Schizophrenia and amyotrophic lateral sclerosis

Schizophrenia and amyotrophic lateral sclerosis (ALS) are central nervous system (CNS) disorders of unknown etiology. The association of these two disorders has been infrequently reported in the literature, but is not a rare occurrence. Various neuromuscular abnormalities involving the alpha-motor neuron have been described in some patients with schizophrenia. This report reviews the literature on schizophrenia, psychosis, and ALS and describes two additional cases of schizophrenia associated with ALS. The possibility that the neuromuscular dysfunction in schizophrenia may predispose to ALS and provide an explanation for the association of these two disorders is discussed. Additional research data are needed to test this hypothesis.     

Immunosuppressive aspects of estrogen

The evidence supports from clinical and epidemiological studies demonstrates that the prevalence of various neurological diseases changes with gender. The reason for the gender difference in these diseases is still unclear, but accumulating evidence suggests a link between gonadal hormone, such as estrogens, levels and the incidence of these diseases. Numerous reports support the idea that immunological processes contribute to the etiopathogenesis of the neurodegenerative disease, such as, Parkinson's or Alzheimer's disease; psychiatric disorders, such as schizophrenia or depression; multiple sclerosis or stroke. The neuroinflammation is regulated by numerous signal molecules, including cytokines. Estrogens have been shown to play a major role in inflammatory processes. One mechanisms by which estrogens could modulated the immune reaction is regulation of the cytokines expression. This article briefly describes different biological mechanisms underlying estrogen anti-inflammatory activity.     

T-helper-1 and T-helper-2 responses in psychiatric disorders

The expanding field of psychoneuroimmunology has markedly increased knowledge about the interference of the central nervous system and the immune system. Immunological abnormalities in psychiatric patients have been repeatedly described in the last century. Modern concepts of immunology and the growing knowledge of psychoneuroimmunology may help in understanding the distinct immunological mechanisms in psychiatric disorders. One of these concepts regarding the adaptive immune system is the discrimination between Th1-like cell-mediated and Th2-like antibody-related immune responses. This article systematically describes alterations of Th1- or Th2-specific parameters in the major psychiatric disorders schizophrenia, major depression, and Alzheimer's disease. There are several hints of associations of these two distinct arms of immune response with subgroups of schizophrenia and major depression. The immunological research in Alzheimer's disease has already led to a preclinical model of immunotherapy. Categorization of immune parameters may also help to identify a possible immune-related pathophysiology in psychotic and affective disorders, resulting in specific treatment strategies.     

Elevated soluble interleukin-2 receptor levels in patients with active multiple sclerosis

The level of soluble interleukin-2 receptor (sIL-2R) was quantitated with enzyme-linked immunosorbent assay in serum and cerebrospinal fluid obtained from 24 patients with multiple sclerosis and 10 patients with other neurological disorders in whom immunological mechanisms are unlikely to participate. The sIL-2R level in the serum and cerebrospinal fluid of patients with multiple sclerosis in relapse was significantly higher compared with patients with multiple sclerosis in remission and with controls. The sIL-2R level, especially in the cerebrospinal fluid, showed higher sensitivity and specificity than other clinical parameters including the cerebrospinal fluid IgG ratio, peripheral lymphocyte CD4/CD8 ratio, cerebrospinal fluid myelin basic protein and oligoclonal bands. Our data suggest that measurement of the sIL-2R level may be useful in evaluating disease activity in patients with multiple sclerosis.     

The immunology of psychiatric disorders

Immunological alterations in psychiatric disorders have gained increasing scientific attention throughout the last decade. Particularly in two disorders, major depression and schizophrenia, some substantial findings have been reported. Although such results stand not uncontradicted, they nevertheless stimulate current research into the neurobiological underpinnings of these diseases. In this review, immunological dysfunctions in major depression and schizophrenia are described in detail, together with studies on posttraumatic stress disorders, panic- and obsessive-compulsive disorders. Possible future research directions are delineated.     

SCHIZOID NEUROCHEMICAL PATHOLOGY-INDUCED MEMBRANE NA+-K+ ATPASE INHIBITION IN RELATION TO NEUROLOGICAL DISORDERS

Psychiatric abnormalities have been described in primary neurological disorders like multiple sclerosis, primary generalized epilepsy, Parkinson's disease, subacute sclerosing panencephalitis (SSPE), central nervous system glioma, and syndrome X with vascular dementia. It was therefore considered pertinent to compare monoamine neurotransmitter pattern in schizophrenia with those in the disorders described above. The end result of neurotransmission is changes in membrane Na+-K+ ATPase activity. Membrane Na+-K+ ATPase inhibition can lead to magnesium depletion, which can lead to an upregulated isoprenoid pathway. The isoprenoid pathway produces three important metabolites--digoxin, an endogenous membrane Na+-K+ ATPase inhibitor; ubiquinone, a membrane antioxidant and component of mitochondrial electron transport chain; and dolichol, important in N-glycosylation of protein. The serum/plasma levels of digoxin, dolichol, ubiquinone, magnesium, HMG CoA reductase activity, and RBC Na+-K+ ATPase activity were estimated in all these disorders. The result showed that the concentration of serum tryptophan and serotonin was high and serum tyrosine, dopamine, adrenaline, and noradrenaline low in all the disorders studied. The plasma HMG CoA reductase activity, serum digoxin, and serum dolichol levels were high and serum ubiquinone levels, serum magnesium, and RBC Na+-K+ ATPase activity were low in all the disorders studied. The significance of these changes in the pathogenesis of syndrome X, multiple sclerosis, primary generalized epilepsy, schizophrenia, SSPE, and Parkinson's disease is discussed in the setting of the interrelationship between these disorders documented in literature     

Schizoid neurochemical pathology-induced membrane Na(+)-K+ ATPase inhibition in relation to neurological disorders

Psychiatric abnormalities have been described in primary neurological disorders like multiple sclerosis, primary generalized epilepsy, Parkinson's disease, subacute sclerosing panencephalitis (SSPE), central nervous system glioma, and syndrome X with vascular dementia. It was therefore considered pertinent to compare monoamine neurotransmitter pattern in schizophrenia with those in the disorders described above. The end result of neurotransmission is changes in membrane Na(+)-K+ ATPase activity. Membrane Na(+)-K+ ATPase inhibition can lead to magnesium depletion, which can lead to an upregulated isoprenoid pathway. The isoprenoid pathway produces three important metabolites--digoxin, an endogenous membrane Na(+) -K+ ATPase inhibitor; ubiquinone, a membrane antioxidant and component of mitochondrial electron transport chain; and dolichol, important in N-glycosylation of protein. The serum/plasma levels of digoxin, dolichol, ubiquinone, magnesium, HMG CoA reductase activity, and RBC Na(+)-K+ ATPase activity were estimated in all these disorders. The result showed that the concentration of serum tryptophan and serotonin was high and serum tyrosine, dopamine, adrenaline, and noradrenaline low in all the disorders studied. The plasma HMG CoA reductase activity, serum digoxin, and serum dolichol levels were high and serum ubiquinone levels, serum magnesium, and RBC Na(+)-K+ ATPase activity were low in all the disorders studied. The significance of these changes in the pathogenesis of syndrome X, multiple sclerosis, primary generalized epilepsy, schizophrenia, SSPE, and Parkinson's disease is discussed in the setting of the interrelationship between these disorders documented in literature.     

Schizophrenic disorders. The development of immunological concepts and therapy in psychiatry

Immunological changes reported in patients with schizophrenia may play an aetiological role in these disorders. Further, immunomodulatory medications can influence the symptoms of psychiatric disorders. Antipsychotic agents such as clozapine may act therapeutically through the modulation of the immune system and also lead to side effects in that domain.Both the understanding and factual foundations of immunological concepts and immunological therapies of schizophrenic disorders have changed throughout the history of medicine. These are important considerations in psychiatry where diagnostic, nosological and therapeutic complexity is the norm. The article exemplarily presents publications of the psychiatrists such as Julius Wagner von Jauregg, Lewis Campbell Bruce and Friedrich Ostmann as well as neuropathologist Hermann Lehmann-Facius and haematologist William Dameshek.     

Decreased suppressor-inducer T lymphocytes in multiple sclerosis and other neurological diseases

Decreased numbers of CD4+CD45R+ suppressor-inducer T cells have been reported in patients with a variety of autoimmune diseases including systemic lupus erythematosus, rheumatoid arthritis and multiple sclerosis but not in patients with other neurological diseases. We now report our findings using murine monoclonal antibodies and two-color flow cytometric analysis on CD4+CD45R+ T cells in 22 patients with chronic progressive multiple sclerosis, 23 patients with other neurological diseases and 42 normal, healthy controls. Suppressor-inducer T cells were significantly reduced (p less than 0.001) in both patients with multiple sclerosis and other neurological diseases as compared to controls. Both patient populations had elevated helper T cell subset ratios. Thus, our data suggests that decreases in suppressor-inducer T cells may represent a common immunological defect among autoimmune and presumably non-autoimmune neurological disorders.     

Identification of autoimmune gene signatures in autism

The role of the immune system in neuropsychiatric diseases, including autism spectrum disorder (ASD), has long been hypothesized. This hypothesis has mainly been supported by family cohort studies and the immunological abnormalities found in ASD patients, but had limited findings in genetic association testing. Two cross-disorder genetic association tests were performed on the genome-wide data sets of ASD and six autoimmune disorders. In the polygenic score test, we examined whether ASD risk alleles with low effect sizes work collectively in specific autoimmune disorders and show significant association statistics. In the genetic variation score test, we tested whether allele-specific associations between ASD and autoimmune disorders can be found using nominally significant single-nucleotide polymorphisms. In both tests, we found that ASD is probabilistically linked to ankylosing spondylitis (AS) and multiple sclerosis (MS). Association coefficients showed that ASD and AS were positively associated, meaning that autism susceptibility alleles may have a similar collective effect in AS. The association coefficients were negative between ASD and MS. Significant associations between ASD and two autoimmune disorders were identified. This genetic association supports the idea that specific immunological abnormalities may underlie the etiology of autism, at least in a number of cases.     

Recent advances in the neuroimmunology of cell-surface CNS autoantibody syndromes,Alzheimer’s disease,traumatic brain injury and schizophrenia

In this update, we review recent advances in antibody-associated disorders of the central nervous system, and the immune mechanisms which may contribute to Alzheimer’s disease, traumatic brain injury and schizophrenia. The field of neuroimmunology is rapidly developing and has concerned itself with an expanding portfolio of diseases. The core neuroimmunological diseases remain, multiple sclerosis, neuromyelitis optica, primary inflammatory and antibody-associated disorders of the central and peripheral nervous system (including Myasthenia Gravis and other disorders of neuromuscular junction and muscle, paraneoplastic syndromes, paraproteinaemic neuropathies), and the neurological involvement seen in systemic inflammatory diseases including lupus, sarcoidosis and vasculitis. But it is increasingly realised that immune mechanisms may contribute to the pathogenesis of degenerative diseases including Alzheimer’s disease, traumatic brain disease and psychiatric diseases including schizophrenia and depression. These common and devastating disorders, often without effective disease-modifying therapies, are yet to be seen in a conventional neuroimmunology clinic, but the immune mechanisms identified have encouraged research into novel therapeutic approaches for them.     

Multiple sclerosis and affective disorders

Affective disorders occurring in association with multiple sclerosis have been attributed both to the psychosocial impact of a chronic disabling illness and to the structural lesions of cerebral demyelination. A review of research evidence suggests that while there is a correlation between chronic depressive symptoms and both progressive disability and lack of social support, acute major depressive and manic episodes may be psychiatric manifestations of demyelinating lesions and may be the initial presenting symptoms of multiple sclerosis. Anti-inflammatory agents may be required in the management of acute psychiatric symptoms despite the fact that these agents have a propensity to precipitate psychotic episodes. Two case reports are presented to illustrate the clinical challenge of distinguishing between organic and functional affective illness in patients with multiple sclerosis. The interplay between biological and psychological aspects of multiple sclerosis in precipitating affective disorders is discussed, with implications for patient assessment and management.     

Cholinesterase inhibitors: beyond Alzheimer’s disease

Cholinesterase inhibitors (ChEIs) are widely licensed for the symptomatic treatment of Alzheimer’s disease, but their use has also been examined in a wide variety of neurological disorders besides Alzheimer’s disease, and this article reviews these uses. The evidence currently available suggests that ChEIs may possibly have a role in the treatment of some patients with dementia with Lewy bodies and Parkinson’s disease dementia, but at this point in time there would seem to be only a limited case for recommending ChEIs in mild cognitive impairment, Down syndrome, progressive supranuclear palsy, pure vascular dementia, frontotemporal lobar degeneration, Huntington’s disease, multiple sclerosis, epilepsy, delirium, traumatic brain injury, sleep-related disorders or certain psychiatric disorders (e.g., schizophrenia and bipolar disorder). Clinical practice with respect to non-Alzheimer’s disease indications for ChEIs may vary according to jurisdiction, specifically with regards to whether national guidelines effectively limit off-licence drug use.     

Differentiation between multiple sclerosis and neuromyelitis optica spectrum disorders by multiparametric quantitative MRI using convolutional neural network

Multiple sclerosis and neuromyelitis optica spectrum disorders are both neuroinflammatory diseases and have overlapping clinical manifestations. We developed a convolutional neural network model that differentiates between the two based on magnetic resonance imaging data. Thirty-five patients with relapsing-remitting multiple sclerosis and eighteen age-, sex-, disease duration-, and Expanded Disease Status Scale-matched patients with anti-aquaporin-4 antibody-positive neuromyelitis optica spectrum disorders were included in this study. All patients were scanned on a 3-T scanner using a multi-dynamic multi-echo sequence that simultaneously measures R1 and R2 relaxation rates and proton density. R1, R2, and proton density maps were analyzed using our convolutional neural network model. To avoid overfitting on a small dataset, we aimed to separate features of images into those specific to an image and those common to the group, based on SqueezeNet. We used only common features for classification. Leave-one-out cross validation was performed to evaluate the performance of the model. The area under the receiver operating characteristic curve of the developed convolutional neural network model for differentiating between the two disorders was 0.859. The sensitivity to multiple sclerosis and neuromyelitis optica spectrum disorders, and accuracy were 80.0%, 83.3%, and 81.1%, respectively. In conclusion, we developed a convolutional neural network model that differentiates between multiple sclerosis and neuromyelitis optica spectrum disorders, and which is designed to avoid overfitting on small training datasets. Our proposed algorithm may facilitate a differential diagnosis of these diseases in clinical practice.     

Antibodies to heat shock proteins in schizophrenic patients: implications for the mechanism of the disease.

OBJECTIVE: The involvement of heat shock proteins has been determined in the pathophysiology of several disorders of the central nervous system, including multiple sclerosis. To elucidate their role in schizophrenia, the authors investigated antibody titers to heat shock proteins in unmedicated and medicated patients with schizophrenia. METHOD: Using the enzyme-linked immunosorbent assay technique, the authors measured titers of antibodies to 60 kilodaltons (kD) heat shock proteins (HSP60) and 70 kD heat shock proteins (HSP70) in 30 patients with schizophrenia before and during neuroleptic treatment and compared the titers with those of 31 healthy individuals. RESULTS: Ten (33%) of 30 patients with schizophrenia but only one (3%) of 31 healthy individuals showed immunoreactivity to HSP60 or HSP70. The authors found especially high anti-HSP70 titers in never-medicated patients. High anti-HSP60 titers were mainly found in patients who were being treated with neuroleptics. CONCLUSIONS: Since heat shock proteins are involved in diverse neuroprotective mechanisms, antibodies against heat shock proteins may inhibit neuroprotection. The authors discuss the implications of these findings for schizophrenia.     

Primary CNS demyelinating diseases in childhood: multiple sclerosis

We report on five children (three female and two male, age span 11–16 years) with laboratory-supported definite multiple sclerosis, or clinically definite multiple sclerosis, diagnosed on the basis of Poser and Paty criteria. All patients were subjected to serial clinical examinations, magnetic resonance investigations, CSF biochemical and immunological studies, and neurophysiological and neuropsychological assessments. Four of the five examined subjects underwent steroid treatment. Over a period of 3 years relapses have been observed in three of them. The first symptoms and signs of multiple sclerosis may be subtle and misleading; careful assessment of them may be crucial for an early diagnosis of the disease.     

The Cotard syndrome. Report of two patients: with a review of the extended spectrum of 'délire des négations'

The Cotard syndrome is characterized by the delusion where an individual insists that he has died or part of his body has decayed. Although described classically in schizophrenia and bipolar disorder, physical disorders including migraine, tumour and trauma have also been associated with the syndrome. Two new cases are described here, the one associated with arteriovenous malformations and the other with probable multiple sclerosis. The delusion has been embarrassing to each patient. Study of such cases may have wider implications for the understanding of the psychotic interpretation of body image, for example that occurring in anorexia nervosa.     

Susceptibility loci for bipolar disorder: overlap with inherited vulnerability to schizophrenia.

Genetic epidemiological studies reveal that relatives of bipolar probands are at increased risk for recurrent unipolar, bipolar, and schizoaffective disorders, whereas relatives of probands with schizophrenia are at increased risk for schizophrenia, schizoaffective, and recurrent unipolar disorders. The overlap in familial risk may reflect shared genetic susceptibility. Recent genetic linkage studies have defined confirmed bipolar susceptibility loci for multiple regions of the human genome, including 4p16, 12q24, 18p11.2, 18q22, 21q21, 22q11-13, and Xq26. Studies of schizophrenia kindreds have yielded robust evidence for susceptibility at 18p11.2 and 22q11-13, both of which are implicated in susceptibility to bipolar disorder. Similarly, confirmed schizophrenia vulnerability loci have been mapped, too, for 6p24, 8p, and 13q32. Strong statistical evidence for a 13q32 bipolar susceptibility locus has been reported. Thus, both family and molecular studies of these disorders suggest shared genetic susceptibility. These two groups of disorders may not be as distinct as current nosology suggests.     

Chemokine network in multiple sclerosis: role in pathogenesis and targeting for future treatments

Multiple sclerosis is the most common inflammatory disorder of the CNS. Evidence suggests that an immunomediated mechanism plays a crucial role during the development of the disease. Currently, two classes of immunomodulatory agents -- interferon-beta and glatiramer acetate (Copaxone, Teva Pharmaceutical Industries), have been approved for the long-term treatment of multiple sclerosis. New drugs which effectively target the immunological processes occurring in multiple sclerosis have been proposed. This review summarizes the immunological background that occurs during the pathogenesis of multiple sclerosis focusing on chemokines and related receptors. The effects of standard treatments on the immune system are analyzed along with the current knowledge of potential new immunomodulatory molecules, such as antiadhesion molecules, statins, estriol, cannabinoids, neurotrophic factors and chemokine antagonists.     

HIV-associated dementia, Alzheimer's disease, multiple sclerosis, and schizophrenia: gene expression review

RNA and protein gene expression technologies are revolutionizing our view and understanding of human diseases and enable us to analyze the concurrent expression patterns of large numbers of genes. These new technologies allow simultaneous study of thousands of genes and their changes in regulation and modulation patterns in relation to disease state, time, and tissue specificity. This review summarizes the application of this modern technology to four common neurological and psychiatric disorders: HIV-1-associated dementia, Alzheimer's disease, multiple sclerosis, and schizophrenia and is a first comparison of these diseases using this approach.