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Background: Maternal diet plays a beneficial role in the health, including the neurodevelopment, of offspring. Insufficient fibre consumption among the general population has increased concern about neurocognitive diseases. However, the association between maternal low-fibre diet (MLFD) and neurocognitive function in offspring is still unclear., Methods: Mice were fed diets containing diverse levels of fibre or administered short-chain fatty acids (SCFAs) during gestation. The neurocognitive functions of the offspring and synaptic plasticity-related protein levels were measured. Gene expression was disrupted by siRNA interference. Samples from pregnant women and paired umbilical cord blood (UCB) samples were analysed by the general linear model., Results: We found that MLFD impaired cognitive function and synaptic plasticity in offspring and that the impairments were reversed by butyrate intake but not propionate intake. Mechanistic studies showed that histone deacetylase (HDAC)-4 is the most likely mediator of butyrate-dependent neurocognitive improvement. In addition, using human maternal serum and paired UCB samples, we demonstrated that SCFA levels in offspring were positively correlated with levels in the maternal serum., Conclusion: These results provide solid evidence that fibre in the maternal diet regulates neurocognitive functions in offspring through altering SCFA levels and supports the use of SCFA-dependent perinatal intervention for improving offspring health in the clinic., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Investigations of Alzheimer's disease (AD), traumatic brain injury (TBI), and related brain disorders have provided extensive evidence for involvement of cathepsin B, a lysosomal cysteine protease, in mediating the behavioral deficits and neuropathology of these neurodegenerative diseases. This review integrates findings of cathepsin B regulation in clinical biomarker studies, animal model genetic and inhibitor evaluations, structural studies, and lysosomal cell biological mechanisms in AD, TBI, and related brain disorders. The results together indicate the role of cathepsin B in the behavioral deficits and neuropathology of these disorders. Lysosomal leakage occurs in AD and TBI, and related neurodegeneration, which leads to the hypothesis that cathepsin B is redistributed from the lysosome to the cytosol where it initiates cell death and inflammation processes associated with neurodegeneration. These results together implicate cathepsin B as a major contributor to these neuropathological changes and behavioral deficits. These findings support the investigation of cathepsin B as a potential drug target for therapeutic discovery and treatment of AD, TBI, and TBI-related brain disorders., Competing Interests: Declaration of Competing Interest None, (Copyright © 2020 Elsevier B.V. All rights reserved.)

The imbalance between MMPs and TIMPs is associated with the HIV dissemination tissue damage pathology neurodegenerative disorders, including HAND. Genetic variations in the TIMP gene may modulate the neurocognitive disorder in HIV patients. Hence, we evaluated the genetic variants of TIMP -2 ( - 418G/C, 303G/A) gene with the risk of HAND. Genotyping of TIMP -2 polymorphism was performed in 50 patients with HAND, 100 no HAND, and 154 healthy controls by PCR-RFLP. TIMP-2 -418GC and 303AA genotypes represented a predominant risk for HAND severity (OR = 1.55, P = 0.30; OR = 4.58, P = 0.24). The variant -418CC genotype, -418A allele, had exhibited a significant risk for the acquisition of HAND (OR = 12.55, P = 0.026; OR = 2.66, P = 0.004). TIMP-2 303GA, 303AA genotype, and 303A allele evinced a higher risk for HAND severity (OR = 1.82, P = 0.14; OR = 1.70, P = 0.63; and OR = 1.68, P = 0.12). In HIV patients, TIMP-2 -418CC genotype and -418C allele significantly occurred in comparison to healthy controls (OR = 10.10, P = 0.006; OR = 2.02, P = 0.009). In the intermediate and early HIV disease stage, TIMP-2 -418CC genotype was significantly increased compared with healthy controls (11.1% vs. 1.3%, OR = 14.63, P = 0.01; 16.9% vs. 1.3%, OR = 14.51, P = 0.002). In patients with HAND among tobacco and alcohol users, TIMP-2 -418CC genotype displayed a risk for HAND severity (OR = 3.96, P = 0.26; OR = 4.83, P = 0.19). On multivariate logistic regression, TIMP-2 303AA genotype, advanced stage, and gender had a risk for HAND severity (OR = 28.98, P = 0.02; OR = 2.35, P = 0.070; and OR = 2.36, P = 0.04). In conclusion, TIMP-2 -418G/C polymorphism independently, along with alcohol and tobacco, may have an impact on the acquisition of HAND and its severity. TIMP-2 303G/A polymorphism bare a risk for HAND severity.

Remodeling of extracellular matrix (ECM) by matrix metalloproteinases (MMPs) is a presumed reason for the development of HIV-associated neurocognitive disorders (HAND). The coding region polymorphism in MMP-21 572C/T gene may have a potential functional effect on ECM remodeling. Hence, we aimed to examine the association of MMP-21 polymorphism with the modulation of HAND severity and its prevalence in HIV-infected and healthy individuals. Genotyping of MMP-21 572C/T polymorphism was performed by PCR-RFLP in total 150 HIV-infected individuals, 50 with HAND, 100 without HAND and 150 healthy controls. MMP-21 572TT genotype was predominantly higher in HAND patients compared with no HAND (OR = 1.63, p = 0.57). MMP-21 572T allele was associated with reduce risk for HAND severity (OR = 0.50, p = 0.04). Similarly, MMP-21 572TT genotype underrepresented in HIV-infected individuals compared to healthy controls (3.0% vs 6.7%, OR = 0.27, p = 0.08). MMP-21 572CT genotype and early HIV disease stage showed a higher risk for the advancement of HIV disease with marginal significance (OR = 1.89, p = 0.07). MMP-21 572CT genotype increased the risk for the modulation of HAND severity in tobacco users (OR = 1.98, p = 0.43). MMP-21 572CT genotype among tobacco and alcohol users showed elevated risk for the development of HAND in HIV-infected individuals (OR = 2.30, p = 0.15; OR = 1.86, p = 0.23). Similarly, MMP-21 572TT genotype enhanced the risk for the development of HAND in tobacco users (OR = 3.48, p = 0.40). In conclusion, the presence of coding region 572T allele may have protection for HAND severity. MMP-21 572C/T polymorphism and tobacco and alcohol usage may facilitate the development of HAND., (© 2018 APMIS. Published by John Wiley & Sons Ltd.)

Senescence is a phenomenon characterized by a progressive decline of body homeostasis. Premature senescence acts when the cellular system is not able to adequately respond to noxious stimuli by synthesis of stressor molecules. Among those, serum-and-glucocorticoidinducible kinase-1 (SGK-1) dramatically increases under typical physiopathological conditions, such as glucocorticoid or mineralcorticoids exposure, inflammation, hyperglycemia, and ischemia. SGK-1 has been implicated in mechanism regulating oxidative stress, apoptosis, and DNA damage, which are all leading to a state of accelerating aging. Moreover, SGK-1-sensitive ion channels participate in the regulation of renal Na(+)/K(+) regulation, blood pressure, gastric acid secretion, cardiac action potential, and neuroexcitability. Recently, we demonstrated in endothelial cells as an increase in SGK-1 activity and expression reduces oxidative stress, improves cell survival and restores insulin-mediated nitric oxide production after hyperglycemia. Moreover, we showed as SGK-1 delays the onset of senescence by increasing telomerase activity, significantly decreasing reactive oxygen species (ROS) production, and by directly interacting with hTERT. Therefore, SGK-1 may represent a specific target to further develop novel therapeutic options against chronic diseases such as diabetes typical of aging. SGK-1 has been also associated with cancer, neurodegenerative diseases, and cardiovascular disease, among other age-related diseases. However, to date, the data available on SGK-1 and aging, are sparse, controversial, and only from C. elegans experimental models. In this review we sought to discuss the possible implication of SGK-1 in mechanisms regulating senescence and age-related diseases. Moreover, we aimed to discuss and identify the possible role of SGK-1 as possible molecular target to counteract and prevent aging.

Antiretroviral therapy has revolutionized the treatment of the human immunodeficiency virus because it has improved the clinical outcomes of patients. It is essential that these drugs cross the blood-brain barrier, since the virus is present in the central nervous system (CNS). Efavirenz passes through this barrier satisfactorily and can reduce the deleterious central effects of the human immunodeficiency virus. However, patients treated with efavirenz have been observed to experience psychiatric symptoms such as mania, depression, suicidal thoughts, psychosis, and hallucinations. The aim of this review is to describe the pharmacokinetic and pharmacodynamic properties of efavirenz and its major neuropsychiatric symptoms and the neurochemical pathways associated with these changes in the CNS. The databases Medline and Lilacs were used to search for review articles and preclinical and clinical research articles published from January 1996 to 2010. The search terms used were efavirenz, central nervous system, neuropsychiatry, neurotransmitters, adverse effects, and neurochemistry. Subject categories considered included effects on viral replication, pharmacokinetic and pharmacodynamic properties of efavirenz, and neuropsychiatric adverse effects including time course, duration, and probable mechanisms involved. The mechanisms involved in these changes include interference with cytochrome P450 enzymes, cytokines, tryptophan-2-3-dioxygenase, and brain creatine kinase.

Group I p21-activated kinases are a family of key effectors of Rac1 and Cdc42 and they regulate many aspects of cellular function, such as cytoskeleton dynamics, cell movement and cell migration, cell proliferation and differentiation, and gene expression. The three genes PAK1/2/3 are expressed in brain and recent evidence indicates their crucial roles in neuronal cell fate, in axonal guidance and neuronal polarisation, and in neuronal migration. Moreover they are implicated in neurodegenerative diseases and play an important role in synaptic plasticity, with PAK3 being specifically involved in mental retardation. The main goal of this review is to describe the molecular mechanisms that govern the different functions of group I PAK in neuronal signalling and to discuss the specific functions of each isoform.

Sex differences in the genetic epidemiology and clinical features of psychiatric disorders are well recognized, but the individual genes contributing to these effects have rarely been identified. Catechol-O-methyltransferase (COMT), which metabolizes catechol compounds, notably dopamine, is a leading candidate. COMT enzyme activity, and the neurochemistry and behavior of COMT null mice, are both markedly sexually dimorphic. Genetic associations between COMT and various psychiatric phenotypes frequently show differences between men and women. Many of these differences are unconfirmed or minor, but some appear to be of reasonable robustness and magnitude; eg the functional Val(158)Met polymorphism in COMT is associated with obsessive-compulsive disorder in men, with anxiety phenotypes in women, and has a greater impact on cognitive function in boys than girls. Sex-specific effects of COMT are usually attributed to transcriptional regulation by estrogens; however, additional mechanisms are likely to be at least as important. Here we review the evidence for a sexually dimorphic influence of COMT upon psychiatric phenotypes, and discuss its potential basis. We conclude that despite the evidence being incomplete, and lacking a unifying explanation, there are accumulating and in places compelling data showing that COMT differentially impacts on brain function and dysfunction in men and women. Since sex differences in the genetic architecture of quantitative traits are the rule not the exception, we anticipate that additional evidence will emerge for sexual dimorphisms, not only in COMT but also in many other autosomal genes.

Elevation of serum creatine kinase (CK) concentrations occurs almost invariably in neuroleptic malignant syndrome (NMS). However, the role of CK levels in the diagnosis of the syndrome remains controversial. This study measured CK levels in patients who became pyrexial while on psychotropic medication and thereby mimicked some of the features of NMS. In all of these cases a diagnosis of infectious illness was made and patients responded to appropriate antibiotic therapy without alteration in psychotropic medication. Two other groups were studied for comparison--patients on psychotropics who were apyrexial and patients who became pyrexial but were not on psychotropics. Significant, unexpected elevations of CK were documented in 70% of those patients who became pyrexial while on psychotropics--in three cases elevation of concentrations to more than 1000 IU/l (ten times reference value) were found. Thirty per cent of patients who became pyrexial but were not on psychotropics also developed elevation of CK but this was of a much smaller magnitude (< 200 IU/l in five out of six cases). The results of the study suggest that elevation of CK is a non-specific finding, particularly in patients who become pyrexial on psychotropics. Use of CK as a diagnostic criterion may lead to overdiagnosis of NMS.

A frequently used method to assess cellular dysfunction and damage in humans is to document the presence of uniquely intracellular proteins in extracellular spaces. Thus, increased plasma levels of transaminases generally reflect hepatocellular damage (Lieber 1978), increases in the cardiac fractions of creatine kinase (CK, or CPK for creatine phosphokinase) or lactate dehydrogenase (LDH) are diagnostic for myocardial infarction (Armstrong et al. 1979; 1982), and increases of skeletal muscle fractions of CK may indicate myopathy (Goto 1974; Ford 1984). Similarly, a number of enzymes and proteins serve as tumor markers in a variety of malignant cancer (e.g., Concannon et al. 1974; Foti et al. 1977).

It has been well-known for at least 100 years that both hypo- and hyperthyroidism may cause almost any psychiatric symptom, depending on the severity of the illness. No thyroid disorder, however, induces symptoms that are specific for a psychiatric disorder. Laboratory tests show depressed patients to be euthyroid. Any abnormalities that have been found, such as slightly elevated T4 levels or decreased T3 or TSH concentrations, have frequently failed to be replicated and do not fit any endocrinological diagnosis. They could reflect either "intervening factors" such as stress, methodological problems or a disturbance of central thyroid hormone metabolism. All antidepressant therapies (antidepressant drugs, carbamazepine, lithium, electroconvulsive therapy and sleep deprivation) have a marked influence on peripheral thyroid hormone levels. In particular, decreases in serum T4 and rT3 levels are often correlated to antidepressant response, suggesting that an effect on central thyroid hormone metabolism is involved in the as yet unknown mechanism of action of these therapies. Indeed, animal studies have shown that antidepressants do affect deiodinase activities and T3 and T4 concentrations in rat brain. However, the effects are highly area specific and dependent on the drug administered and the time of day at which the investigation was conducted. Although the mechanism of thyroid hormone action on CSF signal transduction is as yet unknown, effects on "general CNS functions" such as second messengers, G-proteins or calcium homeostasis seem more likely than specific effects on the different receptor systems.

Out of 100 psychotic patients who underwent neurobiochemical examination, in 24 cases activity of phenylalanine hydroxylase in the thrombocytes was found to be absent. 38% of these cases were susceptible to stimulation in vitro by means of folic acid derivative, without actually reaching a normal level of activity. The patients are presented first as a homgeneous group, then in the two major diagnostic divisions, and divided according to the biochemical data. An account is given of early experiences in the treatment of the more intractable cases.

Previous studies have suggested that arylsulphatase A (ASA - the biochemical marker of metachromatic leucodystrophy) deficiency may be present in a sizeable proportion of patients with chronic psychosis. This study surveyed leucocyte ASA activity in a group of chronic psychotic patients and compared ASA activity in 3 subgroups fulfilling Research Diagnostic Criteria for schizophrenia (undifferentiated), paranoid schizophrenia and schizoaffective psychosis. Three of 45 patients had significantly reduced ASA activity but none had metachromatic leucodystrophy. Although ASA levels did not differ significantly between the groups, schizophrenics without a family history of schizophrenia had significantly lower ASA levels than those with. The implications of these findings are discussed.

A study was made of the activity of the cerebral form of glutamate dehydrogenase (GDH) in 59 patients suffering from vegetative paroxysms (VP), 8 patients with multiple sclerosis and 15 normal test subjects. As compared to the normal test subjects, the patients with VP manifested higher activity and lability of the enzyme. The patients with VP demonstrating the "labile" and "stable" enzyme were subjected to a clinicopsychological analysis which revealed a graver disease course and more pronounced anxiety in the group with the "stable" enzyme. The role of GDH in the pathogenesis of VP is under discussion.

We have previously reported that the activity in platelets of the important antioxidant enzyme glutathione peroxidase (GPx) is inversely correlated with computed tomographic (CT) measures of brain atrophy in a population of patients with chronic schizophrenia, suggesting that low GPx may be a vulnerability factor in those schizophrenic patients with structural brain abnormalities. The significance of this finding has now been explored in a larger clinical population by examining the relation of GPx and CT parameters to psychosocial variables and to the activity of platelet monoamine oxidase (MAO), which has also been reported to be altered in certain schizophrenic populations. In the present study, low platelet GPx and high brain atrophy were found to be associated with DSM-III diagnoses of nonparanoid schizophrenia, a high degree of chronicity, and a predominance of negative symptoms. Contrary to some literature reports, atrophy also correlated with age and length of illness among the schizophrenic patients, although the contribution of these factors was less than that of low GPx, which was itself not age dependent. The ventricle-brain ratio (VBR) and atrophy were highly correlated in a control group of affective disorder patients, but not in the schizophrenic group, where large VBRs were found predominantly in the DSM-III undifferentiated subgroup. The low-GPx/high-atrophy schizophrenic patients had normal platelet MAO levels, and MAO was significantly lower only in the paranoid subgroup, consistent with reported observations. There was no evidence for a neuroleptic-induced effect on either enzyme.

This is a report of the initial results of determinations of the creatine kinase activity in the serum of forty psychiatric and twenty-five neurological patients. A determination of the creatine kinase activity made in the first days of an acute endogenous psychosis invariably showed an increase in creatine kinase which returned to normal values after eight to fourteen days. Patients with residual schizophrenia, conditions of acute excitation accompanying psychopathy, and abnormal personality or circumscribed paranoid development showed creatine activity in the range of normal values. Alcoholics with incipient or strongly marked delirium tremens showed normal creatine kinase activity in those cases where the situation was not complicated by additional traumata or other accompanying diseases.

Plasma glutamate decarboxylase (GAD) activity was measured in patients with endogenous psychoses and neurologic diseases. Unmedicated schizophrenic patients showed no difference in plasma GAD levels compared to controls. Administration of neuroleptics together with anticholinergic agents increased plasma GAD activity in schizophrenic patients. Compared to controls, patients with major depression and bipolar illness showed significantly lower GAD activity. No effect of antidepressants and minor tranquilizers on plasma GAD activity was found. Relatively lower GAD activity was shown in neurotic patients. The enzyme activity in plasma of patients with Huntington's chorea (HC) was lower than control levels. The plasma GAD concentrations correlated with cerebrospinal fluid concentrations in five HC patients.

Recently, reduced platelet monoamine oxidase (MAO) activity was demonstrated in two cases of paranoid schizophrenia exhibiting Capgras' syndrome. The present authors report platelet MAO studies in an additional patient with the Delusion of Doubles. In this case, one of delusional hyperidentification (false recognition), decreased platelet MAO activity compared with normal controls was detected. The patient, while not schizophrenic, showed platelet MAO activity comparable with that of a chronic schizophrenic control group. The possible significance of the findings are discussed.

This paper reviews and correlates three separate recent findings that implicate the one-carbon cycle in neuropsychiatric disease: (i) the demonstration by kinetic studies that the Vmax of methionine adenosine transferase (MAT) is reduced in some schizophrenics and depressives and is increased in some manics, and that the activity of serine hydroxymethyltransferase (SHMT) is reduced in a further subpopulation of schizophrenics; (ii) the demonstration that S-adenosylmethionine (the product of MAT) is an effective clinical antidepressant; and (iii) the reports that L-methionine is an effective treatment for certain of the symptoms of Parkinson's disease. These clinical findings may be correlated with recent findings that transmethylation reactions (lipid and carboxymethylation) play an important role in synaptic events (coupling of receptors to adenylate cyclase and release of neurotransmitters).

A family is described in which adult-onset Gaucher's disease developed, followed years later by atypical psychotic disorders with neurologic and electroencephalographic abnormalities. A biochemical investigation of primary and secondary enzyme alterations in the index case was performed in an attempt to identify a pattern that might be specific to this clinical profile. The literature pertaining to CNS involvement in adult patients with Gaucher's disease is also reviewed. An etiologic link may exist between the inherited metabolic disorder and associated neuropsychiatric impairment. The biochemical basis of this hypothesized association remains unclear, however, and further enzymatic and pathologic investigations are warranted.

Serum dopamine-beta-hydroxylase (DBH) activity was measured in 44 children with psychiatric disorders and 44 controls in order to determine significant variables affecting its potential use as a marker for specific molecular pathology in the neuropsychiatric disorders of childhood. The assay procedure was reliable and the serum enzyme activity for individuals appears to be stable. There is a very broad distribution of serum DBH activity in the population, and it is similar in males and females. The genetic determination of serum DBH activity was clear in this study, and the enzyme activity increased with age through childhood and adolescence. Thyroid hormone had no effect on serum DBH activity in euthyroid subjects. No difference in mean serum DBH activity emerged across diagnostic groups. When the findings were considered in relation to the results of other studies, it was concluded that the wide range of serum DBH activities in normal and patient populations, as well as developmental effects on the activity of the enzyme, make comparison of DBH activity among diagnostic groups in childhood difficult. Large subject groups, and a consideration of genetic and developmental effects, will clarify possible syndrome-related differences in enzyme activity.

Tetrahydrobiopterin metabolism was studied in nine Swedish patients with the Rett disease. Normal values were found for the serum biopterin level, urine biopterins level and dihydropterine reductase activity. These findings suggest that a primary disturbance of tetrahydrobiopterin metabolism is unlikely.

Phospholipase-A2 (PLA2) is a key enzyme in the metabolism of phospholipids, and it may play an important role in neuronal function and neuronal plasticity. We determined the activity of PLA2 in the plasma of 20 drug-free schizophrenic patients, 6 nonschizophrenic psychiatric patients, and 21 healthy controls. Schizophrenic patients showed significantly higher plasma PLA2 activity than controls, and higher than our nonschizophrenic patients. Seventy percent of the schizophrenics had enzyme activity higher than the highest value from the control group. The increased plasma PLA2 activity in schizophrenics was reduced to the level of the controls after 3 weeks of neuroleptic treatment. These findings warrant further study for possible implications of this increased PLA2 activity in the etiopathology of schizophrenia.

Metachromatic leukodystrophy (MLD) is a disease caused by a deficiency of the enzyme sulfatide sulfatase, also known as arylsulfatase A (ASA). We compared the activity of this enzyme in adult psychiatric patients and normal volunteers using nitrocatechol sulfate (ASA-NCS) and cerebroside sulfate (ASA-CS) as substrates. Our results showed that ASA-NCS activity in urine and leukocytes was significantly lower in psychiatric than in normal individuals, but that there were no differences between these two groups in the sulfatide excretion in urine or the ASA-CS activity in leukocytes. There was no correlation between enzyme activity in urine and in leukocytes, indicating that activity in urine does not truly reflect the levels of the enzyme in tissues. The correlation between ASA-NCS and ASA-CS activity in leukocytes was poor (0.51 for psychiatric patients and 0.59 for normals), suggesting that for a valid measure of the enzyme activity the assays should be carried out with CS as substrate. Results of our study also indicate that in 39 of the 145 psychiatric patients studied, the ASA-CS activity in leukocyte was less than 4 nmoles/mg protein/hr, which is below 50% of the normal means, whereas only one of the 30 normal subjects had a value this low. The presence of low levels of ASA-CS activity in a significantly large number of adult patients with varying psychiatric manifestations suggests that such patients may be asymptomatic carriers of the sulfatidase defect (heterozygotes for MLD), and that behavioral and functional disturbances in these patients may at least in part be related to sulfatidase deficiency. The significance of the ASA-NCS abnormality (reduction) in psychiatric patients is unclear.

A 24-hour rhythm in serum dopamine-beta-hydroxylase (DBH) activity in chronic schizophrenic patients showed a similar change as that in normal subjects: the highest activity during day time with a peak at 12.00 h and the lowest activity at night with a bottom at 24.00 hr, 4 h after sleep onset. Between a group of schizophrenic patients who have sleep disturbance and another group of patients who have normal sleep patterns, no significant difference was observed in the 24-hour rhythm in serum DBH activity. Very low but significant DBH activity was found in cerebrospinal fluid of neuropsychiatric patients, and the values were approximately 1/1,000 of the serum activity. A case after cerebral injury showed a high DBH activity in cerebrospinal fluid.

The authors describe an investigation of Adult Metachromatic Leukodystrophy in a Dutch family, of which two persons were affected. The studies of leukocyte arylsulphatase-A activity were made in 47 members of 4 generations of the same family. The propositus, a 30-year old man, showed a conspicious organic brain syndrome, that progressed in two years to a complete dementia. His leukocyte, liver and kidney arylsulphatase-A activities (ASA) were very low; leukocyte-ASA activity increased after aceto-salicylate. His brother had died at 34 years, after a progressive debelitating neuropsychiatric illness of eight years; postmortem metachromatic leukodystrophy was diagnosed. In all living family members, urine and leukocyte arylsulphatase-A activities were determined. The findings are discussed in relation to the genetics and pathogenesis of this adult form of metachromatic leukodystrophy. Allelic heterozygoty is proposed as inheritance model in this family. Suggestions for further research are made.

Preliminary biochemical analyses on plasma, urine, cerebrospinal fluid (CSF) and post mortem brain areas in the rare Rett syndrome indicate no gross disturbance of neurotransmitter function in the periphery. The amino acid pattern, the plasma catecholamines, dopamine, noradrenaline and adrenaline, serotonin in plasma and platelets, and monoamine oxidase (MAO) B-activity in platelets were not different from controls. Urinary metabolites of biogenic amines tended to be increased in the Rett syndrome. Amino acid and noradrenaline concentrations were not changed in lumbar CSF. In a single case of the Rett syndrome, lower values for most amino acids were notable in post-mortem human brain areas and this finding was accompanied by a severe reduction of dopamine, noradrenaline and serotonin, while the metabolite, DOPAC, most times is increased, and HVA and 5-HIAA are decreased. MAO activities, determined in four brain areas, showed no major abnormalities. 3H-spiroperidol binding was significantly below normal in the putamen and 3H tryptamine binding sites in the occipital cortex showed increased binding numbers with no changes in Hill-coefficients. In conclusion, our preliminary data indicate no severe changes in the peripheral neurotransmitter synthesis and turnover, while first post-mortem data indicate severe reduction of biogenic amine synthesis with enhanced turnover and reduced dopaminergic D-2 receptor activity in the advanced stage of a single case of the Rett syndrome.

After concentration the alpha 1-proteinase inhibitors (Pi) of cerebrospinal fluid (CSF) were separated by isoelectric focusing. The relative amounts of the different Pi components in the CSF were compared with those in the serum of the same donor. The Pi components were identified by crossed isoelectric focusing. Most of the serum Pi components could be detected in the CSF but their relative proportions in serum and CSF differed considerably. The typical serum Pi patterns observed for different phenotypes were not reflected in the CSF. In cases when CSF protein levels were abnormally high alterations of the CSF Pi pattern were observed, i.e. the proportions of at least some of the Pi components approached those in serum. It is concluded that CSF Pi components originate from the serum and that a highly selective blood-CSF barrier function results in a considerable alteration of the concentration pattern. It has been shown by crossed isoelectric focusing technique that at least two proteins acting as Pi in serum do not exert antiproteolytic activity in CSF. Consequently, in CSF these Pi components may have been chemically modified, resulting in an alteration of the acceptor sites but not of the isoelectric point of the inhibitor molecule.

In a series of 93 emergency patients, 58 were classified as concussions on a clinical basis. Thirteen of the patients with concussion had increased levels of creatine kinase isoenzyme BB (CK-BB) in their cerebrospinal fluid (CSF). We performed a prospective, follow-up investigation comparing 10 patients with a CK-BB increase and 10 patients without a CK-BB increase after concussion. Within 24 hours, at 6 months and 3 years after concussion, each patient was subject to a special interview to obtain pre-concussional baseline data and post-concussional follow-up data concerning their complaints and capacity for daily activities. We found a definite change towards increasing disability in 8 of the 10 patients with a raised CK-BB, and in only 1 of the 10 patients with normal levels of CK-BB. A careful neuropsychological examination confirmed inferior performance in tests especially sensitive to brain injury in patients with a CK-BB increase. Our results suggest that increased levels of CK-BB after concussion signify a more severe injury which is not found in the clinical examination during the first days after the accident, and that these patients are a high-risk group for the development of post-concussional problems and symptoms.

Adenylate kinase activity in the cerebrospinal fluid (CSF) was investigated in 29 patients with psychiatric symptomatologies. Such activity was demonstrated in 18 of the 19 individuals with schizophrenic or other psychotic or borderline psychotic symptomatology. No activity was seen in the remaining 10 patients with non-psychotic nervous and/or functional somatic complaints, nor in the 20 persons whose CSF was examined in connection with spinal anaesthesia, nor in four who were treated with neuroleptic drugs on nonpsychiatric indications. The findings are compatible with the assumption that in persons with psychotic or borderline psychotic symptomatology a lowered membrane electrochemical potential may be associated with some of the symptoms exhibited.

A higher incidence of erythrocyte ITP pyrophosphohydrolase deficiency was found among a psychiatric population when compared to a nonpsychiatric group of subjects. Although the incidence was highest among schizophrenics, particularly those diagnosed as paranoid, the majority of the patients did not show such deficiency. The parallelisms between ITP pyrophosphohydrolase and hypoxanthine-guanine phosphoribosyl transferase deficiencies, both characterized by the lack of availability of IMP, and correlated to behavioral disorders, suggest that irregularities of hypoxanthine nucleotides may be implicated in abnormal mental processes.