture gas chromatographic method was developed for quantitation of γ-hydroxybutyrate (GHB) in tissue. This method involves an improved, extraction and purification procedure and a one-step derivatization of GHB to the methyl ester-O-heptafluorobutyrate. As low as 5 ng of GHB in tissue was accurately quantitated by this method. By means of this improved method, endogenous levels of GHB in several regions of brains obtained post-mortem from patients with Huntington's disease were determined, and compared with brain samples obtained post-mortem from non-neurological controls. The levels of GHB found in the caudate and substantia nigra obtained from Huntington's patients were significantly higher than the GHB levels found in similar regions of brain obtained from a non-neurological control group. The content of GABA in the same choreic and control brain samples was also determined. No significant correlation between changes in GHB and GABA levels was observed although there was a trend towards an inverse relationship. The high level of GHR in Huntington's disease may be related to the decrease in succinate:oxidoreductase (EC 1.3.99.1) activity reported by Stahl & Swanson (1974). In two subjects (one control and one Huntington patient) the zonal distribution of GHB in substantia nigra was also determined. The zona reticulata from choreic brain contained a substantially higher level of GHB, whereas the zona compacta contained an amount similar to the level found in control brain.     

Deficient Liver Biosynthesis of Docosahexaenoic Acid Correlates with Cognitive Impairment in Alzheimer's Disease

Reduced brain levels of docosahexaenoic acid (C22:6n-3), a neurotrophic and neuroprotective fatty acid, may contribute to cognitive decline in Alzheimer''s disease. Here, we investigated whether the liver enzyme system that provides docosahexaenoic acid to the brain is dysfunctional in this disease. Docosahexaenoic acid levels were reduced in temporal cortex, mid-frontal cortex and cerebellum of subjects with Alzheimer''s disease, compared to control subjects (P = 0.007). Mini Mental State Examination (MMSE) scores positively correlated with docosahexaenoic/α-linolenic ratios in temporal cortex (P = 0.005) and mid-frontal cortex (P = 0.018), but not cerebellum. Similarly, liver docosahexaenoic acid content was lower in Alzheimer''s disease patients than control subjects (P = 0.011). Liver docosahexaenoic/α-linolenic ratios correlated positively with MMSE scores (r = 0.78; P<0.0001), and negatively with global deterioration scale grades (P = 0.013). Docosahexaenoic acid precursors, including tetracosahexaenoic acid (C24:6n-3), were elevated in liver of Alzheimer''s disease patients (P = 0.041), whereas expression of peroxisomal d-bifunctional protein, which catalyzes the conversion of tetracosahexaenoic acid into docosahexaenoic acid, was reduced (P = 0.048). Other genes involved in docosahexaenoic acid metabolism were not affected. The results indicate that a deficit in d-bifunctional protein activity impairs docosahexaenoic acid biosynthesis in liver of Alzheimer''s disease patients, lessening the flux of this neuroprotective fatty acid to the brain.     

FREE AMINO ACIDS AND RELATED COMPOUNDS IN BIOPSIES OF HUMAN BRAIN

Abstract— Contents (μmol/g wet wt.) of 35 free amino acids and related compounds were measured in biopsies of human brain from ten patients. Brain specimens were frozen in liquid nitrogen within 10 sec of their removal at neurosurgery; thus, the values found should approximate those which occur in living brain.
Levels in free pools of biopsied cerebral cortex of most of the amino acids that are constituents of proteins were only 20-50 per cent of those found in autopsied cortex. The content of cystine and ethanolamine was much lower in biopsied than in autopsied cortex. Concentrations of GABA in biopsied cortex were only 20 per cent as high as those found in autopsied cortex, and levels of γ-aminobutyryl dipeptides were also significantly lower in biopsied cortex. Amounts of cystathionine in biopsied cortex varied markedly, but averaged much higher than in autopsied cortex; a single biopsy specimen of cerebellar grey matter had a cystathionine content 36-fold greater than the mean found in autopsied cerebellum.
Appreciable variability in contents among cortical biopsies was found for glycerophosphoethanolamine, phosphoethanolamine, ethanolamine, taurine, aspartic acid, glutamic acid, glutamine, and GABA, as well as for cystathionine. Whether this variability occurred between different subjects, or between different cortical areas, was not clear, although the former possibility was suggested by findings in multiple cortical biopsies from one patient.