Mood disturbances in newly diagnosed Parkinson's Disease patients reflect intrathecal inflammation.

In Parkinson's disease (PD), neuroinflammation may be involved in the pathogenesis of mood disorders, contributing to the clinical heterogeneity of the disease. The cerebrospinal fluid (CSF) levels of interleukin (IL)-1ß, IL-2, IL-6, IL-7, IL-8, IL-9, IL-12, IL-17, interferon (IFN)γ, macrophage inflammatory protein 1-alpha (MIP-1a), MIP-1b, granulocyte colony stimulating factor (GCSF), eotaxin, tumor necrosis factor (TNF), and monocyte chemoattractant protein 1 (MCP-1), were assessed in 45 newly diagnosed and untreated PD patients and in 44 control patients. Spearman's correlations were used to explore possible associations between CSF cytokines and clinical variables including mood. Benjamini-Hochberg (B-H) correction for multiple comparisons was applied. Linear regression was used to test significant associations correcting for other clinical variables. In PD patients, higher CSF concentrations of the inflammatory molecules IL-6, IL-9, IFNγ, and GCSF were found (all B-H corrected p < 0.02). Significant associations were found between BDI-II and the levels of IL-6 (Beta = 0.438; 95%CI 1.313-5.889; p = 0.003) and IL-8 (Beta = 0.471; 95%CI 0.185-0.743; p = 0.002). Positive associations were also observed between STAI-Y state and both IL-6 (Beta = 0.452; 95%CI 1.649-7.366; p = 0.003), and IL-12 (Beta = 0.417; 95%CI 2.238-13.379; p = 0.007), and between STAI-Y trait and IL-2 (Beta = 0.354; 95%CI 1.923-14.796; p = 0.012), IL-6 (Beta = 0.362; 95%CI 0.990-6.734; p = 0.01), IL-8 (Beta = 0.341; 95%CI 0.076-0.796; p = 0.019), IL-12 (Beta = 0.328; 95%CI 0.975-12.135; p = 0.023), and IL-17 (Beta = 0.334; 95CI 0.315-4.455; p = 0.025). An inflammatory CSF milieu may be associated with depression and anxiety in the early phases of PD, supporting a role of neuroinflammation in the pathogenesis of mood disturbances.

Affective Neuropsychiatric Symptoms as Early Signs of Dementia Risk in Older Adults.

BACKGROUND: Affective neuropsychiatric symptoms (aNPS: depression, anxiety, apathy, irritability) have been linked to increased dementia risk. However, less is known whether this association is independent of Alzheimer's disease (AD) pathophysiology. OBJECTIVE: To investigate the contribution of early aNPS to dementia risk in cognitively normal (CN) older adults and mild cognitive impairment (MCI) patients, with and without AD biomarker abnormality. METHODS: Participants included 763 community-dwelling, stroke-free older adults identified as CN and 617 with MCI at baseline, drawn from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Baseline assessments included a neuropsychological battery, the Neuropsychiatric Inventory (NPI), and apolipoprotein E ɛ4 (ApoE4) genotyping. A participant subset completed cerebrospinal fluid (CSF) AD biomarker assessment. Time to progression to dementia was measured based on months at follow-up when an individual was diagnosed with dementia, over the follow-up period of 48 months. RESULTS: Latent class analysis identified 3 subgroups of older adults in CN and MCI, indicated by the baseline profiles of neuropsychiatric symptoms (NPS). Subgroups with higher aNPS were at increased risk of progression to dementia in both CN (HR = 3.65, 95% CI [1.80, 7.40]) and MCI (HR = 1.52, 95% CI [1.16, 2.00]; HR = 1.86 [1.05, 3.30]) groups, adjusting for age, sex, global cognition, and ApoE4, compared with their counterparts with minimal NPS. There was no difference between higher aNPS and minimal NPS subgroups in their CSF AD biomarker profiles. CONCLUSION: Findings suggest that aNPS may represent a neurobiological vulnerability that uniquely contribute to the dementia risk, independent of AD biomarker profiles.

Cerebrospinal fluid markers of inflammation and infections in schizophrenia and affective disorders: a systematic review and meta-analysis.

Infections and inflammatory processes have been associated with the development of schizophrenia and affective disorders; however, no study has yet systematically reviewed all available studies on cerebrospinal fluid (CSF) immune alterations. We aimed to systematically review the CSF immunological findings in schizophrenia spectrum and affective disorders. We identified all studies investigating CSF inflammatory markers in persons with schizophrenia or affective disorders published prior to March 23, 2017 searching PubMed, CENTRAL, EMBASE, Psychinfo, and LILACS. Literature search, data extraction and bias assessment were performed by two independent reviewers. Meta-analyses with standardized mean difference (SMD) including 95% confidence intervals (CI) were performed on case-healthy control studies. We identified 112 CSF studies published between 1942-2016, and 32 case-healthy control studies could be included in meta-analyses. Studies varied regarding gender distribution, age, disease duration, treatment, investigated biomarkers, and whether recruitment happened consecutively or based on clinical indication. The CSF/serum albumin ratio was increased in schizophrenia (1 study [54 patients]; SMD = 0.71; 95% CI 0.33-1.09) and affective disorders (4 studies [298 patients]; SMD = 0.41; 95% CI 0.23-0.60, I2 = 0%), compared to healthy controls. Total CSF protein was elevated in both schizophrenia (3 studies [97 patients]; SMD = 0.41; 95% CI 0.15-0.67, I2 = 0%) and affective disorders (2 studies [53 patients]; SMD = 0.80; 95% CI 0.39-1.21, I2 = 0%). The IgG ratio was increased in schizophrenia (1 study [54 patients]; SMD = 0.68; 95% CI 0.30-1.06), whereas the IgG Albumin ratio was decreased (1 study [32 patients]; SMD = -0.62; 95% CI -1.13 to -0.12). Interleukin-6 (IL-6) levels (7 studies [230 patients]; SMD = 0.55; 95% CI 0.35-0.76; I2 = 1%) and IL-8 levels (3 studies [95 patients]; SMD = 0.46; 95% CI 0.17-0.75, I2 = 0%) were increased in schizophrenia but not significantly increased in affective disorders. Most of the remaining inflammatory markers were not significantly different compared to healthy controls in the meta-analyses. However, in the studies which did not include healthy controls, CSF abnormalities were more common, and two studies found CSF dependent re-diagnosis in 3.2-6%. Current findings suggest that schizophrenia and affective disorders may have CSF abnormalities including signs of blood-brain barrier impairment and inflammation. However, the available evidence does not allow any firm conclusion since all studies showed at least some degree of bias and vastly lacked inclusion of confounding factors. Moreover, only few studies investigated the same parameters with healthy controls and high-quality longitudinal CSF studies are lacking, including impact of psychotropic medications, lifestyle factors and potential benefits of anti-inflammatory treatment in subgroups with CSF inflammation.

Does S100B have a potential role in affective disorders? A literature review.

BACKGROUND: S100B is a calcium-binding protein located in glial cells; it is regarded as a potential biomarker in affective disorders. AIM: To review the literature investigating the role of S100B in patients with affective disorders. METHOD: A systematic review of original English language studies investigating S100B in serum, cerebrospinal fluid, plasma and lymphocytes, in patients with affective disorders, was conducted. The literature search was conducted within the PubMed database. Effect sizes were calculated to adjust for systematic measurement effects. RESULTS: Twenty studies were included, with a total of 1292 participants. Of these, 398 patients had or have had depressive disorder, 301 patients had bipolar disorder and 593 were healthy controls. S100B levels in serum were consistently elevated in studies with statistically significant results which investigated acute affective episodes (comprising major depressive episode in major depressive disorder, and both manic and depressive episodes in patients with bipolar disorder), in comparison to healthy controls. There were few studies assessing S100B levels in cerebrospinal fluid, plasma or lymphocytes, and these had inconsistent results. CONCLUSION: The results indicated that elevated S100B levels might be associated with mood episodes in affective disorders. However, the role of S100B, and its possible impact in affective disorders, requires further investigation and at the present S100B does not have a role as clinically biomarker in affective disorder. Future longitudinal multicentre studies with larger transdiagnostic real life patient cohorts are warranted.

A sensitive and practical RP-HPLC-FLD for determination of the low neuroactive amino acid levels in body fluids and its application in depression.

Ion-exchange high performance liquid chromatography (HPLC) generally fails as a method to determine low levels of free amino acids (AAs) in body fluids. Here we present a modified reversed-phase HPLC (RP-HPLC) protocol for the determination of AAs in body fluids and its application in mood disorder patients. We improved a previous research protocol by modifying i) sample preparation, including deproteination, ii) derivitization, including derivating agent and condition, and iii) sample separation, which is mainly determined by the pH value, the components and the additives of the mobile phases. The combination of these modifications, together with fluorescence detection (FLD), allows sensitive and practical determination of free AA levels in body fluids of depressive patients. This protocol was validated by determining the postmortem cerebrospinal fluid (CSF) glutamic acid (Glu) and γ-aminobutyric acid (GABA) levels of 8 major depressive disorder (MDD) patients, 9 bipolar disorder (BD) patients, and 19 well-matched controls, while also testing the plasma and CSF AA levels of living MDD patients. CSF Glu and GABA levels were both significantly decreased in MDD but not in BD patients. The data indicate that this RP-HPLC-FLD protocol is applicable for detection of low levels of neuroactive AAs in body fluids, as well as for routine clinical applications.

Cerebrospinal fluid 5-hydroxyindolacetic acid correlates directly with negative affective intensity, but not affective lability, in human subjects.

Centrally acting monoamines have long been thought to be associated with component traits of behavior and emotion and are potential biological mediators of psychopathology. In this study we tested the hypothesis that centrally acting monoamines would be associated with measures of affective instability (i.e. affective intensity and affective lability) in healthy and personality disordered human subjects. In total, 57 adult subjects including 19 psychiatrically healthy volunteers and 38 personality disordered individuals were assessed for affective instability with the affective intensity measure (AIM) and the Affective Lability Scale (ALS). Samples of cerebrospinal fluid (CSF) were collected for assay of 5-hydroxyindoleacitic acid (5-HIAA), homovanillic acid (HVA) and 3-methoxy-4-hydroxy-phenylglycol (MHPG). CSF 5-HIAA concentration correlated directly with overall AIM score and, specifically, with the AIM Negative Intensity score, in all subjects and in personality disordered subjects. This result was not affected but the addition of aggression scores or life history of mood disorder to the model. Neither CSF HVA nor MHPG were found to uniquely correlate with either AIM or ALS measure. Higher Affective Intensity scores, Negative Intensity scores, specifically, are directly correlated with higher basal levels of CSF 5-HIAA. This relationship was independent of aggression, life history of mood disorder and general personality traits.

Hemiplegic migraine, seizures, progressive spastic paraparesis, mood disorder, and coma in siblings with low systemic serotonin.

BACKGROUND: Serotonin has an important role in vascular resistance and blood pressure control, and a functional serotonin transporter polymorphism has been associated with migraine. Disturbances in serotonin metabolism have been associated with autism, depression, and myoclonus related conditions, but serotonin has far more functions in the body. Familial hemiplegic migraine is a rare autosomal dominant subtype of migraine with aura in which attacks are associated with hemiparesis. CASES: We present two siblings with hemiplegic migraine, depression, progressive spastic paraparesis, myelopathy, and spinal cord atrophy. One of the sisters presented with prolonged coma after a migraine episode. Both sisters were found to have low cerebrospinal fluid serotonin metabolite (5-hydroxyindoleacetic acid), low platelet serotonin levels, and diminished serotonin transport capacity. Their clinical symptoms improved on 5-hydroxytryptophan replacement therapy. Mutational analysis of the CACNA1A and ATP1A2 genes was negative. CONCLUSION: This is the first time that systemic serotonin deficiency has been described in familial hemiplegic migraine. We hypothesize that the deficiency of serotonin transport may be part of a complex cellular membrane trafficking dysfunction involving not only the serotonin transporter but also other transporters and ion channels.

Cerebrospinal fluid analysis in affective and schizophrenic spectrum disorders: identification of subgroups with immune responses and blood-CSF barrier dysfunction.

Immune and inflammatory mechanisms are detected in a subgroup of treatment resistant hospitalized affective and schizophrenic spectrum disorder patients. We analysed albumin, IgG, IgA, IgM, oligoclonal IgG and specific antibodies in paired cerebrospinal fluid (CSF) and serum samples. Numerical and graphical interpretation of CSF protein data was performed by Reibergrams with a new CSF statistics tool for nonlinear group analysis with reference to a large control group (n=4100). In 41% of the psychiatric patients (n=63) we observed CSF pathologies: 14% displayed intrathecal humoral immune responses, 10% slightly increased CSF cell counts (5-8/microL) and 29% had moderate blood-CSF barrier dysfunctions, in 24% as the only pathological sign with normal IgG, IgA and IgM concentrations in CSF (p=0.9 testing the null hypothesis for intrathecal synthesis with reference to Qmean of the reference group). In the group of affective (n=24) spectrum disorders 20% displayed a systemic immune reaction as detected by oligoclonal IgG. CSF analysis and interdisciplinary clinical approach revealed 6% of psychiatric patients likely to represent a virusspecific, bacterial or autoimmune associated disorder with CNS involvement. Elevated CSF neopterin concentration in 34% of the patients was interpreted as an increased release from astrocytes or from other glia cells. The low level immune response and barrier dysfunctions are discussed on the base of a mild encephalitis pathomechanism in subgroups of psychiatric patients. CSF analysis is shown to be a useful diagnostic tool for differential diagnosis in psychiatric diseases.

Increased risk of suicide attempt in mood disorders and TPH1 genotype.

BACKGROUND: The tryptophan hydroxylase 1 (TPH1) gene is reported to be associated with suicidal behavior. This has not been confirmed by prospective studies of suicide and clinical or biological mediators of this genetic risk have not been identified. METHODS: 343 subjects (Caucasian, African-American, Hispanic) presenting with a Major Depressive Episode were genotyped for polymorphisms A218C in intron 7 and A-6526G in the promoter region of TPH1, and monitored for suicide attempts for up to one year. Clinical correlates of suicidal behavior and CSF-HIAA, HVA and MHPG levels were explored as possible mediators of genetic risk. Analyses were adjusted for ethnicity. RESULTS: The AA genotype on intron 7 and the AA genotype on the promoter (both more prevalent in Caucasians) predicted suicide attempts during the 1 year follow-up, and were associated with past attempts of high medical lethality, regardless of ethnicity. The intron 7 genotype was associated with fewer reported reasons for living, and lower impulsivity. Haplotype analysis indicated significant increase in risk of suicide attempts for subjects with four risk alleles. TPH1 genotype was not associated with CSF metabolite levels. LIMITATIONS: The TPH1 gene is likely one of several genes associated with suicidal behavior. Power to detect differential genotype effects by ethnicity is low. CONCLUSIONS: Polymorphisms of TPH1 may assist in identifying a subgroup of mood disorder patients that is at higher risk for suicidal behavior.

Can biological tests assist prediction of suicide in mood disorders?

Predicting suicide is difficult due to its low base-rate and the limited specificity of clinical predictors. Prospective biological studies suggest that dysfunctions in the serotonergic system and hypothalamic-pituitary-adrenal axis have some predictive power for completed suicide in mood disorders. A prediction model that incorporates biological testing to increase specificity and sensitivity of prediction of suicide is of potential clinical value. Meta-analyses of prospective biological studies of suicide and cerebrospinal fluid 5-hydroxyindoleacetic acid (CSF 5-HIAA) and suicide and the dexamethasone suppression test (DST) in mood disorders using the penalized quasi-likelihood (PQL) and bootstrap method yield odds ratios for prediction of suicide of 4.48 and 4.65 respectively. Two combinatory prediction models, the first requiring positive results on more than one test, and the second requiring a positive result on either one of two tests, were tested to assess their sensitivity, specificity, and predictive power using biological data from published and unpublished studies. The prediction model that requires both DST and CSF 5-HIAA tests to be positive results in 37.5% sensitivity, 88% specificity, and has a positive predictive value of 23%. The prediction model that requires either DST or CSF 5-HIAA tests to be positive results in 87.5% sensitivity, 28% specificity, and has a positive predictive value of 10%. Thus, models attempting to predict a lethal outcome that is uncommon perform very differently making model choice of major importance. Further work on refining biological predictors and integration with clinical predictors is needed to optimize a model to predict suicide in the clinic.

CSF monoamine patterns in pathological gamblers and healthy controls.

Previous reports on compounds in the cerebrospinal fluid (CSF) of pathological gamblers have focused on disturbed NA, DA and 5-HT function in the central nervous system. We have analysed precursors, transmitters and transmitter metabolites in 3 x 6 ml of CSF obtained from one female and 11 male pathological gamblers and 11 healthy male controls lumbar punctured at the L4-5 level after 8 h of fasting without preceding strict bedrest. Pathological gamblers displayed lower CSF levels of tryptophan and 5-HT while the opposite was the case for 5-HIAA, tyrosine, DA, HVA, DOPAC and HMPG. In contrast to previous studies, the NA level did not differ between pathological gamblers and healthy controls. A disrupted CSF gradient was noted for tryptophan, 5-HT, DA, HVA, DOPAC, NA and HMPG, but only in pathological gamblers. A disrupted gradient was found for 5-HIAA in both pathological gamblers and healthy controls. The results are in line with the presence of altered indoleamine and catecholamine function in pathological gamblers as well as an altered CSF transport from the brain to the lumbar compartment in such gamblers.

GABAergic dysfunction in schizophrenia and mood disorders as reflected by decreased levels of glutamic acid decarboxylase 65 and 67 kDa and Reelin proteins in cerebellum.

BACKGROUND: Glutamic acid decarboxylase (GAD) is the rate limiting enzyme responsible for conversion of glutamate to gamma-aminobutyric acid (GABA) regulating levels of glutamate and GABA in the mammalian brain. Reelin is an extracellular matrix protein that helps in normal lamination of the embryonic brain and subserves synaptic plasticity in adult brain. Both GAD and Reelin are colocalized to the same GABAergic interneurons in several brain sites. We hypothesized that levels of GAD and Reelin would be altered in cerebellum of subjects with schizophrenia and mood disorders differentially vs. controls. METHODS: We employed SDS-PAGE and Western blotting to measure levels of GAD isomers 65 and 67 kDa and Reelin isoforms 410-, 330- and 180-kDa proteins as well as beta-actin in cerebellum of subjects with schizophrenia, bipolar disorder and major depression vs. controls (N = 15 per group). RESULTS: GAD 65- and 67-kDa levels were decreased significantly in bipolar, depressed and schizophrenic subjects (p < 0.05) vs. controls. Reelin 410- and 180-kDa proteins decreased significantly (p < 0.05) in bipolar subjects vs. controls. Reelin 180 kDa was decreased significantly (p < 0.05) in schizophrenics vs. controls. beta-Actin levels did not vary significantly between groups. There were no significant effects of confounding variables on levels of various proteins. CONCLUSION: This study demonstrates for the first time significant deficits in GABAergic markers Reelin and GAD 65 and 67 proteins in bipolar subjects and global deficits in the latter proteins in schizophrenia and mood disorders, accounting for the reported alterations in CSF/plasma levels of glutamate and GABA in these disorders.

Lifetime burden of mood swings and activation of brain norepinephrine turnover in patients with treatment-refractory depressive illness.

BACKGROUND: We tested if duration and intensity of episodes in treatment-resistant affectively ill patients were related to cerebrospinal fluid (CSF) concentrations of monoamine metabolites. METHOD: In retrospective life charts were recorded every previous episode of 37 patients with severe treatment-refractory affective disorders. 'Accumulated burden of mood swings' (ABMS, sum of each episode length x episode depth) was used to estimate the accumulated illness burden. Homovanillic acid (HVA), 3-methoxy-4-hydroxyphenylglycol (MHPG), and 5-hydroxyindoleacetic acid (5-HIAA) were analyzed in CSF of all patients and compared with 27 healthy controls. Data were analyzed using multiple regression analysis. RESULTS: CSF MHPG contributed strongly significant and positively to the ABMS. LIMITATIONS: The retrospective nature of the study. CONCLUSION: CSF concentrations of MHPG is positively related to ABMS over life. Thus, a specific involvement of norepinephrine in the long-term burden of affective illness is a likely reality.

Low CSF somatostatin associated with response to nimodipine in patents with affective illness.

BACKGROUND: In patients with depression, treatment with nimodipine has been shown to increase cerebrospinal fluid (CSF) somatostatin (SRIF) and ameliorate baseline global cerebral hypometabolism. This study was conducted to assess whether a low baseline level of CSF SRIF was associated with response to nimodipine treatment. METHODS: Twenty-one depressed patients underwent lumbar puncture for analysis of CSF somatostatin-like immunoreactivity (SRIF-LI) during a medication-free period and after at least 6 weeks of nimodipine monotherapy. Twenty-five healthy control subjects were utilized as a comparison group. Clinical improvement was assessed using the Clinical Global Impression Scale for Bipolar Illness. RESULTS: As predicted, baseline CSF SRIF-LI was significantly lower in eventual nimodipine responders (33.1 +/- 2.8 pg/mol) compared to eventual nonresponders [41.9 +/- 2.6 pg/mL; t(19) = 1.98, p =.03, one-tailed]. CONCLUSIONS: Low baseline CSF somatostatin in depression may be associated with response to nimodipine, which in turn may be related to the ability of nimodipine to increase CSF somatostatin.

Elevated sorbitol concentration in the cerebrospinal fluid of patients with mood disorders.

This study was undertaken to test the hypothesis that a specific pathophysiological mechanism of diabetic neuropathy, namely increased polyol pathway flux, could be operative in patients with bipolar and unipolar mood disorders. Numerous studies have shown abnormalities of carbohydrate metabolism, including high rates of diabetes mellitus, in patients with mood disorders. Several studies have found that peripheral neuropathy is a risk factor for depression in diabetics. Furthermore, increased polyol pathway flux results in elevated sorbitol concentrations in peripheral tissues and cerebrospinal fluid (CSF) of diabetics with neuropathy. The purpose of this study was to determine whether sorbitol concentration is elevated in the CSF of non-medically ill patients with mood disorders. Lumbar punctures were performed on 30 subjects - 10 with bipolar mood disorder, 10 with unipolar mood disorder, and 10 age-matched normal controls, and CSF sorbitol concentrations were measured, using a gas chromatographic-mass spectroscopic technique. The mean+/-standard deviation of CSF sorbitol concentrations differed among the three groups as follows: bipolar (22.9+/-4.6 micromoles/l) > unipolar (19.0+/-2.8 micromoles/l)>normal control (15. 6+/-1.9 micromoles/l). One-way ANOVA showed significant (P=0.0002) differences among the three groups. Post-hoc tests indicated a significant (P<0.05) difference between bipolars and normal controls, bipolars and unipolars, and unipolars and normal controls. Further investigation is needed to determine the pathophysiological significance of this novel finding of elevated sorbitol concentration in the CSF of patients with mood disorders.

CSF monoamine metabolites in relation to the diagnostic interview for borderline patients (DIB).

The cerebrospinal fluid concentrations of the monoamine metabolites 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), 3-methoxy-4-hydroxyphenylglycol, and their ratios were studied in relation to the Diagnostic Interview for Borderline patients (DIB) evaluated retrospectively from hospital records for a sample of 202 patients participating in psychobiological programs on mood disorders. No correlations with the total DIB score were significant. Patients with borderline personality disorder (BPD) defined by a total DIB score of at least 7 or 6, respectively, did not differ significantly from non-BPD regarding the metabolites. However, for section II (impulse action pattern) of the DIB, those with an intermediate value of the section score had significantly higher levels of 5-HIAA and HVA, suggesting that such higher than normal concentrations may be protective against impulsive or suicidal behavior generated by an underlying psychiatric morbidity due to other risk factors.

Dopamine beta-hydroxylase: two polymorphisms in linkage disequilibrium at the structural gene DBH associate with biochemical phenotypic variation.

Levels of the enzyme dopamine beta-hydroxylase (DbetaH) in the plasma and cerebrospinal fluid (CSF) are closely related biochemical phenotypes. Both are under strong genetic control. Linkage and association studies suggest the structural gene encoding DbetaH (locus name, DBH) is a major locus influencing plasma activity of DbetaH. This study examined relationships of DBH genotype determined at two polymorphic sites (a previously described GT repeat, referred to as the DBH STR and a single-base substitution at the 3' end of DBH exon 2, named DBH*444 g/a), to CSF levels of DbetaH protein in European-American schizophrenic patients, and to plasma DbetaH activity in European-American patients with mood or anxiety disorders. We also investigated linkage disequilibrium (LD) between the polymorphisms in the pooled samples from those European-American subjects (n=104). Alleles of DBH*444 g/a were associated with differences in mean values of CSF DbetaH levels. Alleles at both polymorphisms were associated with plasma DbetaH activity. Significant LD was observed between respective alleles with similar apparent influence on biochemical phenotype. Thus, allele A3 of the DBH STR was in positive LD with DBH*444a, and both alleles were associated with lower plasma DbetaH activity. DBH STR allele A4 was in positive LD with DBH*444 g, and both alleles were associated with higher plasma DbetaH activity. The results confirm that DBH is a major quantitative trait locus for plasma DbetaH activity, and provide the first direct evidence that DBH also influences CSF DbetaH levels. Both polymorphisms examined in this study appear to be in LD with one or more functional polymorphisms that mediate the influence of allelic variation at DBH on DbetaH biochemical phenotypic variation

Increased neural cell adhesion molecule in the CSF of patients with mood disorder.

Neural cell adhesion molecule (N-CAM) is involved in cell-cell interactions during synaptogenesis, morphogenesis, and plasticity of the nervous system. Disturbances in synaptic restructuring and neural plasticity may be related to the pathogenesis of several neuropsychiatric diseases, including mood disorders and schizophrenia. Disturbances in brain cellular function may alter concentrations of N-CAM in the CSF. Soluble human N-CAM proteins are detectable in the CSF but are minor constituents of serum. We have recently found an increase in N-CAM content in the CSF of patients with schizophrenia. Although the pathogenesis of both schizophrenia and mood disorders is unknown, ventriculomegaly, decreased temporal lobe volume, and subcortical structural abnormalities have been reported for both disorders. We have therefore measured N-CAM concentrations in the CSF of patients with mood disorder. There were significant increases in amounts of N-CAM immunoreactive proteins, primarily the 120-kDa band, in the CSF of psychiatric inpatients with bipolar mood disorder type I and recurrent unipolar major depression. There were no differences in bipolar mood disorder type II patients as compared with normals. There were no significant effects of medication treatment on N-CAM concentrations. It is possible that the 120-kDa N-CAM band present in the CSF is derived from CNS cells as a secreted soluble N-CAM isoform. Our results suggest the possibility of latent state-related disturbances in N-CAM cellular function, i.e., residue from a previous episode, or abnormal N-CAM turnover in the CNS of patients with mood disorder.

Disturbances of cerebrospinal fluid (CSF) circulation--neuropsychiatric symptoms and neuroradiological contribution.

The present study aimed at relating dementia, pseudo-neurasthenic and affective organic brain syndromes to underlying type of CSF flow disorder and to subsequent alteration of anatomy. T2*-weighted magnetic resonance imaging (MRI) in the midsagittal plane permitted an analysis of aqueductal CSF flow phenomena and hydrocephalus-induced elevation, thinning and dorsal impingement of the corpus callosum. Furthermore, the width of the third ventricle was measured on the transverse scout images. 72 patients with communicating hydrocephalus (increased aqueductal CSF pulsations) and 26 patients with aqueductal stenosis (absence of aqueductal flow phenomena) were compared with 22 controls. Dementia and affective disorders were distributed equally among both CSF flow subgroups whereas pseudo-neurasthenic syndromes were observed more frequently in non-communicating hydrocephalus (p < 0.03). Alzheimer-type and multiinfarct dementia syndromes were found more frequently in communicating hydrocephalus whereas non-classifiable dementia showed some predilection for non-communicating hydrocephalus. Callosal height, area and third ventricular width did not predict affective or pseudoneurasthenic disorder whereas third ventricular width (p < 0.01) and callosal area (p < 0.05) discriminated between demented and non-demented patients. Dorsal impingement of the corpus callosum by the falx was a non-specific finding.

CSF magnesium in affective disorder: lack of correlation with clinical course of treatment.

There has been recent renewed interest in the role of magnesium in affective disorder, particularly in the bipolar subtype. However, determinations of serum magnesium concentrations have not yielded consistent findings and little is known about cerebrospinal fluid (CSF) magnesium in these patients. We analyzed CSF magnesium levels from 173 medication-free patients with affective disorder (76 bipolar I, 54 bipolar II, and 43 unipolar) and 59 healthy volunteers. In addition, we examined CSF magnesium from 32 patients before and during carbamazepine treatment and 13 patients before and during lithium treatment. CSF magnesium levels varied significantly according to gender (with lower concentrations in women) but not with respect to age, diagnosis, mood state, or treatment with carbamazepine or lithium. An abnormality of magnesium in affective disorders, if it exists, is not readily detectable in CSF.