SOD1 and cognitive dysfunction in familial amyotrophic lateral sclerosis.

BACKGROUND: Sporadic Amyotrophic Lateral Sclerosis (sALS) is associated with frontotemporal dementia (ALS-FTD) or milder deficits of cognitive (predominantly executive) dysfunction (ALSCi) in some patients. Some forms of familial ALS (FALS) have a family history of FTD, ALS-FTD, or both, but there have been few reports of ALS-FTD in FALS patients with mutations of the gene superoxide dismutase-1 (SOD1 FALS). The aim of this study was to test the hypothesis that ALSCi may be found in non-SOD1 FALS, but that SOD1 FALS patients would show little or no evidence of cognitive change. METHODS: A neuropsychological test battery was administered to 41 SALS patients, 35 control participants, 7 FALS patients with a SOD1 mutation (SOD1 FALS) and 10 FALS patients without a SOD1 mutation (non-SOD1 FALS). RESULTS: Relative to control participants, non-SOD1 FALS patients had impaired performance on written verbal fluency and confrontation naming, and reported higher levels of executive behavioural problems. These deficits were absent in SOD1 FALS patients. SALS patients performed poorer than controls only on the Graded Naming Test. All ALS groups had higher levels of behavioural apathy and emotional lability than were found in control participants. Cognitive domains of memory, receptive language, and visuospatial perception were spared. Groups were matched for age, gender, premorbid full-scale IQ, anxiety and depression. DISCUSSION: Individuals with SOD1 gene mutations are less likely to have significant cognitive changes compared to non-SOD1 FALS patients. Cognitive abnormalities in ALS are heterogeneous and may reflect underlying genetic variations rather than a simple spectrum of extra-motor involvement.

GSK-3 is a viable potential target for therapeutic intervention in bipolar disorder.

Bipolar disorder is a serious psychiatric condition that has been treated for over 50 years with lithium. Lithium is a well established glycogen synthase kinase-3 (GSK-3) inhibitor, suggesting that manipulating GSK-3 may have therapeutic value in treating bipolar disorder. GSK-3 is regulated by a wide variety of mechanisms including phosphorylation, binding with protein complexes, phosphorylation state of its substrates, cellular localization and autoregulation, thus providing a wide number of potential therapeutic mechanisms. Mounting evidence suggests that GSK-3 regulation can be used to manage bipolar disorder symptoms. Although GSK-3 mutations have not been detected amongst the general bipolar population, they have been correlated with females with bipolar II and most of the drugs used for successful bipolar disorder treatment regulate GSK-3. These drugs produce a weak anti-depressant-like and a strong anti-mania-like effect in a wide range of animal models tested, mirroring their utility in treating bipolar disorder symptoms. Taken together, the evidence suggests that targeting GSK-3 may be a means to control the symptoms of bipolar disorder.

MAOA, maltreatment, and gene-environment interaction predicting children's mental health: new evidence and a meta-analysis.

Previous research on adults has shown that a functional polymorphism in the promoter region of the monoamine oxidase A (MAOA) gene moderates the impact of childhood maltreatment on risk for developing antisocial behavior. Thus far, attempts to replicate this finding have been mixed. The current study (i) presents new data investigating this finding in a sample of 975 seven-year-old boys, and (ii) evaluates the extant data by conducting a meta-analysis of published findings. We replicated the original finding by showing that the MAOA polymorphism moderates the development of psychopathology after exposure to physical abuse, we extended the finding to childhood closer in time to the maltreatment experience, and we ruled-out the possibility of a spurious finding by accounting for passive and evocative gene-environment correlation. Moreover, meta-analysis demonstrated that across studies, the association between maltreatment and mental health problems is significantly stronger in the group of males with the genotype conferring low vs high MAOA activity. These findings provide the strongest evidence to date suggesting that the MAOA gene influences vulnerability to environmental stress, and that this biological process can be initiated early in life.

Association between the catechol O-methyltransferase Val108/158Met polymorphism and alexithymia.

It has been suggested that the characteristics of alexithymia result from deficits in frontal lobe functioning, and the prefrontal cortex is particularly dependent on the catechol O-methyltransferase (COMT) pathway. We investigated the relationship between COMT Val108/158Met, serotonin transporter coding sequence (5-HT transporter gene-linked polymorphic region; 5-HTTLPR) polymorphisms, and alexithymia. The study sample comprised 109 students at the Korea University. All participants were tested using the 20-item Toronto Alexithymia Scale (TAS-20). They were genotyped for COMT Val108/158Met and 5-HTTLPR polymorphisms. Genotyping was analyzed using polymerase chain reaction. Subjects with Val/Val genotype had significantly higher TAS-20 scores than those with Met/Met or Met/Val genotypes. However, there was no significant relationship between the 5-HTTLPR genotype and TAS-20 scores. This indicates a possible association between the COMT Val108/158Met gene polymorphism and alexithymia.

Memory deficits and increased emotionality induced by beta-amyloid (25-35) are correlated with the reduced acetylcholine release and altered phorbol dibutyrate binding in the hippocampus.

In the present study we found that chronic infusion of beta-amyloid fragment (25-35) at nanomolar concentration into rat cerebral ventricle impairs learning and memory. At a concentration of 3 nmol/day but not 0.3 nmol/day, beta-amyloid significantly reduced the spontaneous alternation behavior and the memory performance in the water maze and multiple passive avoidance tests. A significant increase in anxiety was also found in the animals infused with 3 nmol/day beta-amyloid fragment. Memory deficits and the increased emotionality were correlated with a decreased nicotine-evoked acetylcholine release from the frontal cortex/hippocampus, as assessed by microdialysis, in freely moving rats. The amyloid fragment infused either at pico- or nanomolar concentrations reduced the affinity of [3H] phorbol dibutyrate binding, an index of activated protein kinase C (PKC), and increased the total number of binding sites in the hippocampal particulate fraction. Our results suggest that the amnesic and anxiogenic effects of chronic infusion of beta-amyloid (25-35) are related to the decreased acetylcholine release and reduced PKC activation.

Molecular mechanisms of Fyn-tyrosine kinase for regulating mammalian behaviors and ethanol sensitivity.

Mice lacking Fyn, a Src-related non-receptor tyrosine kinase, show impairment of various behaviors, such as spatial learning, suckling, emotional behaviors, and ethanol sensitivity. These mice also display both morphological defects and impairment of synaptic function. Fyn is highly expressed in the mammalian CNS from embryonic day 8.5 to adulthood. Pharmacological and electrophysiological analyses of mice lacking Fyn reveal gamma-aminobutyric acid and glutamatergic defects. We propose here the hypothesis that these defects are caused separately by developmental disorganization and impairment of synapse function by a deficit in Fyn. Regarding the glutamatergic defect, in particular, after ethanol administration the N-methyl-D-aspartate (NMDA)-dependent function is recovered by Fyn, paralleled with tyrosine phosphorylation of NMDA receptor 2B subtype. Thus, modulation of the NMDA receptor function by Fyn may have a significant role in building and regulating sophisticated neural circuits and behavior. In addition, the cadherin-related neural receptor (CNR) family is isolated by binding activity for Fyn. The CNR-Fyn complex will also open a new angle for gaining insight into the molecular mechanisms for regulating mammalian behavior.

Maltreatment, conscience functioning and dopamine beta hydroxylase in emotionally disturbed boys.

OBJECTIVE: Identify associations among early maltreatment, sufficiencies, and psychopathological interferences in the domains of conscience functioning and low serum dopamine beta hydroxylase activity. METHOD: Nineteen emotionally disturbed boys screened for maltreatment experiences were compared according to age at onset of maltreatment, enzyme activity, and their conscience functioning in the domain of moral valuation. They were also compared in conscience functions to 19 age and sex matched normal counterparts. RESULTS: Subjects who endured maltreatment prior to 36 months had developmental delays and interferences with functioning in more conscience domains than those who were either spared such experiences or who endured maltreatment later in life. Subjects with low enzyme activity had significantly more interference with authority and peer valuation than subjects with high enzyme activity. Greater interference with valuation was associated with lower enzyme activity and more frequent abuse prior to 36 months. CONCLUSIONS: Psychosocial sequelae of early maltreatment have been identified in the domains of conscience. An association has been established between pathological interference in the domain of moral valuation and a putative neurobiologic sequelae of early maltreatment. Implications for future research in the psychobiology of maltreatment are discussed.

Platelet monoamine oxidase activity and deficit syndrome schizophrenia.

Measures of affective flattening that combine self-reported emotional experience with observed affect may identify deficit syndrome patients better than ratings based on observed affect alone. In this study, we examined 23 clinically stable but chronically ill schizophrenic patients, 15 of whom were found to have a deficit syndrome. After exclusion of patients with self-reported depressed mood from the deficit syndrome group, the remaining patients with a deficit syndrome not accompanied by self-reported depressed mood showed a strikingly homogeneous distribution of platelet monoamine oxidase activity. Results suggest that inclusion of self-reported emotional experience in clinical definitions of the deficit syndrome will increase the specificity of diagnosis.

Psychiatric morbidity, platelet monoamine oxidase and tribulin output in headache.

A significantly higher proportion of patients with headache showed scores in the psychopathological range of the General Health Questionnaire (GHQ) compared with controls, with ratings particularly high on the anxiety and depression subscales. Across the whole group, there was a significant negative correlation between platelet monoamine oxidase (MAO) activity and GHQ score overall, and with the anxiety and depression subscales. There was a significant positive correlation between platelet MAO activity and urinary output of the endogenous MAO inhibitor, tribulin. Within the migraine group, there was a significant negative correlation between tribulin output and GHQ score. These findings suggest that the biochemical nature of the anxiety associated with migraine may differ from that in other conditions such as generalized anxiety disorder where high platelet MAO activity and high tribulin output have been reported.

Klüver-Bucy syndrome and amyotrophic lateral sclerosis: a case report with biochemistry, morphometrics, and Golgi study.

We studied a patient with amyotrophic lateral sclerosis and the Klüver-Bucy syndrome. At autopsy there was extensive degeneration of the limbic system with the brunt of the changes in the medial temporal lobe, especially the entorhinal cortex and subiculum. Degenerative changes were also seen in the substantia nigra and lower motor neurons. Morphometric and biochemical studies implied a disease process that affected small, possibly somatostatinergic, cortical neurons. These latter findings and the lobar distribution of cortical atrophy were consistent with Pick's disease, but Pick bodies and ballooned neurons were not present.

Erythrocyte COMT-activity in patients with affective disorders.

COMT enzyme characteristics (Km, V, ratio of meta/paramethylation) were determined in the red blood cells of 20 patients with endogenous depression, in 20 healthy controls matched as to age and sex, as well as in 10 patients with mania, and 10 patients with neurotic depression. Assessment was done twice, i.e. before and after remission in patients with endogenous depression and in the manic patients. If male and female patients are considered together there was no statistical difference between the COMT characteristics of these patient groups, either before or after remission. Only the bipolar patients showed a higher COMT-activity (V) than their individually matched controls. If however, only the female patients are taken into consideration, COMT-activity of the patients with endogenous depression vs. controls is significantly increased by 60%. This difference can be demonstrated also after remission ("free interval") though statistical significance is reached only for the unipolar group. Further in vitro experiments indicate that antidepressant drugs do not possess a relevant influence on COMT-activity. Ranking the mean COMT-values leads to the following order: matched controls (< neurotic depression < unipolar depression < bipolar depression, which would be in good agreement with theoretical expectations based on the amine hypothesis of depression. Compared with normal male subjects COMT-activity of female controls is significantly lower. On the other hand, the female patients with endogenous depression show a significantly higher enzyme activity than the corresponding male patients.

Pseudocholinesterase activity and phenotypes in mentally ill patients.

Pseudocholinesterase activities and phenotypes have been determined in 103 affectively ill patients, 168 schizophrenics and 73 Huntington's disease sufferers and compared with those of a sample of healthy controls. The distributions of phenotypes in the patient samples did not differ significantly from those of the controls. When corrections were made for sex, age and E1 phenotypes, the Huntington's disease patients showed a reduced level of cholinesterase activity. Normal levels were found in affective disorders and schizophrenia.

Paranoia and platelet MAO in normals and nonschizophrenic psychiatric groups.

The authors compared the correlation between platelet monoamine oxidase (MAO) activity and the Paranoia (Pa) scale of the Minnesota Multiphasic Personality Inventory in several groups. The data suggest that there is a positive association between high MAO activity and high scores on the Pa scale but only in samples with psychopathology.

No association of red cell adenylate kinase phenotypes with affective disorders.

Red cell adenylate kinase (AK) phenotypes were studies in 195 patients with affective disorders (41 with the bipolar and 81 with the unipolar form of the disease) and 418 controls. No significant differences were found between patients and controls and between patients with different types of affective disorders. Thus the previous observation by Rundle et al. (1977) showing an increased frequency of the AK2 allele in the unipolar group was not confirmed.

Serum dopamine-beta-hydroxylase in affective disorders.

Serum dopamine-beta-hydroxylase (DBH) activity was tested in 160 psychiatric patients suffering from affective disorders. The patients were divided into subgroups according to strict diagnostic criteria and clinical state at the time of the examination. Since no relationship was found between DBH activity and age or sex, these variables have been discarded from further analyses. Bipolar (manic-depressive) patients had lower (p less than 0.05) BDH mean values than patients suffering from unipolar, recurrent depressive psychoses. No other differences were found either among group or in relation to the clinical state. As such a wide range of DBH values was recorded in all the groups examined, measurements of DBH activity do not seem to be useful as a diagnostic acid, or as an indicator of the clinical state of patients suffering from affective disorders.

Suicide attempts, platelet monoamine oxidase and the average evoked response.

The relationship between suicides and suicide attempts and two biological measures, platelet monoamine oxidase levels (MAO) and average evoked response (AER) augmenting, was examined in 79 off-medication psychiatric patients and in 68 college student volunteers chosen from the upper and lower deciles of MAO activity levels. In the patient sample, male individuals with low MAO and AER augmenting, a pattern previously associated with bipolar affective disorders, showed a significantly increased incidence of suicide attempts in comparison with either non-augmenting low MAO or high MAO patients. Within the normal volunteer group, all male low MAO probands with a family history of suicide or suicide attempts were AER augmenters themselves. Four completed suicides were found among relatives of low MAO probands where as no high MAO proband had a relative who committed suicide. These findings suggest that the combination of low platelet MAO activity and AER augmenting may be associated with a possible genetic vulnerability to psychiatric disorders.